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CHAPTER 88 leukemic blast cells in the blood and marrow. The diagnosis of the myelog-

ACUTE MYELOGENOUS
enous form of acute leukemia is confirmed specifically by identification of
myeloperoxidase activity in blast cells or by identifying characteristic cluster
of differentiation (CD) antigens on the blast cells (e.g., CD13, CD33). Because
LEUKEMIA the leukemic stem cell is capable of imperfect differentiation and maturation,
the clone may contain cells that have the morphologic or immunophenotypic
features of erythroblasts, megakaryocytes, monocytes, eosinophils, or, rarely,
Jane L. Liesveld and Marshall A. Lichtman basophils or mast cells, in addition to myeloblasts or promyelocytes. When
one cell line is sufficiently dominant, the leukemia may be referred to by that
lineage: for example, acute erythroid, acute megakaryocytic, acute monocytic
SUMMARY leukemia, and so on. Certain cytogenetic alterations are more frequent; these
abnormalities include t(8;21), t(15;17), inversion 16 or t(16;16), trisomy 8,
Acute myelogenous leukemia (AML) is the result of a sequence of somatic and deletions of all or part of chromosome 5 or 7. A translocation involving
mutations in a primitive multipotential hematopoietic cell. Exposure to chromosome 17 at the site of the retinoic acid receptor–α (RAR-α) gene is
radiation, chronic exposure to high doses of benzene, and chronic inhalation uniquely associated with acute promyelocytic leukemia. AML usually is treated
of tobacco smoke increase the incidence of the disease. Obesity has been with cytarabine and an anthracycline antibiotic, although other drugs may be
found to be an endogenous risk factor. A small but increasing proportion of added or substituted in poor-prognosis, older, refractory, or relapsed patients.
cases develop after a patient with lymphoma, a nonhematologic cancer, or The exception to this approach is the treatment of acute promyelocytic leu-
an autoimmune disorder is exposed to intensive chemotherapy, especially kemia with all-trans-retinoic acid, arsenic trioxide, and sometimes an anthra-
with alkylating agents or topoisomerase II inhibitors. The mutant (leukemic) cycline antibiotic. High-dose chemotherapy and either autologous stem cell
hematopoietic cell acquires the features of a leukemic stem cell capable of infusion or allogeneic hematopoietic stem cell transplantation may be used in
self-renewal and desultory differentiation and maturation. It gains a growth an effort to treat relapse or patients at high risk to relapse after chemotherapy
and survival advantage in relationship to the normal polyclonal pool of treatment. The probability of remission in acute myelogenous leukemia ranges
hematopoietic stem cells. As the progeny of this mutant, now leukemic, multi- from approximately 80 percent in children to less than 25 percent in octoge-
potential cell proliferates to form approximately 10 to 100 billion or more cells, narians. The probability for cure decreases from approximately 50 percent in
normal hematopoiesis is inhibited, and normal red cell, neutrophil, and plate- children to virtually zero in octogenarians.
let blood levels fall. The resultant anemia leads to weakness, exertional limita-
tions, and pallor; the thrombocytopenia to spontaneous hemorrhage, usually
in the skin and mucous membranes; and the neutropenia and monocytopenia
to poor wound healing and minor infections. Severe infection usually does not
occur at diagnosis, but often does if the disease progresses because of lack of DEFINITION AND HISTORY
treatment or if chemotherapy intensifies the decrease of blood neutrophil and
monocyte levels. The diagnosis is made by measurement of blood cell counts Acute myelogenous leukemia (AML) is a clonal, malignant disease
of hematopoietic tissues that is characterized by (1) accumulation
and examination of blood and marrow cells and is based on identification of
of abnormal (leukemic) blast cells, principally in the marrow, and
(2) impaired production of normal blood cells. Thus, the leukemic cell
infiltration in marrow is accompanied, nearly invariably, by anemia and
thrombocytopenia. The absolute neutrophil count may be low or nor-
mal, depending on the total white cell count.
Acronyms and Abbreviations: ALL, acute lymphocytic leukemia; AML, acute The first well-documented case of acute leukemia is attributed to
myelogenous leukemia; APL, acute promyelocytic leukemia; ATRA, all-trans retin- Friedreich,1 but Ebstein2 was the first to use the term acute leukämie
oic acid; CBF, core binding factor; CD, cluster of differentiation; ceAML, clonally in 1889. This work led to the general appreciation of the clinical dis-
evolved acute myelogenous leukemia; CEBPA, CCAAT-enhancer binding protein A; tinctions between AML and chronic myelogenous leukemia (CML).3 In
CML, chronic myelogenous leukemia; CNL, chronic neutrophilic leukemia; DNMT, 1878, Neumann,4 who proposed that marrow was the site of blood cell
DNA methyltransferase; FAB, French-American-British classification; FISH, fluores- production, first suggested that leukemia originated in the marrow and
cence in situ hybridization; FLT, Fms-like tyrosine kinase; G-CSF, granulocyte colony- used the term myelogene (myelogenous) leukemia. The availability of
stimulating factor; GM-CSF, granulocyte-monocyte colony-stimulating factor; GVHD, polychromatic stains, as a result of the work of Ehrlich,5 the description
graft-versus-host disease; HLA, human leukocyte antigen; HSC, hematopoietic stem of the myeloblast and myelocyte by Naegeli,6 and the earliest apprecia-
cell; IDH, isocitrate dehydrogenase; ITD, internal tandem duplication; MDR, multidrug tion of the common origin of red cells and leukocytes by Hirschfield7
resistance; MDS, myelodysplastic syndrome; NPM1, nucleophosmin-1 mutation; OS, laid the foundation for our current understanding of the disease.
overall survival; PAS, periodic acid–Schiff; PCR, polymerase chain reaction; P-gp, Although Theodor Boveri proposed a critical role for chromo-
permeability glycoprotein; ppm, parts per million; PTD, partial tandem duplication; somal abnormalities in the development of cancer in 1914, a series of
RAR, retinoic acid receptor; RT, reverse transcriptase; RUNX, runt-related transcription technical developments in the 1950s was needed to permit informed
factor; SAHA, suberoylanilide hydroxamic acid; t, translocation; TdT, terminal deoxy- examination of the chromosomes of human cancer cells. Thereafter, the
nucleotidyl transferase; TET, ten-eleven translocation; TKD, tyrosine kinase domain; discovery that a G group chromosome consistently had a foreshortened
TMD, transient myeloproliferative disease; TNF, tumor necrosis factor; VEGF, vascular long arm in the cells of patients with CML (Philadelphia chromosome)
endothelial growth factor; WBC, white blood cell; WHO, World Health Organization; supported the concept that chromosome abnormalities may be specif-
WT, Wilms tumor. ically linked to a cancer phenotype. This finding was followed by the
introduction of banding of chromosomes, which enhanced the specific

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 1374 Part X: Malignant Myeloid Diseases

identification of individual chromosomes and the point at which they

TABLE 881. Conditions Predisposing to Development of
break in the formation of a translocation, inversion, or deletion. This
Acute Myelogenous Leukemia
technologic advance unleashed the power of cancer cytogenetics and
initiated an era of leukemia study based not solely on the appearance Environmental factors
of cells under the microscope (phenotype) but also by their chromoso- Radiation14,15
mal or genetic abnormality (genotype).8 The completion of the human Benzene16–18
genome project further enhanced the specificity of the identification of Alkylating agents, topoisomerase II inhibitors, and other
gene alterations.9 These advances permitted (1) more precise under- cytotoxic drugs20–22
standing of the molecular pathology of specific leukemia subtypes, Tobacco smoke19,24,25
(2) improvement of diagnostic and prognostic methods for the study Acquired diseases
of AML, and (3) identification of molecular targets for therapy.
Clonal myeloid diseases
The introduction to the clinic by Holland, Ellison, and colleagues10
of arabinosyl cytosine (cytarabine) in the late 1960s as the first potent Chronic myelogenous leukemias (CML, CMML, CNL, etc.) (Chap. 89)
drug for treatment of AML, followed by their introduction of the com- Primary myelofibrosis (Chap. 86)
bination of 7 days of cytosine arabinoside and 3 days of daunorubicin Essential thrombocythemia (Chap. 85)
in the early 1970s (the “7 plus 3 regimen”)11 opened the era of effective Polycythemia vera (Chap. 84)
therapy for AML. This drug combination or its congeners remains the Clonal cytopenias (Chap. 87)
mainstay of treatment over 4 decades later.12 The description of alloge- Oligoblastic myelogenous leukemia(Chap.87)
neic marrow (stem cell) transplantation as a curative therapy for AML Paroxysmal nocturnal hemoglobinuria (Chap. 40)
by Thomas and colleagues13 in 1977 ushered in the era of hematopoietic Other hematopoietic disorders
stem cell (HSC) transplantation as a modality to cure eligible patients
Aplastic anemia (Chap. 35)
with AML.
Eosinophilic fasciitis (Chap. 87)
Myeloma (Chap. 107)31,32
ETIOLOGY AND PATHOGENESIS Other disorders
Human immunodeficiency virus infection32
ENVIRONMENTAL FACTORS Langerhans cell histiocytosis33,34
Table 88–1 lists the major conditions that predispose to development Thyroid disorders35
of AML. Only four environmental factors are established causal agents: Polyendocrine disorders36
high-dose radiation exposure,14,15 chronic, high-dose benzene exposure Inherited or congenital conditions
(≥40 parts per million [ppm]-years),16–18 chronic tobacco smoking,19
Sibling with AML37–39
and chemotherapeutic (DNA-damaging) agents.20–22 Most patients have
not been exposed to an antecedent causative factor. Exposure to high- Amegakaryocytic thrombocytopenia, congenital40,41
linear energy transfer radiation from α-emitting radioisotopes such as Ataxia-pancytopenia42,43
thorium dioxide increases the risk of AML.23 Case-control studies have Bloom syndrome44,45
sometimes found a relationship between AML and organic solvents, Congenital agranulocytosis (Kostmann syndrome)46–49
petroleum products, radon exposure, pesticides, and herbicides, but Chronic thrombocytopenia with chromosome 21q 22.12
these data have been inconsistent, have shown no association in other microdeletion50
studies, and have not reached a level comparable to the strong associ- Diamond-Blackfan syndrome51,52
ation that exists for high-dose benzene, high-dose external irradiation, Down syndrome53,54
and certain chemotherapeutic agents. There is a significant association Dubowitz syndrome55
between tobacco smoking and AML with a relative risk of about 1.5 to Dyskeratosis congenita56,57
2.0.24,25 Although formaldehyde has been suspected of being a leuke- Familial (pure, nonsyndromic) AML58
mogen, detailed analysis has not supported this contention.26,27
Familial platelet disorder59,60
An endogenous factor that increases risk is obesity. Studies in
Fanconi anemia61,62
North America show an increased risk of AML in men and women with
elevated body mass index, and this is particularly notable for acute pro- MonoMAC and Emberger syndromes (GATA2 mutations)63
myelocytic leukemia. The precise mechanisms are still unclear but may Naxos syndrome64
be related, in part, to elevated leptin levels, decreased adiponectin levels, Neurofibromatosis 165,66
shortened telomeres, and as yet unknown factors in obese subjects.28 Noonan syndrome67,68
Poland syndrome69
Rothmund-Thomson syndrome70,71
EVOLUTION FROM A CHRONIC
Seckel syndrome72
MYELOID NEOPLASM Shwachman syndrome73–75
AML may develop from the progression of other clonal disorders of Werner syndrome (progeria)76–78
a multipotential hematopoietic cell, including CML, chronic mye- Wolf-Hirschhorn syndrome79
lomonocytic leukemia, chronic neutrophilic leukemia (CNL), poly-
WT syndrome80
cythemia vera, primary myelofibrosis, essential thrombocythemia,
and clonal cytopenia or oligoblastic myelogenous leukemia. The latter AML, acute myelogenous leukemia; CML, chronic myelogenous leu-
two are considered forms of myelodysplastic syndrome (MDS) (see kemia; CMML, chronic myelomonocytic leukemia; CNL, chronic neu-
Table 88–1). Clonal progression occurs as a result of genomic instability trophilic leukemia; MonoMAC, monocytopenia and mycobacterial
and the acquisition of additional mutations, although with a different infections.

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 Chapter 88: Acute Myelogenous Leukemia 1375

probability of occurrence in each chronic myeloid neoplasm (Chap. 83). The blood cells of more than 2 percent of individuals (5 to 6 percent
The frequency of clonal progression to AML is enhanced by radiation of people older than 70 years) contain mutations that may represent
or chemotherapy in patients with polycythemia vera (Chap. 84) or premalignant events that can cause clonal hematopoietic expansion.
essential thrombocythemia (Chap. 85).29 Although some refer to this as These events may, in part, explain the age-dependent incidence of AML
secondary AML, it should be called clonally evolved AML (ceAML) to (Fig. 88–1).29a
distinguish it from secondary AML that results from radiation or che-
motherapy given to patients who do not have a precedent clonal mye-
PREDISPOSING DISEASES
loid disease. In the population of patients with preceding clonal myeloid
neoplasms, a myeloid leukemic clone already exists and is not induced Patients who develop AML may have an antecedent predisposing non-
secondarily. Evolution to AML represents the natural history of the neo- myeloid disease, such as aplastic anemia (poly- or oligoclonal T-cell
plasm, albeit sometimes accelerated by various external mutagens. disorder), myeloma (monoclonal B-cell disorder),30,31 or, rarely, AIDS
(HIV-induced polyclonal T-cell disorder).32 An association between
Langerhans cell histiocytosis, immune thyroid diseases, and familial
polyendocrine disorder and AML has been reported.33–36 A number of
AGING AND ACUTE MYELOGENOUS inherited conditions carry an increased risk of AML (see Table 88–1).37–
LEUKEMIA–RELEVANT SOMATIC MUTATIONS 80
In the inherited syndromes, at least several pathogenetic types of
Very low copy number gene mutations characteristic of leukemia or gene alterations are represented: (1) DNA repair defects, for exam-
lymphoma have been detected in the blood of healthy individuals. An ple, Fanconi anemia; (2) susceptibility genes favoring a second muta-
analysis of blood cell DNA sequence data has identified 77 blood cell– tion, for example, familial platelet syndrome; (3) tumor-suppressor
specific mutations in cancer-associated genes, the majority being asso- defects, for example, dyskeratosis congenita; and (4) unknown mech-
ciated with advanced age. A large majority of these mutations were from anisms, for example, ataxia-pancytopenia (See Tables 35-8 and 35-9 in
19 leukemia and/or lymphoma-associated genes, and nine were recur- Chap. 35 for further details of each pathogenetic process). There is
rently mutated (DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, evidence from central registry studies that any disorder that results in
BCORL1, and SF3B1). Additional mutations were found in a very small chronic immune stimulation, such as infection or autoimmune diseases
fraction of blood cells. Comparison of these findings to mutations in may be associated with AML and MDS.81 The prevalence of essential
hematologic malignancies identified other recurrently mutated genes. monoclonal gammopathy is not increased in AML patients.82

100
Incidence rate (cases/100,000 population)

10

Male

1 Female

0.1
+
<1

4
4

4
19
14

85
–7
5–

–3

–4

–5

–6

–7

–8
1–

–2

–2

–3

–4

–5

–6
–
–

70
15

35

45

55

65

75

80
10

20

25

30

40

50

60

Age

Figure 88–1. The annual incidence of acute myelogenous leukemia as a function of age. There is a relatively small increase to approximately 1.5
cases per 100,000 persons in the first year of life, representing congenital, neonatal, and infant AML. The incidence falls to a nadir of 0.4 new cases per
100,000 persons over the first 10 years of life and then rises again to 1 case per 100,000 in the second decade of life. From approximately 25 years of
age, the incidence increases exponentially (log-linear) to approximately 25 cases per 100,000 population in octogenarians.

Kaushansky_chapter 88_p1373-1436.indd 1375 9/21/15 11:00 AM

 1376 Part X: Malignant Myeloid Diseases

MOLECULAR PATHOGENESIS AML cases represent incomplete eradication of founder clones and not
emergence of unrelated clones.94
The Leukemia Stem Cell
AML results from a series of somatic mutations in a primitive hemato-
poietic multipotential progenitor cell or, very occasionally, a more dif- Role of Telomeres
ferentiated, more lineage-restricted progenitor cell.83,84 Some cases of AML with multiple chromosome aberrations is always characterized
monocytic leukemia, promyelocytic leukemia, and AML in younger by critically short telomeres. Age-related critical telomere shortening
individuals may arise in a progenitor cell with lineage restrictions may have a role in generating chromosome instability in AML patho-
(progenitor cell leukemia).85–87 Other morphologic phenotypes and genesis.95 Leukemic cells show variable reduction in length of telomeric
older patients likely have a disease that originates in a primitive mul- DNA, and telomere length in blood cells during remission is greater.96
tipotential cell. In the latter case, all myeloid blood cell lineages can be
derived from the leukemic stem cell because it retains the ability for Somatic Mutations
some degree of differentiation and maturation (Chap. 83). Because the Somatic mutation results from a chromosomal translocation in a large
T lymphocytes, B lymphocytes, and natural killer cells in cases of AML, fraction of patients.97 The translocation results in rearrangement of
often, have not carried a cytogenetic abnormality as did the myeloid a critical region of a protooncogene. Fusion of portions of two genes
cells, claims of origin in the pluripotential lymphohematopoietic cell often does not prevent the processes of transcription and translation;
have been ambiguous. The most compelling data indicate that the bulk of thus, the fusion oncogene encodes a fusion protein that, because of its
AML cases arise from one of two predominant CD34+ cell populations: abnormal structure, disrupts a normal cell pathway and predisposes to a
CD34+CD45RA+CD38–CD90– (multipotential myeloid progenitor) or malignant transformation of the cell. The mutant protein product often
CD34+CD38+CD45RA+CD110+ (granulocyte-monocyte progenitor). is a transcription factor or an element in the transcription pathway that
Both of these cell populations correspond to normal hematopoietic pro- disrupts the regulatory sequences controlling growth rate or survival
genitor cells and not the normal pluripotential lymphohematopoietic of blood cell progenitors and their differentiation and maturation.97–99
stem cell.86,88 This finding was confirmed by showing that the two leu- Examples of genes often mutated are core binding factor (CBF), retinoic
kemic cell populations were more similar to the corresponding normal acid receptor-α (RAR-α), HOX family, mixed-lineage leukemia (MLL),
progenitor populations than to pluripotential lymphohematopoietic and others. CBF has two subunits: CBF-β and runt-related transcription
stem cells by microarray gene expression analysis.88 The AML stem cell factor 1(RUNX1, formerly AML1). Approximately 10 percent of AML
arises from somatic mutations in one of these populations in most, but cases have translocations involving one or the other of these latter two
not all, cases of AML. Because progenitor cells are not self-renewing, genes (CBF-β and RUNX1), although the percentage varies depend-
the somatic mutations transform the normal progenitor cell to an AML ing on the patient’s age at onset. In patients younger than age 50 years,
stem cell capable of sustaining the disease and transplanting it into the frequency is approximately 20 percent. In patients older than age
immunosuppressed (NOD/SCID/IL2Rγ null) mice. 50 years, the frequency is approximately 6 percent. CBF activates genes
involved in myeloid and lymphoid differentiation and maturation. These
primary mutations are not sufficient to cause AML. Additional activat-
Preleukemic Stem Cells ing mutations, for example, in hematopoietic tyrosine kinases Fms-like
There is, also, experimental evidence that some cases of AML can arise tyrosine kinase (FLT)3 and KIT or in N-RAS and K-RAS, are required
from the accumulation of genetic and epigenetic changes in normal to induce a proliferative advantage in the affected primitive cell. Other
pluripotential HSCs.89 Through single-cell analysis, it has been shown protooncogene mutations that occur in leukemic cells involve FES, FOS,
that clonal progression of multiple mutations occurs in the HSC of GATA-1, JUN B, MPL, MYC, p53, PU.1, RB, WT1 (Wilms tumor 1),
some AML patients.90 These HSCs have been given the name “preleu- WNT, NPM1, CEPBA (CCAAT-enhancer binding protein A), and other
kemic HSCs” and it is proposed that AML progresses from such cells genes. Their interaction with loss-of-function mutations in hematopoi-
carrying founder mutations. These are thought to form a reservoir after etic transcription factors probably causes the acute leukemia phenotype
therapy that can lead to relapse.89 An HSC with DNA methyltransferase characterized by a disorder of proliferation, programmed cell death,
3A (DNMT3A) mutants was found to have multilineage repopulation differentiation, and maturation. Because the mutant stem or early pro-
advantage over nonmutated HSCs in xenografts, establishing their iden- genitor cell can proliferate and retains the capability to differentiate, a
tity as preleukemic HSCs. These cells can be found in remission marrow wide variety of phenotypes can emerge from a leukemic transformation.
samples of patients with AML.91 Genes that regulate DNA methylation
such as DNMT3A, ten-eleven translocation (TET) 2, and isocitrate
dehydrogenase (IDH) 1 and 2 promote self-renewal and block differ- EFFECT OF MOLECULAR AND CYTOGENETIC
entiation of stem and progenitor cells. Acquisition of these mutations
in an HSC can lead to their clonal expansion resulting in a preleukemia
MARKERS ON DISEASE PROGRESSION AND
stem cell population.92 THERAPEUTIC RESPONSIVENESS
Gene Markers
Mutational History AML is a heterogeneous disease, and the extent to which cytogenetic
Genome sequencing in AML cells shows that most mutations occur at and molecular markers define severity and influence treatment deci-
random before acquisition of the initiating driver mutation, giving each sions is a rapidly changing arena of investigation as a result of continued
clone a mutational history. The founding clone may acquire additional refinements in correlating individual or a combination of mutations on
mutations, yielding subclones that contribute to disease progression disease progression. Using molecular markers to predict disease course
or relapse.93 When copy number aberrations and copy-neutral loss-of- in AML is complicated because these are incompletely determined,
heterozygosity gene mutation profiles are analyzed in AML cases at and they often interact. Several risk scores based on chromosome and
diagnosis and at relapse, the relapsed leukemia always reflects reemer- molecular markers have integrated factors such as age and white blood
gence of the founder clone. In persistent AML cases, sometimes two cell (WBC) count into the scoring systems.100,101 Others have identified
coexisting dominant clones can be seen, one chemotherapy-sensitive common gene signatures that can be independent predictors of disease
and one chemotherapy-resistant, suggesting that refractory or relapsed progression or therapeutic response and provide a structure for risk

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 Chapter 88: Acute Myelogenous Leukemia 1377

stratification. Some of these signatures have 24 genes,102 and some have miscellaneous 3q abnormalities.117 These generally have an unfavorable
a seven gene-epigene score.103 Some have relied on genetic proflilng,104 prognosis.118
some on expression of a subset of molecular mutations,105 and some Monosomal Karyotype A monosomy has been associated with
have combined epigenetic and genetic markers.106 Prognostic models of decreased chance of achieving remission or of survival, especially when
AML based solely on molecular markers have been proposed. In one, combined with TP53 mutations.119,120
PML-RARa or CEPBA double mutations were very favorable (overall
survival [OS] at 3 years of 83 percent), RUNX1-RUNX1T1, CBF- OTHER ACQUIRED MUTATIONS
B-MYH11, or NPM1 (nucleophosmin-1 mutation) without FLT3-ITD Approximately 45 percent of AML cases have a normal karyotype.
(OS of 62.6 percent), intermediate with no mutation allowing assign- Sequencing has shown that mutations in NPM1, DNMT1, FLT3,
ment to other groups (OS of 44 percent), MLL-PTD or RUNX1, or KIT, CEBPA, TET2, and others may have diagnostic and prognos-
ASXL1 mutation (OS of 22 percent), and very unfavorable, TP53 muta- tic implications. When genomes of APL with a known founder event
tion (OS at 3 years, 0 percent). (PML-RARa) are sequenced and compared with normal karyotype
AML and exomes of HSCs from normal donors, most mutations in
Chromosome Markers AML genomes are random events that occurred in HSC before the
In general, those patients with changes involving CBF, that is, t(8/21), initiating mutation occurred. As the clone expands, one or two addi-
inv(16), t(16;16), or t(15;17), a feature of acute promyelocytic leukemia tional, cooperating mutations may result in development of a leuke-
(APL), are considered predictors of a more favorable outcome. Those mia, and these clones may acquire additional mutations, leading to
with complex karyotype, 11q23, t(6;9), abnormalities of chromosome 5 subclones.121 DNA sequences of leukemia cell and normal skin cell
or 7 or inv3 (t3;3) are associated with a poor outcome. The remainder genomes of a patient with AML showed 12 acquired mutations within
of cytogenetic abnormalities and those patients with a normal karyo- coding sequences of genes and 532 somatic point mutations in con-
type are considered of intermediate risk.107 These are determined by the served or regulatory portions of the genome.122 When whole-genome
behavior of the average of very large groups of patients and confidence or whole-exome sequencing was performed in 200 AML cases, it was
intervals are not calculated. Patients with favorable cytogenetic patterns found that an average of only 13 mutations occurred in the genes. Only
may have poor outcomes and those with less favorable patterns may do a total of 23 genes were mutated. There were nine categories of genes
better than anticipated. thought relevant for pathogenesis: (1) transcription-factor fusions, (2)
Deletions of all or part of a chromosome (e.g., chromosome 5, 7, or nucleophosmin, tumor-suppressor, (3) DNA methylation-related, (4)
9) or additional chromosomes (such as trisomy 4, 8, or 13) are common signaling, chromatin-modifying, (5) transcription-factor, (6) cohe-
cytogenetic abnormalities (Chap. 11), although the specific causative sion-complex, and (7) spliceosome-complex genes. Many of these genes
oncogenes or tumor-suppressor genes in these latter circumstances had patterns of cooperation and mutual exclusivity.123 Table 88–2 lists
have not been defined. Deletions in chromosomes 5 and 7 and complex commonly mutated genes in cytogenetically normal AML in order of
cytogenetic abnormalities are associated with a worse prognosis and are decreasing frequency.
increased in frequency in older patients and cases of AML following Nucleophosmin-1 Mutations NPM1 mutations are the most fre-
cytotoxic therapy compared to de novo cases.108 Because the genes resid- quent genetic alterations in AML, found in approximately half of patients
ing on the undeleted homologous segment of chromosome 5 are not with a normal karyotype.124,125 The mutation in exon 12 results in loss of
mutated, an epigenetic lesion, such as hypermethylation of a gene allelic the residue that requires its binding to nucleoli such that the NPM1 pro-
to one on the deleted segment on chromosome 5, may contribute to the tein is abnormally localized to the cytoplasm.126 Studies show that mutant
leukemogenic event. NPM1 without FLT3-ITD represents a favorable prognostic marker.127
In APL, PML-RAR-α fusion protein represses retinoic acid-induc- NPM1 mutations also have a favorable prognostic impact in older
ible genes, which prevent appropriate maturation of promyelocytes. The patients.128 Mutated regions of NPM1 elicit T-cell responses which might
induced disruption, which involves corepressor–histone deacetylase indicate that immunotherapy could have a role in these mutated cases.129
complexes, results in the leukemic phenotype (see “Acute Promyelocytic FLT3 Mutations FLT3 encodes a tyrosine kinase receptor in
Leukemia” below).109,110 normal myeloid and lymphoid progenitors. ITD of FLT3 on chro-
Patients with CBF leukemias are younger on average and in addi- mosome 13 occurs in approximately 25 percent of adult AML cases,
tion to t(8;21) or inv(16)/t(16;16) may have RUNX1/RUNX1T1 and but occurs more frequently in cases of AML with normal cytogenetic
CBFB/MYH11 oncogenes.111 The cure rate in these so-called good- patterns, monocytic phenotype, and PML-RAR-α or DEK-CAN
risk patients is only approximately 55 percent, however. Patients with translocations.124,125,130 The FLT3-ITD mutation confers a poor prognosis
CBF leukemias expressing KIT have a worse prognosis.112 In the case of if the ratio of mutant to wild-type expression is high.130–132 FLT3-ITD
inv(16)/t(16;16), different fusion transcripts can be formed, and these expression is often higher at relapse.133 FLT3-ITD upregulates MCL-1 to
may have associated with KIT mutations and other abnormal chromo- promote survival of AML stem cells through signal transducer and acti-
somal associations with differing prognosis, possibly from activation vator of transcription (STAT) 5 activation.134 FLT3-ITD adversely affects
of caspase activity.113 Secondary genetic changes in inv(16) or t(16;16) the outcome of an allogeneic stem cell transplant, but more than half of
cases may have an impact on prognosis. RAS, KIT, FLT3-internal tan- patients harboring this mutation who receive transplants can survive
dem duplication (ITD), and FLT3-TKD each affect prognosis. FLT3- leukemia free for 2 or more years.135 Point mutations in the tyrosine
TKD, trisomy 8, age, and therapy-related AML were associated with kinase domain (TKD) of FLT3 (FLT3-TKD) mutations occur in approx-
worse prognosis.114 In t(8;21) leukemias, epigenetic silencing of microR- imately 6 percent of AML cases and have little impact on outcomes.136
NA-193a activates the PTEN/PI3K signaling pathway,115 and wild-type DNMT3A Mutations The DNMT3A gene encodes a DNA meth-
RUNX1 can attenuate nuclear factor-kappaB (NF-κB) signaling, events yltransferase isoform. The process of DNA methylation involves the
not present in the t(8;21) translocation leukemias.116 addition of a methyl group on a cytosine residue at a C-G site. If this
3q Abnormalities EVI1 and MDS1/EVI1 expression in AML methylation happens in the promoter region of a coding gene, the gene
is associated with poor prognosis and is a distinct entity. These chro- will be silenced. The DNMT enzymes contribute to leukemogenesis by
mosome 3 abnormalities are found in only approximately 4 percent of mediating tumor suppressor gene silencing.137 DNMT3A mutations have
AML cases. These include inv(3) or t(3;3), t(3q26), t(3q21), and other been found in approximately 20 percent of AML patients with normal

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 1378 Part X: Malignant Myeloid Diseases

TABLE 882. Commonly Mutated Genes In Cytogenetically Normal Acute Myelogenous Leukemia
Approximate
Frequency in AML
with Normal
Mutated Gene Karyotype (%) Implication Comments References
NPM1 50 More-favorable outcomes Most frequently mutated gene in AML. 124–129
Allogenic transplantation not needed in first
remission if this mutation occurs in absence
of mutated FLT3-ITD
FLT3 ITD 40 Less-favorable outcomes 124, 125, 130–137
DNMT3A 20 Less-favorable outcomes Seen more often in AML patients with nor- 137–143
mal cytogenetics. Mutant NPM1, FLT3-ITD,
and IDH1 have been found more frequently
in AML patients with DNMT3A mutations
compared to those with wild-type DNMT3A
RUNX1 15 Less-favorable outcomes 144–149
TET2 15 Less-favorable outcomes Coincidence of mutated TET2 with NPM1 150–153
mutation in the absence of FLT3-ITD muta-
tion predicts a less-favorable outcome
CEBPA 15 More-favorable outcomes Only cases with double mutations associ- 124, 154–157
ated with favorable outcomes
NRAS 10 Little effect on prognosis 144
IDH1 or IDH2 10 Little effect on outcomes More frequent in AML patients with normal 138, 158, 159–164
cytogenetics. Frequently associated with
NPM1. Adverse prognostic factor if present
with mutated NPM1 without FLT3-ITD. Serum
2-hydroxyglutarate levels indicate high
probability of IDH mutation
MLL-PTD 8 Less-favorable outcomes 144
WT1 6 Less-favorable outcomes More frequent in females than in males (6.6 166, 167
vs. 4.7%; P = 0.014) and in patients <60 than
in patients >60 years (P <0.001)
FLT3-TKD 6 Little effect on outcomes May appear after use of FLT3-ITD inhibitor 132, 136

Gene frequencies are approximations with some variation from study to study. Outcome statement does not reflect effect of interacting muta-
tions unless otherwise noted in comments. Outcome statements are based on consensus and vary from one study to another.
AML, acute myelogenous leukemia; CEPBα, CCAAT/enhancer binding protein alpha; DNMT3A, DNA methyltransferase 3A; FLT, FMS-like tyrosine
kinase; IDH, isocitrate dehydrogenase; ITD, internal tandem duplication; MLL, myeloid-lymphoid (mixed-lineage) leukemia; NPM, nucleophos-
min; PTD, partial tandem deletion; RAS, rat sarcoma; RUNX, Runt-related transcription factor; TET, ten-eleven translocation; TKD, tyrosine kinase
domain; WT, Wilms tumor.

cytogenetic patterns.138 These cases more frequently had mutations in favorable impact in such cases.147 Another series found RUNX1 muta-
NPM1, FLT3, and IDH1 genes as well.139 DNMT3A mutations are asso- tions to be twice as common in older than younger patients with normal
ciated with a poorer prognosis139–142 and their significance appears to be cytogenetics, and to have an adverse outcome effect in both age groups.
age-dependent.143 The R882 mutation was associated with adverse prog- Mutated blasts had molecular signatures suggesting origin in a primitive
nosis in older patients, and non-R882 mutations with adverse prognosis hematopoietic cell.148 RUNX1 mutations have been found to cooperate
in younger patients. with granulocyte colony-stimulating factor receptor (CSFR) mutations
RUNX1 Mutations The RUNX1 gene is located on chromosome in congenital neutropenia to lead to acute leukemia or MDS.149
21q22 and is involved in hematopoiesis at all stages through its interac- TET2 Mutations The TET2 protein inactivation may occur
tion with CBFβ. It acts as an activator or repressor of numerous genes, through a loss of function mutation, deletion, or through IDH1/2 muta-
including transcription factors.144,145 In de novo AML, RUNX1 mutations tions. It is a member of a family of dioxygenases that catalyze conversion
were found with normal and noncomplex karyotypes. They were some- of 5-methyl-cytosine to 5-hydroxymethyl-cytosine and promote DNA
times associated with MLL-PTD (partial tandem duplication [PTD]) demethylation. TET2 has many roles in normal hematopoiesis, and
and FLT3-ITD, and they were associated with a poor prognosis inde- knockout mice show that it is a tumor suppressor, which haploinsuffi-
pendent of other molecular mutations.146 Another group found these ciency initiates myeloid transformations.150 TET2 mutations are found
mutations in 5.6 percent of cases, associated with cytogenetically nor- in approximately 25 percent of patients and in those who have mutated
mal AML and an association with MLL-PTD mutations, refractory dis- CEBPα and/or mutated NPM1 without a FLT3/ITD mutation.151,152
ease, and, as an independent risk factor, an inferior relapse-free survival Patients with AML and a TET2 mutation had a shorter event-free and
and overall survival. The use of allogeneic HSC transplant did have a overall survival compared with patients who were TET2 wild-type. They

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 Chapter 88: Acute Myelogenous Leukemia 1379

did not predict for outcomes in those with cytogenetically normal AML BAALC and miR-3151 in cytogenetically normal AML,171 (2) distinct
and with wild-type CEBPα, NPM1, and/or FLT3/ITD.153 Whether these patterns of dual or multiple gene mutation patterns that have prognostic
patients would benefit from alternate therapies, such as hypomethylat- impact,172 and (3) concurrence of somatic mutations and transcriptional
ing agents or HSC transplantation, has not been determined. regulators such as interaction between ERG expression and a heptad of
CEBPα Mutation CEBPα is a leucine zipper transcription factor transcriptional factors173 that maintains a stem cell-like signature. Fur-
involved in myeloid differentiation. Mutations have been described in thermore, interactions between genetic and epigenetic changes (DNA
approximately 10 percent of AML patients.124 Single or double mutations methylation, histone acetylation, histone methylation, and others) are
can occur, and these rarely are associated with FLT3/ITD or with NPM1 anticipated to have prognostic impact.174,175
mutations. CEBPα-double, but not CEBPα-single, mutation patients had
a significantly better overall survival at 8 years than wild-type, CEBPα-
single, or CEBPα-double and FLT3/ITD-positive patients.154 A multivar-
DEREGULATED SIGNALING PATHWAYS
iate analysis found that only double-mutant CEBPα was associated with The mutations in AML result in deregulation of any of several signal
a favorable event-free, relapse-free, and overall survival. Double-mutant transduction pathways, which disrupt pathways that ensure the normal
cases were also associated with a unique gene signature as compared with behavior of (1) differentiation and maturation, (2) proliferation, and
single-mutant cases.155,156 Some AML patients with CEBPα-double muta- (3) survival signals in hematopoietic cells. The pathways involved are
tions harbor TET2 and GATA2 mutations, which can affect prognostic myriad, but several represent the majority of cases such as the (1) PI3K-
outlook unfavorably with TET2 or favorably with GATA2 mutations.157 AKT, (2) RAS-RAF-MEK-ERK, and (3) STAT3 signaling sequences.176
IDH1 and IDH2 Mutations The IDHs catalyze oxidative decar- The expectation is that a relative small number of downstream signaling
boxylation of isocitrate into α-hemoglutarate. The nicotinamide adenine pathways mediate the leukemogenic effect of gene mutations, making
dinucleotide phosphate–dependent IDH1 enzyme is encoded by the the potential targets for therapy less diffuse than suggested by the num-
IDH1 gene on chromosome 2q33.3, and the nicotinamide adenine dinu- ber of gene mutations involved in AML.
cleotide phosphate–dependent-dependent IDH2 enzyme is encoded by
the IDH2 gene on chromosome 15q26.1.158 Mutations in IDH1 (R132) MODE OF INHERITANCE
or IDH2 (R172) occur in 10 percent of AML patients.158,159 Both were
In most cases, little evidence is seen for a strong influence of inherited
found to adversely impact relapse-free survival and overall survival.
factors. The identical twin of a child with acute leukemia has a height-
Multivariate analysis showed that IDH mutation conferred an adverse
ened risk of developing the disease. However, the risk appears to be
impact in those patients with an NPM1 mutation without FLT3-ITD.
related to intraplacental metastasis and thus falls to the risk of a non-
Favorable genotype cytogenetically normal AML is therefore defined
identical sibling after the first few years of life.177,178 The risk of AML
as NPM1 or CEBPα mutation with neither a FLT3-ITD nor an IDH1
in a nonidentical sibling in the United States is elevated, perhaps two-
mutation. An IDH1 mutation was also associated with a higher relapse
fold to threefold, compared to the risk of AML in unrelated American
rate and shorter overall survival.160 Another group found a higher fre-
children of European descent younger than age 15 years.177,179 A regis-
quency of IDH1 and IDH2 mutations in cytogenetically normal AML.
try study in Sweden showed no significant aggregation in relatives of
Both were found to have an unfavorable impact on outcome.161 IDH1
patients with AML. An increased risk of AML/MDS was found among
was exclusive of other mutations. Serum 2-hydroxyglutarate production
relatives of patients diagnosed at younger than age 21 years (relative
has been found to predict for the presence of IDH1/2 mutations.162,163 A
risk 6.5).180 Clusters of AML cases in families have been documented,
level of 700 mg/mL was found to discriminate mutated from nonmu-
but their frequency is low.58 Clusters of AML in unrelated persons in
tated cases, and those with levels greater than 20 ng/mL at the time of
a community are uncommon and, when investigated, usually prove
remission had shorter overall survival.163 Mutant IDH1 has been found
to be a chance occurrence. Heritable GATA2 mutations may be asso-
to accelerate cell-cycle transition and to activate mitogen-activated pro-
ciated with familial MDS and AML,181 and loss-of-function germline
tein kinase signaling. Mutant IDH1 can be inhibited, suggesting this
GATA2 mutations (the MonoMAC [monocytopenia and mycobacterial
may be a therapeutic target.164
infections] syndrome) may be associated with primary lymphedema
WT1 Mutations Mutations of the WT1 gene have been reported
and a predisposition to AML (Emberger syndrome).182–184 Mutations of
in approximately 5 to 10 percent of cytogenetically normal patients with
CEBPα have been found in familial AML.185 In one study of 27 families
AML.165 Some studies suggest association with a poor prognosis, but
with familial MDS/AML, genetic characterization could be shown in
others have not. WT1 SNP rs 16754 was associated with a favorable
10 (four with GATA2 mutations, five with telomerase mutations, and
risk, but acquired mutations did not affect the development of com-
one with mutated RUNX1).186 Mutations in telomerase RNA (TERC) or
plete remission, relapse-free survival, or overall survival.166 A study of
telomerase reverse transcriptase component (TERT) are also associated
WT1 mutations in older patients with cytogenetically normal AML also
with familial AML.185,187
showed poor treatment response across all age-groups and association
with a distinct gene expression signature.167
EPIDEMIOLOGY
Prognostic Impact of Other Molecular Abnormalities AML is the predominant form of leukemia during the neonatal period
Other methodologies to evaluate genomic aberrations have been but represents a small proportion of cases during childhood and
reported to have prognostic importance beyond the impact of the adolescence. Approximately 20,000 new cases of AML occur annually,
individual mutations described above and in Table 88–2. Abnormal representing approximately 35 percent of the new cases of leukemia in
genome-wide single nucleotide polymorphisms have adverse prognosis the United States each year. Approximately 12,000 patients with AML
in patients with AML and a normal karyotype.168 Expression signatures in the United States die each year as a result of the disease. The inci-
of cytokines and chemokines have an independent prognostic impact in dence rate of AML is approximately 1.5 per 100,000 in infants younger
AML.169 Profiling transcriptional pathways may have prognostic impor- than 1 year of age, decreases to approximately 0.4 per 100,000 children
tance in AML as well.170 ages 5 to 9 years, increases gradually to approximately 1.0 persons per
There is also interplay among molecular aberrancies in AML. 100,000 population until age 25 years, and thereafter increases expo-
These include: (1) gene interaction with a microRNA; for example, nentially until the rate reaches approximately 25 per 100,000 persons

Kaushansky_chapter 88_p1373-1436.indd 1379 9/21/15 11:00 AM

 1380 Part X: Malignant Myeloid Diseases

in octogenarians (see Fig. 88–1). The exception to this exponential age- variants of AML (see Chap. 83, Table 83–1 and Fig. 83–3). A cogent
related increase in incidence is APL, which does not change greatly in argument has been made that, for practical purposes, a classification
incidence with age.188 that initially considers morphologic phenotype and immunophenotype
AML accounts for 15 to 20 percent of the acute leukemias in chil- is advisable. Cytogenetics, molecular genetics, gene-expression profil-
dren and 80 percent of the acute leukemias in adults. It is slightly more ing, and other considerations can, and should, be layered on as available
common in males. Little difference in incidence is seen between indi- and useful in influencing therapy, and these features are starting to be
viduals of African or European descent at any age. A somewhat lower incorporated into the World Health Organization (WHO) Classifica-
incidence is seen in persons of Asian descent.189 An increase in the fre- tion of AML.196 It is anticipated that molecular classifications will con-
quency of AML is seen in Jews, especially those of Eastern European tinue to evolve and dominate clinical decision making in the future.105
descent. The acute promyelocytic variant of AML is somewhat more
common in Latinos.190,191 In a large population study of 426,068 patients
treated with chemotherapy for malignancy, 301 AML cases occurred, CLINICAL FEATURES
4.7 times the number expected. Over time (1975 to 2008), the risks
increased for non-Hodgkin lymphoma, declined for ovarian cancer and
SIGNS AND SYMPTOMS
myeloma, and were heterogeneous for breast and Hodgkin lymphoma, General
reflecting changing treatment patterns.192 Signs and symptoms that signal the onset of AML include pallor,
fatigue, weakness, palpitations, and dyspnea on exertion. The signs and
symptoms reflect the development of anemia; however, weakness, loss
CLASSIFICATION of sense of well-being, and fatigue on exertion can be disproportionate
Variants of AML can be identified by morphologic features of blood to the severity of anemia.197–201
films using polychromatic stains and histochemical reactions,193 Easy bruising, petechiae, epistaxis, gingival bleeding, conjunctival
monoclonal antibodies against surface markers,194 or by the presence hemorrhages, and prolonged bleeding from skin injuries reflect throm-
of specific chromosome translocations or other molecular changes as bocytopenia and are frequent early manifestations of the disease. Very
discussed above.104,105 The epitopes on the progenitor cells of several infrequently, gastrointestinal, genitourinary, bronchopulmonary, or
phenotypic variants overlap, and several monoclonal antibodies are CNS bleeding occurs at the onset of disease.
required to make specific distinctions among cell types (Table 88–3; see Pustules or other minor pyogenic infections of the skin and of
also “Morphologic Variants of Acute Myelogenous Leukemia” below). minor cuts or wounds are most common. Major infections, such as
Correlation between morphologic and immunologic phenotyping of sinusitis, pneumonia, pyelonephritis, and meningitis, are uncommon
AML is poor. However, poor correlation is expected because morpho- presenting features of the disease, partly because absolute neutrophil
logic phenotyping is more subjective, given to observer variation, and counts less than 0.5 × 109/L are uncommon until chemotherapy starts.
is based on qualitative factors, whereas the immunologic phenotyping, With intensification of neutropenia and monocytopenia after che-
which characterizes surface molecular features, is more accurate and motherapy, major bacterial, fungal, or viral infections become more
reproducible. The correlation is improved only somewhat if morphology frequent. Anorexia and weight loss are frequent findings. Fever is pres-
and histochemistry are coupled.195 Gene-expression profiling is early in ent in many patients at the time of diagnosis.200,202–204 Palpable sple-
its use as a classification technique for AML but will be more specific nomegaly or hepatomegaly occurs in approximately one-quarter of
and informative than current methods.104,105 The outcome will depend patients.197,198,201 Lymphadenopathy is extremely uncommon,201,205,206
on the simplification and automation of such techniques, and the avail- except in the monocytic variant of AML.207
ability of drugs that make such distinctions in the prognostic category
of practical utility. Chapter 83 contains the classification of morphologic SPECIFIC ORGAN SYSTEM INVOLVEMENT
Leukemic blast cells circulate and enter most tissues in small numbers.
Occasionally, biopsy (or autopsy) uncovers marked aggregates or infil-
trates of leukemic cells. Collections of such cells may cause functional
TABLE 883. Immunologic Phenotypes of Acute Myelog- disturbances. Extramedullary involvement is most common in mono-
enous Leukemia cytic or myelomonocytic leukemia.208,209
Phenotype Usually Positive Skin involvement may be of three types: nonspecific lesions, leuke-
mia cutis, or granulocytic (myeloid) sarcoma of skin and subcutis.210–213
Myeloblastic CD11b, CD13, CD15, CD33, CD117,
Nonspecific lesions include macules, papules, vesicles, pyoderma gan-
HLA-DR
grenosum, vasculitis,214–216 neutrophilic dermatitis (Sweet syndrome),217
Myelomonocytic CD11b, CD13, CD14, CD15, CD32, CD33, cutis vertices gyrata,218 and erythema multiforme or nodosum.211,212
HLA-DR Skin involvement preceding marrow and blood involvement or relapse
Erythroid Glycophorin, spectrin, ABH antigens, occurs, but is rare.219–222
carbonic anhydrase I, HLA-DR, CD71 Sensory organ involvement is very unusual, but retinal, choroi-
(transferrin receptor) dal, iridial, and optic nerve infiltration can occur.223 Otitis externa and
Promyelocytic CD13, CD33 interna, inner ear hemorrhage, and mastoid tumors with seventh nerve
involvement may be presenting signs.224–226
Monocytic CD11b, 11c, CD13, CD14, CD33, CD65,
The gastrointestinal tract may be involved at any point, but func-
HLA-DR
tional disturbances are unusual.227,228 The mouth, colon, and anal canal
Megakaryoblastic CD34, CD41, CD42, CD61, anti–von are sites of involvement that most commonly lead to symptoms. Oral
Willebrand factor manifestations may prompt the patient to visit the dentist. Gingival or
Basophilic CD11b, CD13, CD33, CD123, CD203c periodontal infiltration and dental abscesses may lead to an extraction,
Mast cell CD13, CD33, CD117 followed by prolonged bleeding of an infected tooth socket.229 Ileoty-
phlitis (enterocolitis), a necrotizing inflammatory lesion involving the

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 Chapter 88: Acute Myelogenous Leukemia 1381

terminal ileum, cecum, and ascending colon, can be a presenting syn-

drome or occur during treatment.230–233 Fever, abdominal pain, bloody
LABORATORY FEATURES
diarrhea, or ileus may be present and occasionally mimic appendicitis. BLOOD CELL FINDINGS
Intestinal perforation, an inflammatory mass, and associated infection
with enteric gram-negative bacilli or clostridial species often are asso- Anemia is an almost constant feature.197–201 Red cell life span may be
ciated with a fatal outcome. Isolated involvement of the gastrointestinal mildly shortened, but the principal cause of anemia is inadequate
tract is rare.234,235 Proctitis, especially common in the monocytic variant production of red cells. The reticulocyte count usually is between 0.5
of AML, can be a presenting sign or a vexing problem during periods of and 2.0 percent. Occasionally patients have rapid destruction of autol-
severe granulocytopenia and diarrhea.227 ogous and transfused red cells as a result of an unknown mechanism,
The respiratory tract can be involved by infiltrates or tumors, lead- referred to as milieu hemolysis. The presence of red cell autoantibodies
ing to laryngeal obstruction, parenchymal infiltrates, alveolar septal (positive direct antiglobulin test) is very uncommon and may be non-
infiltration, or pleural seeding. Each of these events can result in severe specific (anti-C3), perhaps related to circulating immune complexes.
symptoms and radiologic findings.236–240 Red cell morphology is mildly abnormal, with exaggerated variation
Cardiac involvement is frequent but rarely causes symptoms. in cell size and occasional poikilocytes. Nucleated red cells or stippled
Symptomatic pericardial infiltrates, transmural ventricular infiltrates erythrocytes may be present. Less often, extreme abnormalities of red
with hemorrhage, and endocardial foci with associated intracavitary cell size, shape, and hemoglobin content occur (AML with trilineage
thrombi can occasionally cause heart failure, arrhythmia, and death.241 dysmorphia), but these changes are seen more often in oligoblastic mye-
Infiltration of the conducting system or valve leaflets or myocardial logenous leukemia (Chap. 87).
infarction has occurred.242 Thrombocytopenia is nearly always present at the time of diagnosis.
The urogenital system can be affected. The kidneys are infiltrated The mechanism of thrombocytopenia is a combination of inadequate
with leukemic cells in a high proportion of cases, but functional abnor- production and decreased survival of platelets. More than half of
malities are rare. Hemorrhage in the pelvis or collecting system is patients have a platelet count less than 50 × 109/L at the time of diag-
frequent.243,244 Cases of vulvar, bladder neck, prostatic, and testicular nosis.267 Giant platelets and poorly granulated platelets with func-
involvement have been described.245–247 tional abnormalities can occur.268 Defects in platelet aggregation and
Osteoarticular symptoms may occur. Bone pain, joint pain, and 5-hydroxytryptamine release are frequent.268
bone necrosis can occur, and, rarely, arthritis with effusion is present.248 The total leukocyte count is less than 5 × 109/L in approximately half
Crystal-induced arthritis of either calcium pyrophosphate dihydrate of patients at the time of diagnosis.197–201 The absolute neutrophil count
(pseudogout) or monosodium urate (gout) may be responsible for the is less than 1 × 109/L in more than half of cases at diagnosis.97–201 Patients
synovitis in some cases.249 with very elevated total leukocyte counts have a low proportion of mature
Central or peripheral nervous system involvement by infiltration of neutrophils but may have a normal absolute neutrophil count. Hyperse-
leukemic cells is very uncommon, although meningeal involvement is gmented, hyposegmented, and hypogranular mature neutrophils may be
an important consideration in the treatment of the monocytic type of present. Cytochemical abnormalities of blood neutrophils include low or
AML.250,251 An association of CNS involvement and diabetes insipidus absent myeloperoxidase or low alkaline phosphatase activity.269 Defects
in AML with monosomy 7252 and inversion of chromosome 16253,254 has in phagocytosis or microbial killing are common.270,270A
been reported. Myeloblasts almost always are present in the blood but may be
infrequent in severely leukopenic patients. Diligent search may uncover
the myeloblasts, or examination of a white cell concentrate (buffy coat)
MYELOID (GRANULOCYTIC) SARCOMA
may permit their identification. Classic leukemic blast cells are agran-
Myeloid sarcoma (synonyms: granulocytic sarcoma, chloroma, mye- ular, but mixtures of immature cells, including agranular and slightly
loblastoma, monocytoma) is a tumor composed of myeloblasts, granular cells ranging up to overt progranulocytes, can occur. Auer rods
monoblasts, or megakaryocyes.255–260 The tumor may occur as an are elliptical cytoplasmic inclusions approximately 1.0 to 1.5 μm long
extramedullary mass without evidence of leukemia in blood or mar- and 0.5 μm wide that derive from azurophilic granules (Fig. 88–2B). The
row, so-called nonleukemic myeloid sarcomas, or in association with inclusions are present in the blast cells of approximately 15 percent of
AML. When the tumor appears as an isolated lesion, it initially may be cases. When present, the inclusions are found in only a small percentage
misdiagnosed as extranodal lymphoma because they look like lymphoid of blast cells when examined with polychrome stains.193 An exception
cells on biopsy.257 They may be found in virtually any location, including is APL, in which a higher proportion of cells have Auer rods and some
the skin; orbit; paranasal sinuses; bone; chest wall; breast; heart; gas- have multiple (bundles) of rods (faggot cells). This finding can be dra-
trointestinal, respiratory, or genitourinary tract; central or peripheral matic if peroxidase stain is used to highlight the Auer rods.
nervous system; or lymph nodes and spleen. The tumors originally
were called chloromas because of the green color imparted by the high
concentration of the enzyme myeloperoxidase present in myelogenous
MARROW FINDINGS
leukemic cells. Biopsy specimens are positive for chloracetate esterase, Morphology
lysozyme, myeloperoxidase, and cluster of differentiation (CD) markers The marrow always contains leukemic blast cells. From 3 to 95 per-
of myeloid cells. When myeloid sarcomas are the initial manifestation cent of marrow cells are blasts at the time of diagnosis or relapse (see
of AML, the appearance of the disease in the blood and marrow may Fig. 88–2A). The WHO has invoked an arbitrary threshold of 20 per-
follow weeks or months later. Abnormalities in chromosome 8 are the cent of marrow nucleated cells being blast cells to distinguish polyblastic
most frequent cytogenetic disturbance in myeloid sarcomas.258 Systemic AML (≥20 percent blasts) from oligoblastic myelogenous leukemia (<20
chemotherapy, rather than local therapy, should be used for treatment, percent blasts).197–201 The latter situation is referred to as refractory ane-
although the long-term outcome in such cases usually is poor.260–262 mia with excess blasts, a MDS (Chap. 87). The WHO choice of ≥20 per-
Patients having AML with t(8;21) or inv16 have a propensity to develop cent blasts is an arbitrary standard as acute monocytic leukemia, APL,
extramedullary leukemia,263–266 and such patients with myeloid sarco- acute erythroid leukemia, and other variants often have less than 20 per-
mas have a poorer outcome after treatment than those who do not have cent blast cells at the time of diagnosis,271 and if any blasts are found with
extramedullary lesions.263,265 a case of AML in which the cells have a t(8;21) or other CBF inversions or

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 1382 Part X: Malignant Myeloid Diseases

A B C

D E F

G H I

J K L

M N O

Figure 88–2. Blood and marrow images of major subtypes of acute myelogenous leukemia. A. Blood film of acute myelogenous leukemia (AML)
without maturation (acute myeloblastic leukemia). Five myeloblasts are evident. High nuclear-to-cytoplasmic ratio. Agranular cells. Nucleoli in each
cell. B. Blood film. AML without maturation (acute myeloblastic leukemia). Three myeloblasts, one containing an Auer rod. C. Marrow film. AML with
maturation. Three leukemic myeloblasts admixed with myelocytes, bands, and segmented neutrophils. D. Blood film. Acute promyelocytic leuke-
mia. Majority of cells are heavily granulated leukemic promyelocytes. E. Blood film. Acute promyelocytic leukemia. Myeloperoxidase stain. Intensely
positive. Numerous stained (black) granules in cytoplasm of leukemic progranulocytes. F. Blood film. Acute myelomonocytic leukemia. Double esterase
stain. Leukemic monocytic cells stained dark blue and leukemic neutrophil precursors stained reddish-brown. G. Marrow film. AML with inv16. Note
high proportion of eosinophils in field. Note myeloblasts with very large nucleoli at upper right. Also, intermediate leukemic granulocytic forms.
H. Blood film. Acute monocytic leukemia. Leukemic cells have characteristics of monocytes with agranular gray cytoplasm and reniform or folded
nuclei with characteristic chromatin staining. This case had hyperleukocytosis as evident by leukemic monocyte frequency in the blood film.
I. Blood film. Acute erythroid leukemia. Note population of extremely hypochromic cells with scattered bizarre-shaped poikilocytes admixed with
normal-appearing red cells. J. Marrow film. Acute erythroid leukemia. Giant erythroblasts with multilobulated nuclei. K. Marrow film. Acute erythroid
leukemia. Note giant trinucleate erythroblast and other leukemic erythroblasts with periodic acid–Schiff–positive cytoplasmic staining (reddish gran-
ules). L. Marrow section. Acute megakaryoblastic leukemia. Marrow replaced with atypical two- and three-lobed leukemic megakaryocytes with bold
nucleoli. M. Marrow film. Acute megakaryoblastic leukemia. Marrow replaced with atypical megakaryocytes and megakaryoblasts with cytoplasmic
disorganization, fragmentation, and budding. N. Marrow film. Acute megakaryoblastic leukemia. Marrow replaced with atypical megakaryocytes and
megakaryoblasts staining for platelet glycoprotein IIIA (reddish-brown). Platelets in background also stained. O. Marrow section. Acute megakary-
oblastic leukemia. Argentophilic (silver) stain shows marked increase in collagen, type III fibrils (marrow reticulin fibrosis), characteristic of this AML
subtype. (Reproduced with permission from Lichtman’s Atlas of Hematology, www.accessmedicine.com.)

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 Chapter 88: Acute Myelogenous Leukemia 1383

translocations, AML is the diagnosis. Moreover, relapse of AML can be Approximately 45 percent of cases of AML contain cells that are
identified at any increase in blast count >2 percent. In addition, patients cytogenetically normal. When five genes—NPM1, FLT3, CEPBA, MLL,
with oligoblastic leukemia with 10 to 19 percent marrow leukemic blast and NRAS—were examined in 872 adults who were younger than
cells are identical in all other phenotypic findings and survival to those 60 years of age with a normal karyotype, approximately 85 percent had
with 20 to 29 percent marrow blast cells. Any distinctions between the a mutation in at least one of these genes. Mutations in NPM1 or CEPBA
two groups in survival are a function of age, cytogenetic risk category, were associated with more favorable outcomes, analogous to the category
and molecular features, not the blast count.272 This arbitrary boundary of favorable cytogenetics noted above. The microarray expression signa-
prevents patients, otherwise suitable, to enter clinical trials. ture in patients with AML younger than age 60 years who have cytogenet-
Myeloblasts are distinguished from lymphoblasts by any of three ically normal cells but high-risk molecular features, especially FLT3-ITD
pathognomonic features: reactivity with specific histochemical stains; and/or wild-type NMP1 expression, is correlated with outcome of ther-
Auer rods in the cells (see Fig. 88–2B); or reactivity with a panel of apy (see “Effect of Molecular and Cytogenetic Markers on Disease Pro-
monoclonal antibodies against epitopes present on myeloblasts (e.g., gression and Therapeutic Responsiveness” above and Table 88–2).
CD13, CD33, CD117) (see Table 88–3). Leukemic myeloblasts give MicroRNAs regulate gene expression and the downregulation of the
positive histochemical reactions for myeloperoxidase, Sudan black B, or microRNA-181 family predicts a poor outcome. The microRNAs studied
naphthyl AS-D-chloroacetate esterase stains. Auer rods can be found also revealed several important gene families that appear to be involved
in the marrow blast cells in approximately one-sixth of cases. Blast cells in the pathogenesis of AML, including genes involved in innate immu-
may express granulocytic (CD15, CD65) or monocytic (CD11b, CD11c, nity (e.g., toll-like receptors and interleukin-1β expression and regula-
CD14, CD64) surface antigens. They typically do not express either lym- tion).309 (Chapters 13 and 83 provide further discussion of gene-array
phoid surface markers or membrane or cytoplasmic immunoglobulin. profiling and microRNA analysis and the section “Other Acquired
No immunoglobulin gene rearrangement or T-lymphocyte receptor Mutations” on molecular pathogenesis has a more detailed discussion
gene rearrangement is evident with molecular probes (see “Hybrid and of specific molecular markers.) Microarray-based gene-expression pro-
Mixed Leukemias” below). In a proportion of otherwise typical cases filing is anticipated to become more important in precise diagnosis and
of AML, the cells may contain terminal deoxynucleotidyl transfer- subclassification of AML in the future.310
ase (TdT).273,274 Variations in marrow findings are discussed below in
“Morphologic Variants of Acute Myelogenous Leukemia.” Normal ery-
thropoiesis, megakaryocytopoiesis, and granulopoiesis are decreased or PLASMA CHEMICAL FINDINGS
absent in the marrow aspirate. The biopsy may contain residual islands
Prior to treatment, mild to moderate increases in serum uric acid
of erythroblasts or megakaryocytes. Dysmorphic changes in hemato-
and lactic dehydrogenase levels are frequent. Both levels are higher
poietic cells, including very small or large erythroblasts with nuclear
in myelomonocytic and monocytic AML than in other AML
fragmentation or binucleation or delayed nuclear condensation; small
phenotypes.200,201 Occasional patients have very elevated uric acid lev-
or monolobed megakaryocytes; or hypogranulated, bilobed, or mono-
els, which usually occur after chemotherapy if proper precautions are
lobed neutrophils, may occur in 30 to 50 percent of patients with
not taken (e.g., hypouricemic agents and hydration therapy).311 Abnor-
de novo AML.275 Marrow reticulin fibrosis is common but usually
malities of sodium, potassium, calcium, or hydrogen ion concentration
is slight to moderate except in cases of megakaryoblastic leukemia,
are infrequent and usually mild.312,313 Severe hyponatremia associated
in which intense fibrosis is the rule.276 Increased blood vessel density
with inappropriate antidiuretic hormone secretion has occurred at
(angiogenesis) is present in the marrow of patients with AML compared
presentation.312,313 Severe hypernatremia as a consequence of diabetes
to normal subjects.277,278 Various angiogenic factors, including vascular
insipidus can be an initial event.314 Hypokalemia is a more frequent
endothelial growth factor (VEGF), basic fibroblast growth factor, angio-
finding at presentation and is related to kaliuresis, although the reason
genin, and angiopoietin-1, are increased. VEGF detected histochem-
for the proximal renal tubular dysfunction is unclear.312,313,315 The hypo-
ically in human marrow is closely correlated with the prevalence of
kalemia can be severe and often is worsened by the effects of treatment,
leukemic myeloblasts in the various AML subtypes.279 AML cytogenetic
especially use of kaliuretic antibiotics.315 Factitious elevations in serum
variants may result in marrow basophilia (usually t(6;9))280 or marrow
potassium levels have been reported in patients with hyperleukocytosis
eosinophilia (usually inv16 or t(16;16)).281
as a result of leakage from white cells in vitro.316,317 Factitious hypogly-
cemia and spurious hypoxia from the effects of high blast cell counts in
Cytogenetic and Genic Features blood can occur.314,318
An abnormal number (aneuploidy) or structure (pseudodiploidy) The presence of hypercalcemia is multifactorial,319 but cases
of chromosomes or both are evident in approximately 55 percent of with increased ectopic parathormone-like activity in the plasma have
cases.282–285 The most prevalent abnormalities are trisomy 8, mono- been described.320 Severe lactic acidosis prior to treatment has been
somy 7, monosomy 21, trisomy 21, and loss of an X or Y chromosome. reported.312,321,322 Hypophosphatemia as a result of phosphate uptake
However, any chromosome can be rearranged, added, or lost (Chap. by leukemic cells can occur.323 Ectopic adrenocorticotropic hormone
13). In cases of AML following chemotherapy or radiotherapy, loss secretion,324 circulating immune complexes,325 and abnormal concen-
of part or all of chromosomes 5 and 7 are a common features,286–288 as trations of coagulation factors or their inhibitors326 may be present.
are the cytogenetic findings noted above for AML, occurring de novo. Although prothrombin and partial thromboplastin times usually
Table 88–4 lists the most frequent abnormalities and translocations seen are normal or near normal, abnormal concentrations of coagulation
in AML.282,283,286–308 The t(8;21) and inv(16) confer a more favorable out- factors are frequent. Elevations of platelet factor 4 and thromboxane
come on average. t(15;17) confers a highly favorable prognosis. Dele- B2 occur often.327 Decreases in α2-antiplasmin, protein C, and antith-
tion of all or part of chromosomes 5 and 7 or the presence of complex rombin III levels are frequent327 and may be associated with venous
changes (greater than 3 abnormalities) confers an unfavorable progno- thrombosis.328 APL and acute monocytic leukemia are associated with
sis. Other findings (e.g., normal karyotype, +8, 11q23) generally confer hypofibrinogenemia and other indicators of activation of coagula-
an intermediate prognosis (Chap. 13 has further details and discussion tion or fibrinolysis (see “Morphologic Variants of Acute Myelogenous
regarding impact of specific translocations).282–284 Leukemia” below).329

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 1384 Part X: Malignant Myeloid Diseases

TABLE 884. Clinical Correlates of Frequent Cytogenetic Abnormalities Observed in Acute Myelogenous Leukemia
Chromosome
Abnormality Genes Affected Clinical Correlation
Loss or gain of chromosome
Deletions of part or all Not defined Frequent in patients with acute myelogenous leukemia (AML) occurring de novo and in
of chromosome 5 or 7 patients with history of chemical, drug, or radiation exposure and/or previous hematologic
disease.282,283,286,287
Trisomy 8 Not defined Very common abnormality in acute myeloblastic leukemia. Poor prognosis, often a secondary
change.283,289
Translocation
t(8;21) (q22;q22) RUNX1(AML1)– Present in ~8% of patients <50 years old and in 3% of patients >50 years old with AML.288
RUNX1T1(ETO) Approximately 75% of cases have additional cytogenetic abnormalities, including loss of Y in
males or X in females. Secondary cooperative mutations of KRAS, NRAS, KIT common. Present
in ~40% of myelomonocytic phenotype. Higher frequency of myeloid sarcomas.263–266
t(15;17) (q31; q22) PML-RAR-α Represents ~6% of cases of AML.288 Translocation involving chromosome 17, t(15;17), t(11;17),
or t(5;17) is present in most cases of promyelocytic leukemia.290,291
t(9;11); (p22; q23) MLL (especially Present in ~7% of cases of AML. Associated with monocytic leukemia.292,293 11q23 transloca-
MLLT3) tions in 60% of infants with AML and carries poor prognosis. Rearranges MLL gene.292–296 Many
translocation partners for 11q23 translocation.295–298 MLL1, MLL4, MLL10 may also result in
AML phenotype.
t(9;22) (q34; q22) BCR-ABL1 Present in ~2% of patients with AML.299,300
t(1;22)(p13;q13) RBMIS-MKL1 <1% of cases of AML. Admixture of myeloblasts, megakaryoblasts, micromegakaryocytes
with cytoplasmic blebbing, dysmorphic megakaryocytes. Reticulin fibrosis common.301
t(10;11) PICALM-MLLT10 Outcome similar to that of intermediate prognosis group; more extramedullary disease and
(p12-13;q14-21) CD7 expression.302
Inversion
Inv(16) (p13.1;q22) or CBF-β MYH11 Present in ~8% of patients <50 years of age and in ~3% of patients >50 years of age with
t(16;16) (p13.1;q22) AML288; often acute myelomonocytic phenotype; associated with increased marrow eosino-
phils; predisposition to cervical lymphadenopathy,303 better response to therapy.304–307 Predis-
posed to myeloid sarcoma.
Inv(3) (q21q26.2) RPN1-EVI1 ~1% of cases of AML. Approximately 85% of cases with normal or increased platelet count.
Marrow has increased dysmorphic, hypolobulated megakaryocytes. Hepatosplenomegaly
more frequent than usual in AML.308

SPECIAL CLINICAL FEATURES upregulation of endothelial cell intercellular adhesion molecule-1 and
of leukemic blast cell lymphocyte function-associated antigen-1 may
Hyperleukocytosis mediate the vessel wall interaction contributing to leukostasis.349
Leukocyte count is an independent prognostic factor in the out-
come of AML treatment.330 Approximately 5 percent of patients with Hypoplastic Leukemia
AML develop signs or symptoms attributable to a markedly elevated Approximately 10 percent of patients with AML present with a syn-
blood blast cell count, usually greater than 100 × 109/L (Chap. 83).331 drome that includes pancytopenia, often with inapparent blood blast
Several subsets of AML are associated with a greater likelihood of cells, and absence of hepatic, splenic, or lymph nodal enlargement.350–352
presenting with hyperleukocytosis. These include acute myelomono- If one corrects for the decrease in marrow cellularity with age, hypoplas-
cytic, acute monocytic, the microgranular variant of APL, and AML tic AML occurs in approximately 2 percent of cases.353 Approximately
with inv16,11q23 rearrangements, or FLT3-ITD. The circulations of the 75 percent of these patients are men older than 50 years of age. Marrow
CNS, lungs, and penis are most sensitive to the effects of leukostasis. biopsy is hypocellular, which is the unusual feature of the syndrome,
Intracerebral hemorrhage from vascular occlusion, invasion, and dis- but leukemic blast cells are evident and present in a proportion of
ruption, sometimes complicated by thrombocytopenia and vascular 10 to 90 percent of marrow cells. Response to intensive chemotherapeu-
insufficiency are the most virulent manifestations of the syndrome.332–336 tic treatment, often with low-dose cytarabine because of the patients’
Dizziness, stupor, dyspnea, and priapism may occur. Diabetes insip- very advanced age, has been relatively good, and 3-year survival rates
idus is another association.337,338 Other severe organ involvement also are approximately the same as the rates of other age-matched patients.354
may occur infrequently. A high early mortality in patients with AML
correlates with hyperleukocytosis greater than 100 × 109/L.334,335,339,340 Oligoblastic Myelogenous (Subacute, Smoldering, Low-
Chemotherapy in hyperleukocytic patients may lead to a pulmonary Infiltrate, Pauciblastic) Leukemia
leukostatic syndrome, presumably from the effects of rigid, effete blast Not infrequently, usually in patients older than 50 years of age, myel-
cells, or the discharge of large amounts of cell contents and resultant ogenous leukemia is manifested by anemia and often thrombocytope-
cell aggregation or other effects.341–343 Larger-vessel vascular occlusion nia. The leukocyte count may be low, normal, or increased, and a small
as a result of white thrombi or masses of leukemic cells is rare.344,348 The proportion of blast cells are present in the blood (0 to 15 percent) and

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 Chapter 88: Acute Myelogenous Leukemia 1385

marrow (3 to 19 percent). Such cases have been referred to as oligoblastic malignancies and about one-quarter of cases occur in patients with
myelogenous leukemia, subacute, or smoldering leukemia,355 or classified AML.376 Bone pain (approximately 80 percent of patients) and fever
as a MDS, particularly refractory anemia with excess blasts. The clinical (approximately 70 percent of patients) are the two most common symp-
course of the untreated disease can be protracted. The disease has a high toms or signs. Anemia and thrombocytopenia, if not already present,
morbidity and mortality from infection and hemorrhage and can evolve results. White cell counts may be low or high. The blood may contain
into overt (polyblastic) AML. The smoldering or oligoblastic leukemias nucleated red cells and myeloid immaturity (approximately 50 percent
(refractory anemia with excess blasts) historically have been grouped of cases). Lactic dehydrogenase and alkaline phosphatase are elevated in
along with the clonal cytopenias as composing MDS; and, the diagnosis approximately 50 percent of cases. The marrow aspirate is often watery
and treatment of these variants are discussed in Chap. 87. Biologically and serosanguineous. An amorphous extracellular eosinophilic back-
and clinically, the disorders in this subset of the MDS with blast cell ground with disintegrating cells that have lost their staining charac-
proportions in the marrow above normal are leukemias, not dysplasias, teristics with indistinct margins and varying degrees of pyknosis and
but they have a slower rate of progression than polyblastic myelogenous karyorrhexis is characteristic. Rare cases have been described in which
leukemia. Dysmorphogenesis of red cells, neutrophils, and platelets is the marrow contained Charcot-Leyden crystals without an increase in
more frequent and more striking than in the average case of polyblastic eosinophils or basophils.377 Bony spicules may also show evidence of
AML (Chap. 87), but such dysmorphogenesis also occurs in polyblastic necrosis. Destruction of spicule architecture with loss of osteocytes,
leukemia, so-called AML with trilineage dysmorphia.275 A discussion osteoblasts, and osteocytes may be seen. It is important not to identify
of the spectrum of myelogenous leukemias, ranging from minimal to these changes as artifact. Usually more than 50 percent of the biopsy
severe deviation neoplasms, can be found in Chap. 83. is involved. Careful search may identify the underlying hematologic
disorder in small islands of intact cells. Technetium-99m sulfur colloid
Philadelphia Chromosome–Positive Acute Myelogenous scans show little or no uptake. Magnetic resonance imaging (MRI) may
Leukemia not be diagnostic but can show the extent of the necrosis by changes in
Approximately 2 percent of patients with AML have the Philadelphia signal intensity signifying an increase in water content in relation to fat.
(Ph) chromosome t(9;22)(q34;q11) in a significant proportion (10 Both technetium scanning and MRI can point to areas of intact marrow
to 100 percent) of leukemic blast cells.356–358 The blast cells have sur- that may be used to make a diagnosis of the underlying disease, if it is
face antigens, such as CD13 and CD33, characteristic of myeloid unknown. The pathophysiology is uncertain but is thought to be related
leukemias.359,360 One interpretation of the concurrence of AML with to marrow vascular injury and or thrombosis secondary to inflamma-
t(9;22) is that it represents CML presenting in myeloid blast crisis.361–363 tory or immune factors and cytokines. The prognosis of marrow necro-
The arguments in favor of this proposal are as follows: (1) Blast crisis may sis is largely related to the underlying disease. Repair of marrow can
occur within days after diagnosis of Ph chromosome–positive CML. occur, if the patient enters remission.
(2) Cases can present with additional cytogenetic changes comparable
to CML in blast crisis.361,363 (3) Marked hepatosplenomegaly, uncharac-
teristic of AML, may be present.362,363 (4) Platelet counts may be normal,
NEONATAL MYELOPROLIFERATION
and basophils can be increased.361,363 (5) A long prodromal period of AND LEUKEMIA
weakness and weight loss may occur, and some features of CML, such as Four myeloproliferative syndromes related to AML have been identified
granulocytosis, can appear after treatment with chemotherapy.364 (6) Ph in the neonate: transient myeloproliferative disorder, transient leuke-
chromosome–positive AML has a poor prognosis, as in myeloid blast mia, congenital leukemia, and neonatal leukemia. Transient myelopro-
crisis of CML. (7) The breakpoint on chromosome 22 in the M-bcr may liferative disorder and transient leukemia are considered to represent
be typical of CML, and the product of the fusion BCR-ABL gene is a the same phenomenon.
p210 tyrosine kinase identical to that of classic CML.360,363–368 (8) Occa- Transient myeloproliferative disease (TMD) can be present at birth
sional cases express p210 and p190 tyrosine kinases, now known to be or occur shortly thereafter in approximately 10 percent of infants with
features of CML.368 (9) Some patients enter a remission by converting Down syndrome.378–384 The leukocyte count is markedly elevated, blast
to a phenotype analogous to chronic phase CML. An alternative view has cells are present in the blood and marrow, and anemia and thrombo-
been promulgated because (1) cases of Ph chromosome–positive AML can cytopenia may be present, but the latter are not constant findings. The
be a mosaic (normal and abnormal karyotypes)360; (2) the Ph chromosome liver and spleen may be enlarged. Results of cytogenetic studies and
may appear later in the course of the disease369; (3) additional chromosomal marrow cell culture studies are normal, except for trisomy 21, which
abnormalities often are different from those seen in the myeloblastic crisis is characteristic of Down syndrome. The blast cells usually have the
of CML360,370,371; and (4) in some cases, the BCR-ABL gene is not encoding immunophenotype of megakaryocytes. In contrast to congenital leu-
a p210 but a p190 mutant tyrosine kinase,357,365,368,372 the former being most kemia, the elevated white cell and blast cell counts disappear in most
characteristic of CML. Moreover, Ph chromosome–positive AML has patients (approximately 80 percent) over a period of weeks to months.
developed following Ph chromosome–negative oligoblastic myelogenous In approximately 20 percent of patients, severe and potentially lethal
leukemia.357,373,374 Many cases of Ph chromosome–positive acute leukemia complications of hydrops fetalis, hepatic fibrosis, or cardiorespiratory
are myeloid-lymphoid hybrids.364,368,370,375 Thus, Ph chromosome–positive failure may occur.
AML comes in two varieties: one with a break in M-BCR of chromo- In some cases, an additional cytogenetic abnormality is present,
some 22 with a p210 product, which could be considered analogous to which disappears after regression of the myeloproliferative syndrome,
acute blast crisis of CML, and one with a molecular pathology resulting in suggesting a reversible clonal disorder (transient leukemia) that is
the oncogene product being a p190 protein (m-BCR) that could be con- replaced by normal hematopoiesis. The presence of a trisomy of chro-
sidered a de novo case. mosome 21 is essential for the disease as judged by three observations:
the trisomy occurs in (1) the TMD clone of patients with constitutional
Marrow Necrosis trisomy 21, (2) the TMD clone in patients with Down syndrome with
Necrosis of the marrow is an uncommon event and can be seen in a wide a cell mosaic pattern of trisomy 21, and (3) in the TMD clone of phe-
variety of malignant and nonmalignant clinical disorders, but approx- notypically normal infants without a constitutional trisomy 21, but
imately two-thirds of cases are associated with lymphoid or myeloid with TMD. In the last case, trisomy 21 disappears with resolution of

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 1386 Part X: Malignant Myeloid Diseases

the myeloproliferation.385 Candidate oncogenes on chromosome 21 In bilineal (interlineal) acute leukemias, a proportion of cells
responsible for the phenomenon include FPDMM, RUNX1 (CBF-β), (>10 percent) have lymphoid and myeloid markers; interlineal here
and IFNAR, among others.385 GATA-1 mutations have been found in refers to lymphopoietic and myeloid gene expression. Bilineal (biphe-
nearly all patients with TMD and in acute megakaryocytic leukemia in notypic) leukemias are heterogeneous. Some patients have cells with
Down patients.386 The TMD syndrome may disappear, only to be fol- both lymphoid and myeloid markers (chimeric), whereas other patients
lowed shortly thereafter by acute leukemia, predominantly AML, but have cells with either lymphoid or myeloid markers but evidence that
occasionally acute lymphocytic leukemia (ALL). all the cells are part of the same malignant clone (mosaic). The bilin-
One hypothesis for TMD is that the disorder originates in a primi- eal leukemias may be synchronous (lymphoid and myeloid cells are
tive cell of fetal hepatic hematopoiesis. The cell involutes and is replaced present simultaneously) or asynchronous (in which lymphoid cells are
with marrow stem cells. Approximately 25 percent of newborns with succeeded by myeloid cells or vice versa), but evidence exists for their
Down syndrome and transient leukemia develop acute megakaryocytic origin from the same clone.
leukemia in the first 4 years of life.387–389 Cases of biphenotypic leukemia that are morphologically or cyto-
Very-low-dose cytarabine has been suggested for those patients chemically indicative of myelogenous leukemia have been referred to as
with severe hepatic fibrosis, very high white cell counts, or hydrops LY+AML; the cases that are more indicative of lymphocytic leukemia
fetalis.385 TMD cells in these infants are very sensitive to cytarabine.390,391 are referred to as MY+ALL. As a group, interlineal hybrid leukemias
Children with Down syndrome have a 150-fold risk of AML treated with current regimens respond to therapy at approximately the
and about a 40-fold risk of ALL by age 5 years. A slightly increased same rate as AML cases without lymphoid markers.406 Some observers
risk of acute leukemia persists into older age. Myelogenous leukemia suggest altering drug regimens, depending on the balance between lym-
in patients with Down syndrome often has a megakaryoblastic or phoid and myeloid biochemical (drug-response) patterns.412
erythroid phenotype and may have an interstitial deletion of Acute leukemias may be intralineal hybrids in that the blast cells
chromosome 21.380,381,392–395 This requires mutation in the GATA1 gene in have markers for two or more myeloid lineages (e.g., erythroid, granu-
addition to trisomy 21, and sequential epigenetic changes occur as well locytic, and megakaryocytic) or, in the case of lymphocytic leukemias,
in the evolution of acute megakaryoblastic leukemia.395,396 The response both immunoglobulin gene rearrangement (B-lymphocyte type) and
rate of infants with Down syndrome and AML to chemotherapy is very T-cell receptor gene rearrangement (T-lymphocyte type).
high over prolonged followup and better than the response of patients
without Down syndrome.387,391,397,398 The response to adjusted-dose Myeloid–Natural Killer Cell Hybrids and t(8;13) Myeloid–
anthracycline antibiotic and cytarabine in Down syndrome children Lymphoid Leukemias
with AML is approximately 90 percent and the event-free 5-year sur- Although most hybrid leukemias share myeloid and either B- or T-
vival is approximately 80 percent.394 In those cases with relapsed or lymphocyte markers, two notable syndromes are associated with hybrid
refractory disease, outcomes are poor even with allogeneic HSC trans- leukemias: (1) the myeloid leukemia and natural killer cell hybrid
plantation.399 ALL may occur, and the response to therapy is similar to (CD56+, CD7+, CD13+, CD33+)413–419 and (2) the lymphoma, eosin-
the response of patients without Down syndrome of the same age. Most ophilia, and t(8;13) myeloid leukemia hybrid.420,421 Signs of lymphoma,
solid tumors occur less frequently in Down syndrome patients.390 such as mediastinal or other lymphadenopathy and extranodal lym-
Congenital or neonatal leukemia, a rare syndrome, occurs 10 times phoid tumor, are mixed with findings compatible with AML in both
more frequently in newborns with Down syndrome than in newborns syndromes. The morphology of the myeloid–natural killer cell leukemia
without trisomy 21.392,393 Leukocytosis, blood and marrow blast cells, often simulates APL, with hypergranular cytoplasm present but abnor-
hepatosplenomegaly, thrombocytopenia, purpura, anemia, and skin mality of chromosome 17 absent. The hybrids can appear de novo or
infiltrates are usual. The disease has been diagnosed prenatally. Cyto- after relapse of a lymphoma, T-cell leukemia, or blast crisis of CML. The
genetic abnormalities can occur and mark the leukemic clone.393,400,401 hybrid leukemias usually have a poor prognosis. Myeloid antigens may
Monocytic leukemia and t(4;11) are the most common phenotype and not be evident at diagnosis in the natural killer cell hybrid but appear
karyotype.401–403 A case of vertical (transplacental) transmission of acute later in the course.422 Hematopoietic stem cell transplantation should be
monocytic leukemia from mother to son has been reported.404 considered in an eligible patient.423
Infants who are normal at birth but develop AML in the first few Hybrid leukemias may result from either lineage infidelity caused
weeks of life (neonatal leukemia) often display pallor, inadequate food by genetic misprogramming413 or promiscuous gene expression, which
intake, insufficient weight gain, diarrhea, and lethargy. The presence of occurs transiently in the differentiation of normal pluripotential
a cytogenetic abnormality on band q23 of chromosome 11 is a very poor HSCs. In the case of promiscuity, persistence of the transient normal
prognostic sign. Most infants with congenital or neonatal leukemia do event is thought to be present because of the block in differentiation
not survive for more than a few weeks or months. Because treatment that occurs.408 Genetic misprogramming (infidelity) could result from
has been largely ineffective, observation to ascertain if TMD or a tran- rearrangements of the DNA sequences that control the transcription of
sient leukemia is present has been recommended if the clinical picture genes designating differentiation antigens.424
is unclear.405
Mixed Leukemias
In these cases, lymphoid and myeloid cells are present simultaneously
HYBRID AND MIXED LEUKEMIAS but are derived from separate clones, or sequential myeloid and lym-
Hybrid Leukemias phoid leukemia are present but the two lineages are derived from sep-
Although coincidental myeloid and lymphoid clonal diseases have been arate clones.
reported for more than 60 years, the availability of techniques to iden-
tify surface antigens with monoclonal antibodies, immunoglobulin
MEDIASTINAL GERM CELL TUMORS AND
gene, and T-lymphocyte receptor gene rearrangements with molecular
methods, and chromosome translocations by chromosome banding ACUTE MYELOGENOUS LEUKEMIA
cytogenetic techniques has led to the appreciation of several types of An unusual but significant concordance has been reported between
hybrid acute leukemia.406–411 nonseminomatous mediastinal germ cell tumors and AML, especially

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 Chapter 88: Acute Myelogenous Leukemia 1387

the megakaryoblastic variant.425–430 Mediastinal tumors are rare variants the FAB classification. The WHO has divided acute myeloblastic leuke-
of germ cell tumors. The latter ordinarily occur as testicular teratomas mia into three types: AML without differentiation, AML without mat-
and seminomas in men or as ovarian teratomas in women. They are uration, and AML with maturation. There is no evidence of a clinical
thought to be derived from yolk sac cells that failed to migrate.428,429 AML distinction in response to therapy or in prognosis within these rarified
is a HSC tumor derived from a cell type that is present in the yolk sac. designations.
Cytogenetic studies are compatible with a clonal relationship (identity) In many cases of myeloblastic leukemia, more prominent granu-
of mediastinal germ cells and myelogenous leukemia cells.426,427 Appar- locytic maturation is evident (FAB type M2 or WHO designation AML
ently, hematopoietic lineage genes are predisposed to expression in with maturation). This variant is present in approximately 15 percent of
extragonadal (mediastinal) germ cell tumors. Use of etoposide, plati- AML cases; thus, approximately 45 percent of cases of AML are mye-
num, and related cytotoxic drugs for treatment of mediastinal germ cell loblastic leukemia with or without maturation. Blasts usually consti-
tumors may induce secondary AML in a predisposed cell population.431 tute at least 20 percent of the marrow cells. Auer rods may be present
in blast cells. Promyelocytes, myelocytes, and segmented neutrophils,
the latter often with the acquired Pelger-Huët anomaly, may constitute
GASTROINTESTINAL TUMORS AND ACUTE 20 to 60 percent of marrow granulocytes. The anomaly is reflected in
MYELOGENOUS LEUKEMIA bilobed or monolobed neutrophils. Histochemical and surface markers
A study of 1892 patients with KIT-positive mesenchymal gastrointes- of blast cells are typical of myeloblastic leukemia, and monocytic mark-
tinal stromal tumors found a significant subsequent incidence of AML ers are absent or infrequent. Monocytes represent less than 10 percent
(nine patients). The standardized incidence ratio was approximately 3.0 of cells. A translocation between chromosomes 8 and 21 t(8;21)(q22;
(confidence interval: 1.1 to 5.8). The patients had not received prior che- q22), often accompanied by loss of the Y chromosome in men or loss
motherapy or radiotherapy and the median duration of gastrointestinal of an X chromosome in women, is associated with the phenotype and
stromal tumors before onset of AML was 6 years.432 occurs in younger patients (average age approximately 30 years).439–441
Patients whose cells contain t(8;21) are more prone to develop myeloid
sarcoma.263,266
MORPHOLOGIC VARIANTS OF ACUTE
MYELOGENOUS LEUKEMIA ACUTE MYELOMONOCYTIC LEUKEMIA
Morphologic variants of AML (Table 88–5) may occur de novo or may The ability of AML to express cells of the monocytic and granulocytic
be the manifestation of clonal evolution from essential thrombocythe- lineages was first highlighted in the early 1900s by Naegeli. Later, Hal
mia, idiopathic myelofibrosis, CML, or other chronic clonal myeloid Downey, a leading hematologist of the day, proposed the eponym
disorders. For example, every phenotypic variant of AML can occur as Naegeli type for myelomonocytic leukemia.442 Approximately 15 per-
the blast crisis of CML (Chap. 89). cent of patients with AML present with this variant, and they are more
likely to have extramedullary infiltrates in gingiva, skin, or CNS than
are patients with acute myeloblastic leukemia (see “Myeloid [Granulo-
ACUTE MYELOBLASTIC LEUKEMIA cytic] Sarcoma” above).443 A mixture of myeloblasts and monoblasts is
The designation acute myeloblastic leukemia came into existence in the found in the blood and marrow. More than 30 percent of marrow cells
second decade of the 20th century,4 following the specific description are a mixed population of myeloblasts, which react with peroxidase or
of the myeloblast.6 Approximately 25 percent of AML cases have the chloracetate esterase, and monoblasts or promonocytes, which react
features of acute myeloblastic leukemia, a variant in which the leukemic with fluoride-inhibitable nonspecific esterase (see Fig. 88–2F). More
myeloblast is the predominant cell in the marrow. Acute myeloblastic than 20 percent of cells are monoblasts or promonocytes in blood and
leukemia was divided into two forms, designated M0 and M1 in the marrow. In some cases, individual cells react with monocytic and gran-
French-American-British (FAB) Classification. In either type, little evi- ulocytic histochemical stains.444 Serum and urinary lysozyme levels are
dence of maturation of myeloblasts exists, and the marrow is replaced increased in most cases. This variant of AML is referred to as M4 in the
by a monotonous population of blasts. In acute myeloblastic leukemia FAB classification and as acute myelomonocytic leukemia in the WHO
(M0), the patient’s age distribution, presenting white cell count, and classification. Translocations involving chromosome 3 are associated
cytogenetic abnormalities are not distinctive. The blasts are nonreac- with this phenotype.445
tive when stained for myeloperoxidase activity, and Auer rods are not The proportion of marrow eosinophils446 or basophils447 may
seen. The blasts react with antibodies to myeloperoxidase and antibod- be increased. A particular variant of myelomonocytic leukemia has
ies to CD13, CD33, and CD34. Human leukocyte antigen (HLA)-DR increased numbers of marrow eosinophils (10 to 50 percent), Auer rods
is positive in most patients. Occasional cases require in situ hybridiza- in blast cells, and inversion or rearrangement of chromosome 16 (see
tion to identify the myeloperoxidase gene433 or genomic profiling for Fig. 88–2G).304–307 The eosinophils are abnormally large, and the eos-
early myeloid-associated genes.434 Abnormal and unfavorable karyo- inophilic myelocytes contain large basophilic granules. Macrophages
types (e.g., 5q–,7q–) and expression of the multidrug resistance (MDR) with ingested Charcot-Leyden crystals may be present. This pheno-
glycoprotein (p170) are more frequent. This phenotypic variant has a typic variant of AML has been designated M4Eo in the FAB classifica-
poor prognosis.435–438 In the other type of myeloblastic leukemia, desig- tion. Although this variant has an increased risk of CNS involvement,
nated M1, myeloblasts are present in the blood and make up more than it carries a more favorable prognosis than the average case of AML.
70 percent of marrow cells. Less than 15 percent of marrow cells are Fluorescence in situ hybridization (FISH) is a more accurate method
promyelocytes and myelocytes. Auer rods may be present in occasional for detection of cryptic 16q22 gene rearrangements and is useful in
blasts, but azurophilic granules are not evident in the blasts by light conjunction with conventional cytogenetics for patients with M4Eo
microscopy. At least 3 percent, but usually a much higher percentage, AML. AML with t(6;9)(p23;q34) is an uncommon variant, occurring in
of the blast cells, have a positive reaction when stained for peroxidase or approximately 1 percent of cases, and may express itself as acute mye-
with Sudan black or react with monoclonal antibodies specific to mye- lomonocytic or acute myeloblastic leukemia. Anemia, thrombocytope-
loblasts, such as CD33. This morphologic subtype is denoted as M1 in nia, a variable white cell count, and increased myeloblasts are frequent.

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 1388 Part X: Malignant Myeloid Diseases

TABLE 885. Morphologic Variants of Acute Myelogenous Leukemia

Variant Cytologic Features Special Clinical Features Special Laboratory Features
Acute myeloblastic leukemia 1. Myeloblasts range from 1. Most common in adults, 1. Chromosomes +8, –5, –7,
(M0, M1, M2) 20–90% of marrow cells. and most frequent variety in del(11q), and complex
Cytoplasm occasionally con- infants. abnormalities common.
tains Auer bodies. Nucleus 2. Three morphologic- RUNX1(AML1) and FLT3 muta-
shows fine reticular pattern cytochemical types tions occur in approximately
and distinct nucleolus (1 or (M0, M1, M2) 20–25% of cases.
2 usually). 2. M0 type blast cells positive
2. Blast cells are sudanophilic. with antibody to myeloper-
They are positive for myelop- oxidase and CD34 and CD13
eroxidase and chloroacetate or CD33 coexpression. AML1
esterase, negative for nonspe- mutations in ~25%.
cific esterase, and negative or 3. M1 expresses CD13 and
diffusely positive for PAS (no CD33. Positive for myeloper-
clumps or blocks). oxidase by cytochemistry.
3. Electron microscopy shows 4. M2 AML with maturation
cytoplasmic primary often associated with t(8;21)
granules. karyotype.
5. M2 AML with t(6;9)(p23;q34),
an uncommon variant, is
associated with marrow
basophilia, a high blast count,
a high frequency of FLT3-ITD,
and a poor outcome.
Acute promyelocytic leukemia 1. Leukemic cells resemble pro- 1. Usually in adults. 1. Cells contain t(15;17) in >95%
(M3, M3v) myelocytes. They have large 2. Hypofibrinogenemia and of cases or another rearrange-
atypical primary granules hemorrhage common. ment involving the RAR-α
and a kidney-shaped nucleus. gene on chromosome 17.
Branched or adherent Auer 3. Leukemic cells mature in
response to all-trans-retinoic 2. Cells are HLA-DR–negative.
rods are common.
acid.
2. Peroxidase stain intensely
positive.
3. A variant has microgranules
(M3v), otherwise the same
course and prognosis.
Acute myelomonocytic leukemia 1. Both myeloblastic and mono- 1. Similar to myeloblastic leuke- 1. Leukemic cells in eosinophilic
(M4, M4Eo) blastic leukemic cells in blood mia but with more frequent variant (M4Eo) usually have
and marrow. extramedullary disease. inversion or translocation of
2. Peroxidase-, Sudan-, chloro- 2. Mildly elevated serum and chromosome 16.
acetate esterase-, and non- urine lysozyme.
specific esterase-positive
cells.
3. M4Eo variant has marrow
eosinophilia.
Acute monocytic leukemia (M5) 1. Leukemia cells are large; 1. Seen in children or young 1. t(4;11) common in infants.
nuclear cytoplasmic ratio adults. 2. Rearrangement of q11;q23
lower than myeloblast. Cyto- 2. Gum, CNS, lymph node, and very frequent.
plasm contains fine granules. extramedullary infiltrations
Auer rods are rare. Nucleus is are common.
convoluted and cell simulates
promonocytes (M5a) or may 3. DIC occurs.
simulate monoblasts (M5b) 4. Plasma and urine lysozyme
and contain large nucleoli. elevated.
2. Nonspecific esterase-positive 5. Hyperleukocytosis common.
inhibited by NaF; Sudan-,
peroxidase-, and chloroace-
tate esterase-negative. PAS
occurs in granules, blocks.
(continued)

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 Chapter 88: Acute Myelogenous Leukemia 1389

TABLE 885. Morphologic Variants of Acute Myelogenous Leukemia (Continued)

Variant Cytologic Features Special Clinical Features Special Laboratory Features
Acute erythroid leukemia (M6) 1. Abnormal erythroblasts are in 1. Pancytopenia common at 1. Cells reactive with antihemo-
abundance initially in marrow diagnosis. globin antibody. Erythrob-
and often in blood. Later the lasts usually are strongly PAS
morphologic findings may be and CD71-positive, express
indistinguishable from those ABH blood group antigens,
of AML. and react with antihemoglo-
bin antibody.
2. Cells reactive with anti–Rc-84
(antihuman erythroleukemia
cell-line antigen).
Acute megakaryocytic leukemia 1. Small blasts with pale agran- 1. Usually presents with 1. Antigens of von Willebrand
(M7) ular cytoplasm and cyto- pancytopenia. factor, and glycoprotein Ib
plasmic blebs. May mimic 2. Markedly elevated serum lac- (CD42), IIb/IIIa (CD41), IIIa
lymphoblasts of medium to tic dehydrogenase levels. (CD61) on blast cells.
larger size. 2. Platelet peroxidase positive.
3. Marrow aspirates are usu-
2. Leukemic cells with ally “dry taps” because of
megakaryocytic mor- the invariable presence of
phology may coexist with myelofibrosis.
megakaryoblasts.
4. Common phenotype in the
AML of Down syndrome.
Acute eosinophilic leukemia 1. Mixture of blasts and cells 1. Hepatomegaly, splenomeg- 1. Cyanide-resistant peroxidase
with dysmorphic eosinophilic aly, lymphadenopathy may stains eosinophilic granules.
granules (smaller and less be prominent. TEM shows eosinophilic gran-
refractile). 2. Absence of neurologic, respi- ules to be smaller and miss-
ratory, or cardiac signs or ing central crystalloid.
symptoms characteristic of 2. Biopsy may show Charcot-
chronic eosinophilic leukemia Leyden crystals in skin,
(clonal hypereosinophilic marrow, or other sites of eos-
syndrome). inophil accumulation.
Acute basophilic leukemia Mixture of blast cells and cells 1. Often has hepatomegaly and 1. CD9-, CD11b-, CD25-,
with basophilic granules in or splenomegaly; symptoms CD123-positive cells are usu-
blood and marrow. often present. ally present.
2. Rash with urticaria, head- 2. Toluidine blue-positive cells.
aches, prominent gastrointes- 3. Hyperhistaminemia and
tinal symptoms. hyperhistaminuria.
4. Cells negative for tryptase
but positive for histidine
decarboxylase.
Acute mast cell leukemia 1. Mast cells in blood and mar- 1. Fever, headache, flushing of 1. CD13, CD33, CD68, CD117
row. Most contain granules face and trunk, pruritus may often positive.
but some are agranular and be present. 2. Cells positive for tryptase
may simulate monocytes. 2. Abdominal pain, peptic ulcer, staining and serum tryptase
bone pain, diarrhea more elevated.
common than other AML 3. Hyperhistaminemia and
subtypes. hyperhistaminuria.
3. Hepatomegaly, splenomegaly
common.
4. Hemorrhagic diathesis may
be evident.

AML, acute myelogenous leukemia; DIC, disseminated intravascular coagulation; HLA-DR, human leukocyte antigen-D related; NaF, sodium
fluoride; PAS, periodic acid–Schiff; RAR, retinoic acid receptor; TEM, transmission electron microscopy.
NOTE: Parentheses indicate French-American-British (FAB) classification designations M0 through M7.

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 1390 Part X: Malignant Myeloid Diseases

The myeloblasts often contain Auer rods. Marrow basophilia is present ACUTE PROMYELOCYTIC LEUKEMIA
in about half the cases.208,280,448 The variant occurs at a younger age, has a
The association of an exaggerated hemorrhagic syndrome with certain
poor prognosis, and has a tendency to trilineage dysmorphia and ringed
leukemias was described by French hematologists in 1949.466 In 1957,
sideroblasts.449
Hillstad467 bestowed the appellation promyelocytic leukemia upon this
morphologic-clinical subtype of AML. This variant, which is called M3
in the FAB classification and APL in the WHO classification, occurs at
ACUTE ERYTHROID LEUKEMIA any age and constitutes approximately 7 percent of AML cases.290,291,468,469
Prominence of erythroid cell proliferation in AML cases was noted by APL occurs with greater frequency among Latinos from Europe and
Copelli450 and DiGuglielmo451 in the early 20th century. Moeschlin452 South and Central America.190,191 APL represents 19 percent of AML
used the term erythroleukemia. Dameshek453 suggested the name cases in the Chinese189 as compared to 8 percent among persons of Euro-
DiGuglielmo syndrome and dissected the disorder into three phases, pean descent. APL is also increased among persons with an increased
depending on the decreasing prevalence of dysmorphic erythroblasts body mass index.470–472 Unlike all other major variants of AML, which
and the reciprocal increasing prevalence of myeloblasts. Erythroid leu- increase in incidence logarithmically with age, the incidence of APL is
kemia makes up approximately 5 percent of AML cases and is referred constant over the human life span.188 Hemorrhagic manifestations are
to as M6 in the FAB classification.454 Familial erythroleukemia has been prominent including hemoptysis, hematuria, vaginal bleeding, melena,
described.455,456 Erythroid leukemia is arbitrarily divided into three hematemesis, and pulmonary and intracranial bleeding, as well as the
degrees of severity: (1) erythroleukemia in which more than 50 percent more typical skin and mucous membrane bleeding. In severely leu-
of the marrow cells are dysmorphic; (2) erythroblasts admixed with kopenic patients, blasts may not be evident in the blood. Moderately
myeloblasts, the latter composing approximately 20 percent of non- severe thrombocytopenia (<50 × 109/L) is present in most cases. The
erythroid cells or approximately 5 to 10 percent of total marrow cells; marrow contains few agranular blast cells and some blast-like cells with
and (3) a form in which dysmorphic erythroblasts dominate the mar- scant granules. The dominant cells are promyelocytes, which comprise
row, pure erythroid leukemia, in which more than 80 percent of marrow 30 to 90 percent of marrow cells (see Fig. 88–2D and E). Auer rods and
cells are dysmorphic erythroblasts with a trivial granulocytic propor- cells with multiple Auer rods (1 to 10 percent) are present in nearly
tion of cells and very few if any myeloblasts. This last form of the disease every case. Promyelocytes with multiple Auer rods have been referred
may start in as a milder variant, formerly called erythremic myelosis, in to as faggot cells. Leukemic promyelocytes stain intensely with myelop-
which granulopoiesis, and thrombopoiesis may be only mildly abnor- eroxidase and Sudan black and express CD 9, CD13, and CD33, but not
mal. This phase, dominated morphologically by bizarre dysmorphia of CD34 or HLA-DR.290,291,468,469
erythroblasts, can be protracted but eventually evolves into a dimorphic A variant type of promyelocytic leukemia is referred to as micro-
phase in which myeloblasts are more prominent, severe neutropenia granular (M3v in the FAB nomenclature).473–476 Microgranular cases
and thrombocytopenia develop, and the patient progresses to erythroid represent approximately 20 percent of patients with promyelocytic
leukemia. The disease may evolve further into polyblastic AML.457–460 leukemia. The leukemic cells may mimic promonocytes with convoluted
In the erythremic myelosis variant, erythropoiesis is ineffective. How- or lobulated nuclei. Auer rods may be present but are less evident. The
ever, some normal regulation may remain because hypertransfusion majority of the leukemic cells contain azurophilic granules that are so
decreases both erythropoietin levels and the amount of abnormal ery- small they are not visible by light microscopy, but the peroxidase stain
thropoiesis.461 Spontaneous growth of leukemic erythroid clonogenic usually is strongly positive. Typical hypergranulated promyelocytes usu-
cells is a feature of the disease.462 Periodic acid–Schiff (PAS)-positive ally are present on careful inspection. The total white cell count often is
erythroblasts are evident in almost all cases.457,460 highly elevated, and severe coagulopathy is prominent in microgranular
The erythroid leukemias are characterized by a striking population cases.474 Rarely, the cells contain eosinophilic or basophilic granules, but
of dysmorphic erythroblasts in marrow and red cells in blood (see Fig. t(15;17) is present, and the response to all-trans retinoic acid (ATRA)
88–2I, J, and K). Anemia and thrombocytopenia are present in nearly persists,477–479 although the basophilic variant can be virulent.480
all cases. Some patients may have elevated total leukocyte counts. The A translocation between chromosome 17(q21), which rearranges
red cells show marked anisocytosis, poikilocytosis, anisochromia, and the RAR-α gene at band q21, and another chromosome is present in
basophilic stippling. Nucleated red cells are present in the blood. The all cases of APL and in the acute promyelocytic transformation of
marrow erythroblasts are extremely abnormal, with giant multinucle- CML; it is not found in other AML variants. The t(15;17)(q22;q21) is
ate forms, nuclear budding, and nuclear fragmentation. Cytogenetic the most frequent cytogenetic abnormality (>95 percent), but variant
abnormalities are present in approximately 70 percent of patients and translocations between chromosome 3, 5, or 11 and chromosome 17
complex cytogenetic abnormalities are frequent. The frequency of ery- or isochromosome 17, and other even less common variants have been
throid leukemia is increased if methods for detecting erythroid dif- described.290,468,481–483 In some cases, cytogenetic analysis is inadequate
ferentiation more sensitive than light microscopy are used. These cell and Southern blot analysis is required to identify the rearrangement
features include glycophorin A, spectrin, carbonic anhydrase I, ABH of the RAR-α gene. A functional distinction is that the t(15;17), PML–
blood group antigens, and other antigens that occur on early erythroid RAR-α fusion, the t(5:17), NPM–RAR-α fusion, and the t(3;17), TBLR1–
progenitors, such as the transferrin receptor (CD71).463–465 Antihemo- RAR-α fusion confer retinoid therapy responsiveness, whereas t(11;17),
globin antibody and antihuman erythroleukemic cell line antibody PLZF–RAR-α fusion, usually is retinoid resistant. In cells with the
often are positive.458 t(11;17), Auer rods are absent and CD56 expression usually is present,
Erythremic myelosis can have an indolent course and may be man- offering some clinical variables to provoke special molecular investiga-
aged for a time without intensive chemotherapy. Treatment is warranted tions.484 The retinoid resistance may not always be present.485
in patients with erythroleukemia and acute erythroid leukemia, and the The breakpoint on chromosome 17 is within the gene encod-
results are approximately the same as with other phenotypes in patients ing the RAR-α, and the breakpoint on chromosome 15 is within the
of similar age.460 The more predominant the erythroid component and locus of a gene originally referred to as MYL and renamed PML (to
the lower the proportion of myeloblasts, the better the response to indicate its relationship to promyelocytic leukemia).290,486 The gene
therapy.403 encodes a unique transcription factor. The translocation results in two

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 Chapter 88: Acute Myelogenous Leukemia 1391

new chimeric or fusion genes: RAR-α–PML, which is actively tran- Hepatomegaly, splenomegaly, and lymphadenopathy are more frequent
scribed in APL, and PML–RAR-α, which also is transcribed and may in monocytic leukemia.207,505–507
account for the aberrancy in hematopoiesis. The PML–RAR-α gene has The proportion of monocytic cells is usually greater than
two isoforms that produce a short- and a long-type fusion messenger 75 percent. The total leukocyte count is higher in a larger proportion
RNA, respectively.487 Patients with the short isoform may have a worse of patients, and hyperleukocytosis occurs more frequently (approxi-
outcome than those with the longer form. Polymerase chain reaction mately 35 percent) than in other variants.508–510 The marrow and blood
(PCR) for the mRNA of the fusion gene can be used to identify resid- cells may be largely monoblasts (acute monoblastic leukemia) or more
ual cells during remission and may predict relapse. The PML–RAR-α mature-appearing promonocytes and monocytes (acute monocytic
transgene can reproduce the disease in mice,488 although in some mod- leukemia) (see Fig. 88–2H). When the blood contains more mature-
els a superimposed FLT3 mutation is required to express the disease. appearing monocytic cells, the marrow contains a lower proportion of
FLT3 mutations are frequently found in human disease, especially in the blast cells, approximately 15 to 50 percent. When the blood monocytes
hypogranular variant.157 are largely blast cells, the marrow contains approximately 50 to 90 per-
A propensity to hemorrhage is a striking feature of this subtype. cent blasts. In nearly all cases, 10 to 90 percent of monocytic cells react
The prothrombin and partial thromboplastin times are prolonged, and for nonspecific esterase stains, α-naphthyl acetate esterase, and naphthol
the plasma fibrinogen level is decreased in most cases. The disturbance AS-D-chloroacetate esterase; in a cytochemical or chemoluminescence
in coagulation first was thought to principally result from intravascu- assay; or with monoclonal antibodies against monocyte surface anti-
lar coagulation initiated by procoagulant released from the granules of gens, especially CD14. Immunoreactivity of cells for lysozyme is charac-
the leukemic promyelocytes. Elevated thrombin–antithrombin com- teristic. Serum and urine lysozyme levels are elevated in most patients.
plexes, prothrombin fragment 1+2, and fibrinopeptide A plasma levels Serum lactic dehydrogenase and β2-microglobulin concentrations are
support that supposition. Increased levels of fibrinogen–fibrin degrada- increased in greater than 80 percent of patients.511 Plasminogen activa-
tion products, D-dimer, and evidence of plasminogen activation indi- tor inhibitor-2 is present in the plasma and the cells of a high proportion
cate fibrinolysis.489–491 Furthermore, decreased levels of plasminogen, of patients.512 Auer rods are absent when monoblasts dominate but may
increased expression of annexin II on the leukemic cells,492 and reports of be present in cases where promonocytes and monocytes are prevalent
responses to tranexamic acid support a role for fibrinolysis in the bleed- in blood and marrow. Leukemic monocytes have Fc receptors and can
ing in APL.493 Release of nonspecific proteases may further contribute to ingest and kill microorganisms in some cases.513,514
fibrinogenolysis. Thus, the coagulopathy is now considered tripartite.494 There is an association between translocations involving chro-
Although APL responded to chemotherapy regimens for AML, mosome 11, especially region 11q23, and monocytic leukemia.292–294
especially those containing an anthracycline antibiotic,495 the cyto- In particular, t(9;11) is found in leukemic monocytes.295,296,507,508 In
logic pattern of response in the marrow often was paradoxical.496–499 t(9;11) the β1-interferon gene is translocated to chromosome 11, and
Persistence of leukemic promyelocytes preceded remission in the the protooncogene ETS-1 is translocated to chromosome 9 adjacent to
absence of further therapy, whereas induction of marrow cell hypopla- the α-interferon gene. The latter juxtaposition may be important in the
sia was classically considered a requirement for remission in patients pathogenesis of monocytic leukemia.515
with AML. Generally, if leukemic blast cells persist after therapy for The expression of FOS is closely correlated with monocytic matu-
AML, relapse ensues unless hypoplasia is induced by more cytotoxic ration of cells in myelomonocytic and monocytic leukemia and in nor-
therapy. The unusual pattern of response in APL was put into context by mal monocytopoiesis.516,517 Absence or markedly decreased expression
reports of successful treatment with isomers of retinoic acid, an agent of the retinoblastoma gene growth-suppressor product (p105) is pres-
that leads to maturation of leukemic promyelocytes in vitro.499 In 1988, ent in approximately half of patients with monocytic leukemia. Patients
the success of ATRA in remission induction was reported500,501 and express a more dramatic phenotype.518 A variant of acute monocytic
confirmed.290,291 Relapse occurs invariably, however, so chemotherapy leukemia in which the leukemic cells have monocytoid features and
regimens or addition of arsenic trioxide also were required. Use of are positive for early and late monocytic lineage antigens and for TdT
ATRA has decreased the risk of early hemorrhagic complications and activity often occurs after prior radiotherapy or chemotherapy and is
death and has enhanced the long-term response to chemotherapy. relatively resistant to treatment.519 A syndrome of acute monoblastic
Despite the improvement in therapy, approximately 5 to 10 percent of leukemia with t(8;16), resulting in MOZ-CBP fusion gene, is charac-
patients die during remission induction, most of hemorrhage, often into terized by mildly granular promonocytes (simulating hypogranular
the brain. The prolonged remissions of patients with promyelocytic leu- promyelocytes), intense phagocytosis of red cells, erythroblasts, and
kemia has been interrupted in approximately 3 percent of cases by the sometimes neutrophils and platelets in blood and marrow, simulating
later appearance of oligoblastic myelogenous leukemia with deletions macrophagic hemophagocytic syndrome, intravascular coagulation or
of all or part of chromosome 5 or 7 and no evidence of involvement of primary fibrinolysis, and a high frequency of extramedullary disease.520
chromosome 17, compatible with a myelogenous leukemia secondary The management of monocytic leukemia is complicated by a
to cytotoxic chemotherapy.501–503 The responsiveness to arsenic trioxide greater incidence of CNS or meningeal disease either at the time of
has provided additional treatment approaches that are discussed in the diagnosis or as a form of relapse during remission. Thus, examina-
“Therapy” section below. tion of cerebrospinal fluid is often recommended, even in the absence
of symptoms, when remission has been achieved.208,507,508 Some thera-
pists recommend prophylactic intrathecal therapy with methotrexate
ACUTE MONOCYTIC LEUKEMIA or cytosine arabinoside for patients who enter remission after having
Monocytic leukemia was first reported by Reschad and Schilling- presented with hyperleukocytic acute monocytic leukemia because of
Torgau504 in 1913. Approximately 8 percent of patients with AML the risk of subclinical meningeal involvement. Others posit that high-
present with monocytic leukemia, which is referred to as M5 in the dose cytarabine with CNS penetration potential used in consolidation
FAB classification. Patients with monocytic leukemia have a higher chemotherapy suffices for this purpose. There are few data for guidance
prevalence (50 percent) of extramedullary tumors in the skin, gin- in this matter.
giva, eyes, larynx, lung, rectum and anal canal, bladder, lymph nodes, Rare cases of dendritic cell or Langerhans cell phenotype have been
meninges, CNS, and other sites than do other phenotypes (<5 percent). described (Chap. 71).521,522 Uncommon cases of histiocytic sarcoma are

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 1392 Part X: Malignant Myeloid Diseases

the tissue or extramedullary variant of monocytic leukemia (Chap. esterase or myeloperoxidase. The thrombopoietin receptor gene (MPL)
71).523,524 The outcome of treatment, once thought to be less favorable is expressed in megakaryocytes (CD116) and exhibits the gain-of-
than with other forms of AML, is comparable to the outcome of other function point mutation W515K/L in approximately 25 percent of cases
subtypes.525 of acute megakaryoblastic leukemia.533
The serum lactic acid dehydrogenase level frequently is strikingly
increased and has an isomorphic pattern unlike that seen with other
ACUTE MEGAKARYOBLASTIC acute leukemias. Complex chromosome aberrations are common.534
(MEGAKARYOCYTIC) LEUKEMIA An association of megakaryoblastic leukemia in infants with t(1;22)
(p13;q13) has been reported.534–537 Abnormalities of chromosome 3 have
In 1963, Szur and Lewis526 reported patients with pancytopenia, low been linked to clonal hemopathies expressing a prominent megakaryo-
percentages of blast cells, and intense myelofibrosis but an absence of cytic phenotype.538,539 Progression of primary myelofibrosis or essential
teardrop red cells, splenomegaly, leukocytosis, and thrombocytosis, the thrombocythemia to AML may have the phenotype of acute megakary-
usual features of primary myelofibrosis. They designated the syndrome ocytic leukemia. Paradoxically, in children with Down syndrome the
malignant myelosclerosis.526 Reports of similar cases ensued, with some disease can be treated with modified doses of chemotherapy, with a very
investigators referring to the syndrome as acute myelofibrosis.527 The high remission rate and long-term event-free survival.540–542 The result
development of methods to phenotype megakaryoblasts indicated the is thought to be related to the exquisite sensitivity of the leukemic cells
cases were variants of AML rather than of primary myelofibrosis and to drug-induced apoptosis,475 whereas the long-term remission rate as
have been designated acute megakaryocytic or acute megakaryoblastic a result of chemotherapy in children without Down syndrome or in
leukemia.391,528,529 This leukemia is referred to as M7 in the FAB classifi- adults are not as good.543,544
cation. The prevalence of this phenotype is approximately 5 percent of
all AML cases if appropriate cell markers are used in the diagnosis, and
is at least twice that frequency in childhood AML.530,531 The syndrome ACUTE EOSINOPHILIC LEUKEMIA
is an especially prevalent variant of AML that develops in patients with Acute eosinophilic leukemia is rare. Increased eosinophils in the mar-
Down syndrome398,532 or in patients with mediastinal germ cell tumors row but not in the blood is a variant of acute myelomonocytic leuke-
and coincident AML.425–429 mia and inversion 16 or other abnormalities of chromosome 16 but is
Leukemic megakaryoblasts and promegakaryocytes can be diffi- not considered an acute eosinophilic leukemia.303–306 First described in
cult to identify by light microscopy using polychrome staining. How- 1912,545 acute eosinophilic leukemia is a distinct entity that can arise
ever, with experience, heightened suspicion can be engendered by de novo as AML, with 50 to 80 percent of eosinophilic cells in the blood
blasts in the blood with abundant budding cytoplasm or blasts having and marrow.546–549 Anemia, thrombocytopenia, and blast cells in blood
a lymphoid appearance, especially if the marrow cannot be aspirated and marrow are present. There is apparent eosinophilic differentiation
because of intense myelofibrosis, the latter evident on the marrow in striking proportions. The eosinophilic cells are dysmorphic and
biopsy. Initially high-resolution histochemistry for platelet peroxidase the cytoplasm hypogranulated with smaller than normal eosinophilic
and identification of the demarcation membrane system using trans- granules. The granules stain less intensely and are less refractile with
mission electron microscopy were required for diagnosis. Now anti- polychrome stains. These findings are the result of the loss of the cen-
bodies to von Willebrand factor or to platelet glycoprotein Ib (CD42), tral crystalloid in the eosinophilic granules that can be identified with
IIb/IIIa (CD41), or IIIa (CD61) can be used to identify very primitive electron microscopic analysis. Biopsy of skin, marrow, or other sites
megakaryocytic cells.528,529 A small proportion of megakaryoblasts may of eosinophil accumulation often shows Charcot-Leyden crystals. A
be present in other cases of AML, but in megakaryocytic leukemia specific histochemical reaction, cyanide-resistant peroxidase, permits
they are the prominent or the dominant leukemic cells (see Fig. 88–2L identification of leukemic cells with eosinophilic differentiation and
through O). Moreover, the other key features of the syndrome usually diagnosis of acute eosinoblastic leukemia in some cases of AML with
are present, especially severe myelofibrosis.530 fewer identifiable eosinophils in blood or marrow.550 Eosinophilia, not
Patients usually present with pallor, weakness, excessive bleeding part of the malignant clone, may be a feature of occasional patients with
and anemia, and leukopenia. Lymphadenopathy or hepatosplenomeg- AML, an uncommon reactive phenomenon. In many cases, idiopathic
aly is uncommon at the time of diagnosis. High leukocyte and blood eosinophilia (hypereosinophilic syndrome) is a monoclonal disorder
blast cell counts may be present initially or may develop later. The plate- representing a spectrum of more indolent chronic or subacute eosin-
let count may be normal or elevated in many patients at the time of ophilic leukemia to more progressive acute leukemia (Chaps. 62 and
presentation. Abnormal platelets or megakaryocytic cytoplasmic frag- 89).551 Acute eosinophilic leukemia may develop in patients having the
ments may be found in the blood. Marrow aspiration often is unsuc- chronic form of a hypereosinophilic syndrome. Overexpression of WT
cessful (“dry tap”) because of extensive marrow fibrosis in most cases, gene expression has been proposed as a means of distinguishing acute
although not all. The marrow biopsy contains small blast cells, large eosinophilic leukemia from a polyclonal, reactive eosinophilia.552
blast cells, or a combination of both. The former have a high nuclear- Patients with acute eosinophilic leukemia do not usually develop
to-cytoplasmic ratio, have dense chromatin with distinct nucleoli, bronchospastic signs, neurologic signs, and heart failure from end-
and resemble lymphoblasts. Cases have been mistaken for ALL. The omyocardial fibrosis as is seen in chronic eosinophilic leukemia, prob-
larger blasts may have some features of maturing megakaryocytes with ably because those tissue changes are the result of release of toxins in
agranular cytoplasm with cytoplasmic protrusions, clusters of plate- the granule crystalloid, absent in most eosinophils in acute eosinophilic
let-like structures, or shedding of cytoplasmic blebs. The blast cells leukemia and because of the shorter duration of survival in acute eos-
are peroxidase negative and tend to aggregate. Confirmation of their inophilic leukemia. Hepatomegaly, splenomegaly, and lymphadenopa-
megakaryoblastic maturation requires immunocytologic studies for thy are more common than in other variants of AML. The treatment
the presence of von Willebrand factor and the immunoreactivity to approach is similar to other types of AML. A combination of cytarabine
CD41, CD42, or CD61. The more mature megakaryocytes, which often and an anthracycline antibiotic is an appropriate choice for treatment.
coexist in the marrow, stain with PAS reagent, contain sodium fluoride- Response to treatment is approximately the same as in other types of
inhibitable nonspecific esterase, and fail to react for α-naphthylbutyrate AML.550

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 Chapter 88: Acute Myelogenous Leukemia 1393

ACUTE BASOPHILIC AND MAST HISTIOCYTIC AND ACUTE MYELOID

CELL LEUKEMIA DENDRITIC CELL LEUKEMIA
First described in 1906,553 basophilic differentiation as a feature of Chapter 71 discusses histiocytic and myeloid dendritic cell leukemia.
AML is an uncommon event, occurring in approximately one in 100
cases of AML.549 Most cases of acute basophilic leukemia evolve from
the chronic phase of CML,554 but de novo acute basophilic leukemia, in DIFFERENTIAL DIAGNOSIS
which the cells do not contain the Ph chromosome, does occur.549,535–560 Acute leukemia in infants with Down syndrome should be differen-
The cells stain with toluidine blue, and the basophilic granules can be tiated from TMD (see “Neonatal Myeloproliferation and Leukemia”
most striking in myelocytes. In some cases of acute myelomonocytic above). In adults, the term pseudoleukemia has been applied to circum-
leukemia associated with t(6;9)(p23;q34), basophils may be increased stances that mimic the marrow appearance of promyelocytic leukemia.
in the marrow but not in the blood. Because CML with t(9;22)(q34;q11) Recovery from drug-induced or Pseudomonas aeruginosa–induced
has the same breakpoint (q34) on chromosome 9 as AML with t(6;9) and agranulocytosis is characterized by a striking cohort of promyelocytes
both diseases are strongly associated with marrow basophilia, a gene(s) in the marrow, which upon inspection of the marrow aspirate or biopsy
at the breakpoint on chromosome 9 may influence basophilopoiesis.448 mimics promyelocytic leukemia.568–570
Anemia, thrombocytopenia, and blast cells in the blood are present In pseudoleukemia, the platelet count may be normal; the degree
at the time of diagnosis. The blood leukocyte count usually is elevated, of leukopenia often is more profound (<1.0 × 109/L) than usually seen
and proportions of the cells are basophils. The marrow is cellular with in AML511,512; promyelocytes contain a prominent paranuclear clear
a high proportion of blasts and early and late basophilic myelocytes. (Golgi) zone not covered with granules; and promyelocytes do not have
Special staining with toluidine blue or Astra blue often is necessary to Auer rods.570–572 Similar reactions have been reported after granulocyte
distinguish basophilic from neutrophilic promyelocytes and myelo- colony-stimulating factor (G-CSF) administration.573 In patients sus-
cytes. Immunophenotyping may show myeloid markers (CD33, CD13) pected of having pseudoleukemia, observation for a few days usually
that are not specific. Presence of CD9, CD25, or both is characteristic clarifies the significance of the marrow appearance, because progressive
of basophilic differentiation. Cells may have granules with ultrastruc- maturation to segmented neutrophils normalizes the marrow and leads
tural features of basophils and mast cells.558 Electron microscopy can to an increased blood neutrophil count.
be useful in identifying basophilic granules in cases where no granules In patients with hypoplastic marrows, careful examination of
are evident by light microscopy and the phenotype simulates M0.558 specimens is required to distinguish among aplastic anemia, hypoplas-
Basophilic leukemia can be confused with promyelocytic leukemia if tic acute leukemia,350–352 and hypoplastic oligoblastic myelogenous
the basophilic early myelocytes are mistaken for promyelocytes.561 On leukemia (MDS).574 Leukemic blast cells are evident in the marrow
the contrary, promyelocytic leukemia may have basophilic maturation in hypoplastic leukemia, and islands of dysmorphic cells, especially
and can be mistaken for basophilic leukemia. However, if the cells con- megakaryocytes, are present in hypoplastic oligoblastic leukemia.
tain t(15;17), the disease should respond to ATRA and an anthracycline Leukemoid reactions and nonleukemic pancytopenias can be dis-
antibiotic.474,477,478 Prolonged clotting time, intravascular coagulation, tinguished from AML by the absence of leukemic blast cells in the blood
and hemorrhage are uncommon presenting features in patients with or marrow.575 In older children and adults, myeloblasts usually do not
basophilic leukemia, but are common in patients with promyelocytic constitute more than 2 percent of marrow cells except in patients with
leukemia. Coagulopathy can occur after chemotherapy. Cluster head- a myeloid neoplasm, and the proportion of blast cells usually decreases
aches, skin rashes, often with an urticarial component, and gastroin- in the marrow as a result of exaggerated expansion of the myelocyte
testinal symptoms may be present. Elevated blood and urine histamine compartment with neutrophilic leukemoid reactions.
and urinary methylhistamine levels are characteristic features. Rare
cases of a chronic course in BCR-ABL–negative basophilic leukemia
preceding the onset of rapid progression have occurred.562 Treatment THERAPY
for acute (Ph-negative) basophilic leukemia is similar to that for other
variants of AML. OVERVIEW OF TREATMENT PLAN
Mast cell leukemia is a rare manifestation of systemic mast cell The usual treatment of AML includes an initial program termed the
disease (Chap. 63).549,563 It can be related to a mutation of the KIT induction phase. Induction may involve the simultaneous use of mul-
gene.507 The leukemic mast cells are KIT (CD117) positive, naphthol tiple agents or a planned sequence of therapy called timed sequential
AS-d-chloracetate esterase positive, tryptase positive, myeloperoxidase treatment. Once a remission is obtained, further treatment is indicated
negative, and CD25-negative.564,565 Plasma tryptase is elevated. In some to preserve the remission state. Remission is defined as elimination of
cases, electron microscopy of the granule-containing cells, which dem- the leukemic cell population in marrow as judged by microscopy and
onstrates the characteristic scroll-like granules of mast cells, may aid in flow cytometry and the restitution of marrow hematopoiesis resulting
distinguishing basophils from mast cells (Chap. 63). Extensive, appar- in a normal or virtually normal white cell, hemoglobin, and platelet
ently reactive, mast cell tissue infiltrations may be provoked by cytok- concentrations in the blood. The postinduction treatment can consist
ines during the course of AML.566,567 of cytotoxic chemotherapy, HSC transplantation, or low-dose mainte-
The key laboratory distinctions between acute basophilic leukemia nance chemotherapy, depending upon patient performance status and
and acute mast cell leukemia are that the cells in the former are naphthol risk factors. If relapse occurs, treatment options may include differ-
AS-d-chloracetate esterase negative, CD11b positive, CD117 negative ent chemotherapy regimens, allogeneic HSC transplantation, or other
or weakly positive, CD123 positive, have no increase in cell or plasma investigational regimens, often as part of a clinical trial.
tryptase, and have basophilic-like granules on electron microscopy;
whereas, the cells in mast cell leukemia are naphthol AS-d-chloracetate DECISION TO TREAT
esterase positive, CD11b-negative, CD117-positive, CD123-negative,
have an increase in cell and plasma tryptase, and have mast cell-like Most patients with AML should be advised to undergo treatment
granules on electron microscopy.549 promptly after diagnosis. Patients younger than 60 years of age have a

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 1394 Part X: Malignant Myeloid Diseases

poorer outcome as the time from diagnosis to treatment lengthens.576 than approximately 20 × 109/L, as long as hydration is adequate and
Although remission rates are lower in older patients, a significant urine flow is high (>150 mL/h). The dermatitis may appear when anti-
proportion enter remission. Occasionally, very elderly patients refuse biotics are instituted. This concurrence may confound the decision to
treatment or are so ill from unrelated illnesses that treatment may be continue antibiotics. Thus, allopurinol should be discontinued after the
unreasonable. Age per se is not a contraindication to treatment, and risk of acute hyperuricosuria or tumor lysis has passed (usually 4 to
septuagenarians and octogenarians who are fit can enter remissions. 7 days). Recombinant urate oxidase (rasburicase) can be used to pre-
Treatment can be tailored to the decreased tolerance of older patients, vent urate-induced nephropathy. This preparation, although costly, can
some of whom have a smoldering course (see “Treatment of Older reduce plasma urate levels by approximately 80 percent within 4 hours
Patients” below). Associated problems, such as hemorrhagic manifesta- of the first drug dose. It is well tolerated, and the recommended dose
tions, severe anemia, or infections, should be treated in parallel. of rasburicase is 0.2 mg/kg daily for 5 to 7 days intravenously, although
shorter courses are usually effective.580
Attention to decreasing pathogen exposure by assiduous hand
PREPARATION OF THE PATIENT washing and meticulous care of catheter and intravenous sites is impor-
Orientation of the patient and the family should provide them with an tant, especially when the total neutrophil count is less than 0.5 × 109/L.
understanding of the disease, the treatment planned, and the adverse Care of the patient in a single room is advisable to provide privacy dur-
effects of treatment, as well as information about long-term prognosis to ing periods of intensive care and to help decrease the risk of exogenously
the extent this can be provided while awaiting cytogenetic and molecu- acquired infection until the neutrophil count recovers.
lar markers. Socioeconomic status and distance from the treatment cen-
ter have minimal effects on survival in AML,577 but impaired Karnofsky
performance status and instrumental activities of daily living score do REMISSION-INDUCTION THERAPY
impact outcomes.578 Principles
Pretreatment laboratory examination should include blood cell The cytotoxic therapy of AML rests on two tenets: (1) two competing
counts, cytochemistry analysis and immunophenotyping of leukemic populations of cells are present in marrow—a normal polyclonal and a
cells from blood or marrow, marrow examination including cytogenetic leukemic monoclonal population; and (2) profound suppression of the
and molecular analyses to include FLT3 ITD, NPM-1, CEBPα, and KIT leukemic cells to the point they are inapparent in the marrow aspirate and
mutation status in CBF leukemias, if available. If these are not available, biopsy is required to permit restoration of polyclonal hematopoiesis.581,582
they can performed later as required based on AML subtype from a Although these two principles hold in most cases, two deviations from
cryopreserved specimen. Blood chemistry studies, chest radiography, these guidelines are (1) the predisposition of patients with APL to
electrocardiogram, and determination of partial thromboplastin time, enter remission despite cellular posttherapy marrow583 and (2) the rare
prothrombin time, and fibrinogen level should be obtained. More presence of monoclonal hematopoiesis in some cases of AML during
extensive evaluation of coagulation factors should be made if (1) clot- remission (see “Results of Treatment” below). AML is a heterogeneous
ting times are abnormal, (2) bleeding is exaggerated for the level of the disease, and subgroups with different prognosis can be identified. In the
platelet count, or (3) APL or acute monocytic leukemia is the pheno- future, incorporation of knowledge about the biology of the particular
type. Early HLA typing is useful so that compatible platelet products AML subtype may be utilized for adapted therapies, but at present, all
can be provided if alloimmunization (Chap. 139) occurs and for patients subtypes of AML classified by cytogenetics or molecular changes with
who will become marrow transplantation candidates (Chap. 23). Herpes the exception of APL are approached similarly during induction, and
simplex virus and cytomegalovirus serotyping may be helpful, especially often induction therapy must be started before knowledge of cytoge-
if transplantation is a consideration. HIV and hepatitis serology is indi- netic and molecular factors is available.584
cated in patients with appropriate risk factors, and patients should have The goal of induction therapy in AML is achievement of complete
a baseline cardiac scan to determine ejection fraction prior to adminis- remission (<2 percent blasts in the marrow), a neutrophil count greater
tration of an anthracycline antibiotic. than 1000/μL, and a platelet count greater than 100,000/μL. An Inter-
A peripherally inserted central catheter or a tunneled central national Working Group for Diagnosis, Standardization of Response
venous catheter should be placed. This access to the circulation facil- Criteria, Treatment Outcomes, and Reporting Standards has redefined
itates administration of chemotherapy, blood components, antibiotics, outcomes in an effort to standardize reporting and comparison of data
and other intravenous fluids and medications. It also permits sampling (see “Course and Prognosis: Results of Treatment: Definition of Remis-
blood for analysis without patient discomfort or concern about venous sion” below).585 Other treatment guidelines have been published.586,587
access. Meticulous skin care at the catheter exit site is required to min- The majority of adults enter remission with standard induction therapy,
imize tunnel infections. Central venous catheters have become a major but for patients with high-risk disease, consideration can be given to an
source of infection during neutropenia, especially with Gram-positive experimental approach, and complete remission rates do not reach 100
organisms.579 In some patients with severe coagulopathy such as those percent, so clinical trial participation can be considered during induc-
with APL, a tunneled catheter may be best deferred to avoid significant tion chemotherapy. How durable a complete remission will be attained
bleeding or vessel activation during insertion. In those with neurologic in an individual patient often is difficult to predict at diagnosis. Gene-
symptoms, a head computed tomographic study or MRI followed by a expression profiling can separate some patients into prognostic groups
lumbar puncture should be obtained. Before procedures, adequate plate- that may indicate patients with a high risk of not responding to standard
let counts and control of coagulopathy should be achieved, if possible. approaches.105
Therapy for hyperuricemia is required if (1) the pretreatment
uric acid level is greater than 7 mg/dL (0.4 mmol/L), (2) the marrow is
packed with blast cells, or (3) the blood blast cell count is moderately Cytotoxic Regimens
or markedly elevated. Allopurinol 300 mg/day orally should be given. Anthracycline Antibiotic or Anthraquinone and Cytarabine Current
Allopurinol can cause allergic dermatitis and should not be used if the standard induction treatment for non-APL AML involves drug regi-
uric acid level is less than 7 mg/dL and the total white cell count is less mens with two or more agents that include an anthracycline antibiotic

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 Chapter 88: Acute Myelogenous Leukemia 1395

TABLE 886. Remission Induction for Acute Myelogenous Leukemia: Examples of Cytosine Arabinoside and Anthracycline
Antibiotic Combinations
Anthracycline Age Range in Complete Year of
Cytarabine Antibiotic ± Another Agent No. of Patients Years (Median) Remissions (%) Report Reference
100 mg/m2, days 1–7 DNR 50 mg/m2 days 1–5 407 15–64 (47) 77.5 2011 596
100 mg/m2, days 1–7 IDA 12 mg/m2 days 1–3 525 15–64 (47) 78.2 2011 596
100 mg/m2, days 1–7 DNR 45 mg/m2, days 1–3 330 17–60 (47) 57 2009 593
100 mg/m , days 1–7
2
DNR 90 mg/m , days 1–3
2
327 18–60 (48) 71 2009 593
200 mg/m2, days 1–7 DNR 60 mg/m2, days 1–3 200 16–60 (45) 72 2004 611
200 mg/m , days 1–7
2
DNR 60 mg/m , days 1–3
2
200 16–60 (45) 69 2004 611
Cladribine 5 mg/m2, days 1–5
200 mg/m2 twice per DNR 50 mg/m2, days 1, 3, 5 64 18–59 (46.5) 91 2003 609
day for 10 days (some Thioguanine 100 mg/m2
in this report received twice per day, days 10–20
FLAG-IDA vs. H-DAT)
Gemtuzumab ozogamicin
3 mg/m2, day 1
3 g/m2 every 12 h for 60 mg/m2 DNR daily for 122 Adults 80 2000 603
8 doses 2 days
100 mg/m2 daily for IDA 12 mg/m2 daily for 3 days 153 NR 63 2000 589
7 days (2 courses
always given)
500 mg/m2 by Mitoxantrone 12 mg/m2 for 133 15–70 (43) 60 1996 606
continuous infusion, 3 days
days 1–3, 8–10 Etoposide 200 mg/m2 days
8–10
100 mg/m2 daily for DNR 45 mg/m2 for 3 days 113 NR (55) 59 1992 588
7 days
100 mg/m2 daily for IDA 13 mg/m2 for 3 days 101 NR (56) 70 1992 588
7 days

DNR, daunorubicin; FLAG, fludarabine, cytarabine, and granulocyte colony-stimulating factor; H-DAT, hydroxydaunorubicin, cytarabine, and
thioguanine; IDA, idarubicin; NR, not reported.
All drugs are administered intravenously, except for thioguanine, which is administered orally. The reader is advised to consult the
original reports for details of induction, consolidation or continuation therapy, and ancillary therapy.

or an anthraquinone and cytarabine (see “Special Therapeutic Con- Choice of Anthracycline Development of drug resistance is
siderations: Acute Promyelocytic Leukemia” below for therapy of reduced with idarubicin relative to other anthracyclines. Idarubicin
APL).588–617 Remission rates in the studies cited range from approxi- does not induce P-glycoprotein expression, but daunorubicin, doxoru-
mately 55 to 90 percent in adult subjects, depending on the composi- bicin, and epirubicin do.590 Idarubicin 12 mg/m2 gives better complete
tion of the population treated (Table 88–6). The two most important remission rates in younger adults than does daunorubicin 45 mg/m2,
variables are the age of the patients and the proportion of patients with each given for 3 days. Amsacrine, aclarubicin, and mitoxantrone give
therapy-induced leukemia or an antecedent clonal myeloid disease. In improved results over standard-dose daunorubicin. In older adults,
the studies listed in Table 88–6, the median age of the patient popu- mitoxantrone may reduce cardiotoxicity, but this is controversial.591 In
lations was much younger (approximately 50 years) than the median two randomized studies, high-dose daunorubicin (90 mg/m2) for 3 days
age of the population of AML patients at large (approximately 70 resulted in superior complete remission rates as compared to 45 mg/
years); thus the results cannot be generalized (see “Treatment of Older m2 for 3 days when combined with cytarabine.592,593 When idarubicin
Patients” below). A combination of anthracycline and cytarabine has 12 mg/m2 was compared to daunorubicin 80 mg/m2 for 3 days in
been the standard induction therapy since 1973.11,12 A now classic stan- patients 50 to 70 years of age, the remission rate with idarubicin was
dard induction regimen is cytarabine 100 mg/m2 daily by continuous 83 percent compared to 40 percent with daunorubicin.594 Another anal-
infusion on days 1 through 7 and daunorubicin at 45 to 90 mg/m2 on ysis of idarubicin compared with high-dose daunorubicin in patients
days 1 through 3, the “7 plus 3” regimen. Dose or schedule modula- with AML showed idarubicin to result in a higher remission rate but not
tion of the anthracycline or cytarabine, addition of other agents such as overall survival.595 In contrast, a randomized study showed no differ-
etoposide, in various schedules of administration, represent attempts to ence in remission and long-term efficacy between idarubicin 12 mg/m2
improve upon results obtained with “7 plus 3” therapy. daily for 3 days as compared to daunorubicin, 50 mg/m2 daily for

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 1396 Part X: Malignant Myeloid Diseases

5 days.596 In light of these studies, many therapists, when using dauno- characteristics, did not show clinically relevant differences in outcome
rubicin, use the 90 mg/m2 dose for 3 days in younger patients, and this when compared to a standard cytarabine and anthracycline containing
is in keeping with the current National Comprehensive Cancer Net- arm.617 Thus, the standard practice guideline for AML, other than pro-
work (NCCN) guidelines.597 This benefit of higher dose applies only myelocytic leukemia, recommends standard-dose cytarabine plus an
to younger and favorable or intermediate-risk patients.593 Dexrazox- anthracycline antibiotic as treatment.587
ane may be given during induction to reduce the risk of cardiotoxicity Hematopoietic Cytokines to Enhance Chemotherapy G-CSF
in patients at higher than usual risk because of a history of coronary and granulocyte-monocyte colony-stimulating factor (GM-CSF), when
artery disease or congestive heart failure, but this is rarely used in used in untreated leukemia, can increase the percentage of leukemic
adults.598 Other regimens that incorporate fludarabine with cytarabine cells in the DNA synthetic phase, resulting in blast population expan-
can be used in those patients for which an anthracycline would not be sion during short-term administration. This process could render the
ideal. cells more sensitive to simultaneous chemotherapy, but clinical bene-
High-Dose versus Standard-Dose Cytarabine High-dose cyta- fit from growth-factor priming has not been observed618,619 despite an
rabine does not increase complete remission rates and increases toxicity increased ratio of intracellular cytosine arabinoside triphosphate to
compared to conventional doses, especially in older patients (for doses of deoxycytidine-5′-triphosphate and enhanced cytarabine incorporation
these regimens, see “Intensive Consolidation Therapy” below). Patients into the DNA of AML blasts.619 Remission rates or overall survival did
receiving high-dose cytarabine have more leukopenia, thrombocytope- not differ among adult patients who received cytarabine plus idarubicin
nia, gastrointestinal problems, and eye toxicity. Disease-free survival or cytarabine plus amsacrine with or without G-CSF given concurrently,
and overall survival may be better than that achieved with standard but relapse rates decreased in patients who received G-CSF.620 GM-CSF
therapy, leading some investigators to suggest use of high-dose therapy priming in a younger patient group treated with timed-sequential
for induction in patients younger than age 50 years, but this approach is therapy increased complete remission rates but did not impact overall
not a standard one, and these studies do not take into account the role survival.621 Thus, these growth factors are not generally considered use-
of high-dose cytarabine in postremission therapy.599 Some studies show ful as enhancers of chemotherapy. A study did, however, suggest that an
that marrow blast clearance is higher after an induction with high-dose improved event-free survival and overall survival was noted in patients
cytarabine and that there is an improvement in disease-free survival for treated with high-dose cytarabine during remission induction,622 and
patients 50 years of age or younger.600 When high-dose cytarabine was complete remissions have occurred in hypoplastic AML after G-CSF
compared to intermediate doses in induction therapy, no improvement treatment without chemotherapy.623
in outcome was noted, and higher incidences of grades 3 and 4 toxic Reinduction Therapy Patients who have persistent leukemia after
effects were noted.600 A trial in younger patients with multiple arms; the first course of induction chemotherapy generally are given the same
fludarabine, high-dose cytarabine, and G-CSF (FLAG regimen) with regimen a second time. The effect is usually assessed by marrow aspirate
idarubicin resulted in a higher remission rate than did standard dauno- and biopsy 7 to 10 days after completion of chemotherapy (the “14-day
rubicin plus cytarabine with or without etoposide. Relapse rates were marrow” examination). For those with hypocellular marrow and no evi-
also less with the high-dose cytarabine induction (38 vs. 55 percent).601 dence of residual leukemic blasts, recovery of normal counts is awaited,
A superior remission rate and survival was achieved in younger patients and for those with a hypocellular marrow and a small number of resid-
(<46 years) induced with a regimen containing high-dose cytarabine, ual blasts, additional therapy may be delayed until count recovery or
82 versus 76 percent rate of remission and a 52 versus 43 percent rate until another marrow assessment. For those with significant amounts
of overall survival. These differences were also seen in secondary AML of leukemic cells remaining, repeating the original induction therapy or
cases and in those with FLT3-ITD mutations.602 Also, complete remis- use of a high-dose cytarabine regimen can be considered. The patient’s
sion rates of greater than 60 percent have been noted with high-dose long-term outcome is worse if two courses of treatment are required,
cytarabine in patients with poor-risk cytogenetics.603,604 even if a complete remission is achieved. Approximately 40 percent of
Timed Sequential Therapy and Other Drugs Timed sequential patients with persistent AML after one course of induction therapy have
therapy, which uses agents in a scheduled sequence rather than con- a complete remission after a second course,624 and disease-free survival
currently, may prolong remission duration.605–607 Timed sequential che- at 5 years is approximately 10 percent. In some European centers, two
motherapy combining mitoxantrone intravenously (IV) on days 1 to 3, courses of induction chemotherapy are given routinely, but the impact
etoposide IV on days 8 to 10, and cytarabine IV on days 1 to 3 and on remission rates or overall survival is uncertain.625 The longer the time
8 to 10 resulted in a complete remission in 60 percent of patients, but to remission after the first induction therapy, the shorter the duration of
treatment-related death in 9 percent of patients. Median disease-free disease-free survival.626 High-risk cytogenetic abnormalities, antecedent
survival was 9 months.605 hematologic disorders, and other poor prognostic factors can be used
Adding ATRA,608 gemtuzumab ozogamicin,609 fludarabine,610 to assign nonresponders to an experimental chemotherapy regimen
cladribine or topotecan611,612 to induction regimens has not improved designed to treat refractory disease, rather than repeating induction
results significantly. A recent randomized study showed that the addi- therapy. In one study, overall response to reinduction was 53 percent.
tion of the purine analogue cladribine, but not fludarabine, to dauno- Those patients with poor risk cytogenetics and those with a marrow
rubicin and cytarabine improved the remission rate and prolonged blast percentage of 60 percent or greater following the 7-plus-3 regimen
survival in patients younger than 60 years of age.613 The addition of induction treatment were found to have a low probability of achieving
bortezomib to daunorubicin and cytarabine in those 60 to 75 years of a complete remission with reinduction.627 Mortality during induction
age resulted in a remission rate of 65 percent. This was a single-arm trial therapy correlates with age628 and, perhaps, leukocyte count.629
with dose escalation of bortezomib.614 There are preliminary reports
suggesting that the addition of gemtuzumab ozogamicin to standard
induction chemotherapy may increase disease-free survival in patients Special Considerations during Induction Therapy
with low- and standard-risk cytogenetic abnormalities,615 and inhibi- Hyperleukocytosis Patients with blast counts greater than 100 × 109/L
tors of FLT3 ITD are now being examined, but no data are available require prompt treatment to prevent the most serious complications of
regarding utility of this approach.616 A recent prospective comparison of hyperleukocytosis: intracranial hemorrhage or pulmonary insufficiency.
five different treatment strategies, adjusted for differences in prognostic Hydration should be administered promptly to maintain urine flow

Kaushansky_chapter 88_p1373-1436.indd 1396 9/21/15 11:01 AM

 Chapter 88: Acute Myelogenous Leukemia 1397

greater than 100 mL/h/m2. Cytoreduction therapy can be initiated with without coagulation abnormalities, anticoagulant use, sepsis, or other
hydroxyurea 1.5 to 2.5 g orally every 6 hours (total dose 6 to 10 g/day) complications usually can maintain hemostasis with platelet counts of
for approximately 36 hours. Appropriate remission-induction therapy 5 to 10 × 109/L. Initially, random donor platelets can be used, although
should be initiated as soon as possible after the leukocyte count has single-donor platelets or HLA-matched platelets may be preferable
been decreased significantly. Simultaneous leukapheresis can decrease products and should be tried if random-donor platelets do not raise the
blast cell concentration by approximately 30 percent within several platelet count significantly A no-prophylaxis platelet-transfusion strat-
hours331,630,631 without contributing to uric acid or cellular phosphate egy for blood cancers has been examined, but data support the need
release. Leukapheresis may improve acute disturbances resulting from for prophylactic platelet transfusions.645 Family members may be effec-
the vascular effects of blast cells, but the procedure may not alter the tive donors, if allogeneic HSC transplantation is not being considered
long-term outcome with current therapeutic programs.339,340,630 Inhaled (Chap. 139). There are data that fever should result in increasing the
nitric oxide may improve the hypoxemia related to hyperleukocytosis.631 platelet count used as a transfusion threshold, and there is some sugges-
Antibiotic Therapy Pancytopenia is worsened or induced shortly tion that higher hemoglobin values protect against bleeding related to
after treatment is instituted. Absolute neutrophil counts less than thrombocytopenia.646
100/μL (0.1 × 109/L) are expected and are a sign of effective drug action. All red cell and platelet products should be depleted of leukocytes,
The patient usually becomes febrile (>38°C), often with associated rig- and all products, including granulocytes for transfusions, should be
ors. Cultures of urine, blood, nasopharynx, and, if available, sputum irradiated to prevent transfusion-associated graft-versus-host disease
should be obtained. Because the inflammatory response is blunted by (GVHD) in this immunosuppressed population (Chaps. 138 and 139).
severe neutropenia and monocytopenia, evidence of exudates on phys- Granulocyte transfusion should not be used prophylactically for
ical examination or imaging studies may be minimal or absent. Anti- neutropenia but may be used in patients with high fever, rigors, and
biotics should be started immediately after cultures are obtained.632 bacteremia unresponsive to antibiotics, with blood fungal infections, or
Chapter 24 describes antibiotic usage in the setting of intensive chemo- with septic shock. G-CSF administration to a volunteer donor increases
therapy. Infections remain a major cause of therapy-associated morbid- neutrophil yield fourfold and results in posttransfusion blood neu-
ity and mortality.633,634 Gram-positive bacterial isolates now outnumber trophil increments for more than 24 hours after transfusion.647 There is
Gram-negative organisms.634 Cultures are often negative, but if fever still ambiguity about the usefulness of this approach. GM-CSF admin-
and other signs are present, antibiotic therapy should be continued until istration may be warranted for treatment of major fungal infections
neutrophil recovery. (Chap. 24).
Some centers use prophylactic antibacterial, antifungal, and/or Jehovah’s Witnesses and others who refuse blood product support
antiviral antibiotics, whereas other centers do not. Antifungal prophy- can survive tailored chemotherapy.648 In general, phlebotomy is mini-
laxis can consist of low-dose amphotericin or azoles such as fluconazole, mized, and antifibrinolytics, hematinics, and growth factors are used to
itraconazole, posaconazole, or voriconazole.635,636 In a randomized study support such patients during severe cytopenias.
in patients undergoing induction therapy, posaconazole was more Therapy for Hypofibrinogenemic Hemorrhage Patients with
effective in preventing invasive fungal infections than fluconazole or itra- evidence of intravascular coagulation (Chap. 129) or exaggerated pri-
conazole.637 Voriconazole was not included in the comparison. Acyclo- mary fibrinolysis (Chap. 135) should be considered for platelet and
vir, valacyclovir, or famciclovir prophylaxis during remission-induction fresh-frozen plasma administration before antileukemic therapy is
therapy of patients with AML does not affect the duration of fever or started. Infusion of cryoprecipitate can be used for fibrinogen levels
the need for antibiotics. The incidence of bacteremia is not reduced, under approximately 125 mg/dL. If the findings are equivocal, patients
but acute oral infections are less severe.638 Liposomal amphotericin, the should be monitored closely with measurements of fibrinogen levels,
caspofungins and azoles are available for treatment of established fungal fibrin(ogen) degradation products, D-dimer assay, and coagulation
infections.639 Some centers use outpatient supportive therapy, including times. Intravascular coagulation or primary fibrinolysis may occur in
oral antimicrobials, immediately after induction therapy administration patients with APL and acute monocytic leukemia, but also may occur in
in adult AML.640 occasional patients with other AML subtypes.
Hematopoietic Growth Factors to Treat Cytopenias Cytokine Management of Central Nervous System Disease CNS disease
therapy as an adjunctive treatment for AML remains controversial.641 occurs in approximately one in 50 cases at presentation.649 Prophylac-
GM-CSF and G-CSF accelerate neutrophil recovery; neither GM-CSF tic therapy usually is not indicated, but examination of the spinal fluid
nor G-CSF reproducibly decreases major morbidity or mortality. How- after remission should be considered in (1) monocytic subtypes,508
ever, one study has shown decreased mortality from fungal infections in (2) cases with extramedullary disease, (3) cases with inversion 16254
older patients.642 Use of cytokines during periods of cytopenia following and t(8;21)263,266 cytogenetics, (4) CD7- and CD56-positive (neural-cell
induction therapy is safe, and nearly all trials have shown a modestly adhesion molecule) immunophenotypes,650 and (5) patients who pres-
reduced duration of severe neutropenia with a variable effect on the ent with very high blood blast cell counts. In these situations, the risk of
incidence of severe infections, antibiotic usage, and duration of hospi- meningeal leukemia or a brain myeloid sarcoma is heightened, but pro-
tal stays. Although no increase in relapse has been noted when growth phylactic intrathecal chemotherapy is not recommended if high-dose
factors are started after completion of chemotherapy, no consistent cytarabine is used for consolidation. Patients who present with neuro-
enhancement of remission, event-free survival, or overall survival has logic symptoms should have a head computed tomogram or MRI to rule
been noted.643 Therefore, the cost-effectiveness and clinical effectiveness out hemorrhage or mass effect. If negative, a lumbar puncture should
of growth factor usage is doubtful. Also, growth factor usage can cloud be performed. Treatment of meningeal leukemia can include high-dose
marrow interpretation when used during induction. intravenous cytarabine (which penetrates the blood–brain barrier),
Component Transfusion Therapy Red cell transfusions should intrathecal methotrexate, intrathecal cytarabine, cranial radiation, or
be used to keep the hemoglobin level greater than 7.0 g/dL, or higher chemotherapy and radiation in combination.649 If CNS leukemia is pres-
in special cases (e.g., symptomatic coronary artery disease; Chap. 138). ent, intrathecal therapy is often given twice per week until blasts are
Platelet transfusions should be used for hemorrhagic manifestations cleared, and then once per week for 4 to 6 weeks. This therapy can be
related to thrombocytopenia and prophylactically if necessary to main- accomplished via the lumbar puncture route or through placement of
tain the platelet count between 5 × 109/L and 10 × 109/L.644 Patients an Ommaya reservoir. If there is a mass present, radiation or high-dose

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 1398 Part X: Malignant Myeloid Diseases

cytarabine with glucocorticoids can be considered.651 Systemic relapse chemotherapy have led to comparable overall survival rates. However,
commonly follows relapse in the meninges, and concurrent systemic leukemia-free survival was greater after allogeneic transplantation.658 In
treatment usually is indicated. Long-term success is unusual unless allo- the last decade, treatment-related mortality from transplantation has
geneic HSC transplantation is possible. Unless the patient has neuro- declined and matched unrelated donor transplantations are as effective
logic symptoms, lumbar puncture generally is deferred until blood blast as those from a matched sibling donor, so currently, transplantation
cells have cleared. No consensus exists on a trigger for platelet transfu- is recommended for all but good-prognosis patients (CBF leukemias
sion in adults with AML undergoing lumbar puncture, but a platelet or those with NPM1 mutation without a FLT3 mutation).659 A Markov
count less than 20 × 109/L has been proposed as such a trigger,652 but decision analysis has shown that patients treated with allogeneic HSC
many therapists use a higher platelet count (e.g., 50 × 109/L) as a safety transplantation have a longer life expectancy compared with those
threshold for lumbar puncture. treated with chemotherapy among patients with an intermediate- or
Management of Nonleukemic Myeloid Sarcoma Some patients unfavorable-risk prognosis.660 A prospective matched-pairs analysis has
present with myeloid (granulocytic) sarcomas without evidence of leu- also concluded that allogeneic HSC transplantation is the most effective
kemia in the blood or marrow (see “Myeloid [Granulocytic] Sarcoma” postremission therapy for AML, especially for those 45 to 59 years of
earlier). Myeloid sarcoma may be the presenting finding in approxi- age and/or with high-risk cytogenetics.661 When quality of life was mea-
mately 1 percent of patients with AML. Such patients should receive sured for patients in complete remission for 1 to 7 years, those treated
intensive AML induction therapy.262 Intensive therapy results in a lon- with chemotherapy had the highest quality of life, whereas those who
ger nonleukemic period than patients who have undergone surgical underwent allogeneic HSC transplantation had the lowest.662
resection or resection followed by local irradiation.250 Whether such The decision to utilize autologous or allogeneic HSC transplanta-
patients should undergo allogeneic HSC transplantation in first remis- tion or high-dose cytarabine alone for consolidation should be individ-
sion irrespective of other factors has not been determined.653,654 Median ualized, based on the patient’s age and other prognostic factors, such
relapse-free survival is approximately 12 months after AML-type as high-risk cytogenetic findings and antecedent hematologic disease.
chemotherapy.262 Patients with trisomy 8 have poorer survival rates.260 Patients with good-risk cytogenetics should receive up to four cycles
of high-dose cytarabine. Patients with poor-risk cytogenetics should
be considered for allogeneic HSC transplantation as soon as feasible. A
POSTREMISSION THERAPY meta-analysis has also shown that compared with nonallogeneic thera-
Cytotoxic Therapy pies, allogeneic HSC transplantation has superior relapse-free survival
General Considerations Postremission therapy is intended to pro- and overall survival for cases of AML classified intermediate and poor-
long remission duration and overall survival, but no consensus exists risk, but not for cases considered good-risk AML in first remission.663
regarding the best approach. Postremission chemotherapy that does not Intensive Consolidation Therapy For patients who do not
produce profound prolonged cytopenias, closely simulating intensive receive high-dose chemotherapy with autologous or allogeneic trans-
induction therapy, has produced on average only slight prolongation plantation in first remission, consolidation chemotherapy regimens
of remission or life. Regimens that fall between these intensities have containing high-dose cytarabine provide better results than inter-
been used, with equivocal results. Intensive consolidation therapy after mediate-dose cytarabine,664,665 but these regimens are not universally
remission results in a somewhat longer remission duration and, more accepted.666 Patients who are to have allogeneic HSC transplantation do
significantly, a subset of patients who have a remission of more than not require four cycles of high-dose cytarabine, and may not benefit
3 years. The issue of postremission therapy and its impact is compli- from even one, if a donor is readily available.667 RAS mutations are asso-
cated by the large proportion of patients with AML who are older than ciated with benefit from high-dose cytarabine therapy.668 Patients with
60 years of age and have limited tolerance for intensive therapy. In addi- CBF leukemias such as t(8;21) also have particularly favorable responses
tion, a very small pool of leukemic stem cells may sustain the process, to repetitive cycles of high-dose cytarabine. In patients who received
and elimination of these cells may require approaches other than inten- three or more cycles, a relapse rate of 19 percent was reported.669
sive chemotherapy, especially in adults. Other regimens, such as those containing gemtuzumab ozogamicin
Several randomized trials have studied whether AML patients and fludarabine, have been used in postremission therapy, but whether
in first remission should receive consolidation chemotherapy alone, they provide benefit over use of high-dose cytarabine has not been
autologous transplantation, or allogeneic HSC transplantation, with- studied.670 Long-term disease-free survival at 5 years generally is approx-
out reaching a consensus. Allogeneic transplantation was compared to imately 30 percent when two to four cytarabine-containing regimens are
autologous transplantation using unpurged marrow and two courses of administered.671,672 Adding mitoxantrone or amsacrine to high-doses
intensive chemotherapy in 623 patients who had a complete remission cytarabine has not improved treatment outcomes in consolidation,673
after induction chemotherapy.655 Disease-free survival was 53 percent and timed sequential chemotherapy used in consolidation did not
at 4 years for those receiving allogeneic transplantation, 48 percent for improve outcome as compared with high-dose cytarabine.674 Most cen-
those receiving autologous transplantation, and 30 percent for patients ters use four cycles of therapy. A cycle is 3 g/m2 twice daily on days 1,
receiving intensive chemotherapy. Overall survival after complete 3, and 5, providing six doses per cycle, with cycle durations dependent
remission was similar in all three groups because patients who relapsed on normal blood count recovery. The optimal number of cycles for this
after chemotherapy could be rescued with allogeneic HSC transplan- therapy is not known.675 High-dose cytarabine can be administered at a
tation. No significant difference in the 4-year disease-free survival dose of 3 g/m2 in a 1- to 3-hour intravenous infusion every 12 hours for
between allogeneic HSC transplantation (42 percent) and other types up to 6 days (12 doses), but this schedule is almost never used because of
of intensive postremission therapy (40 percent) has been found.656 In its toxicity. There is some evidence that two cycles of intermediate-dose
another study, only patients younger than 35 years of age with poor-risk cytarabine (1 g/m2 every 12 hours for 6 days) may be a viable alterna-
cytogenetics had improved disease-free survival if they had a sibling tive to the 3 g/m2 for six doses schedules.676 When 36 g/m2 total dosing
donor and underwent allogeneic transplantation (43.5 percent vs. 18.5 was compared with 12 g/m2 dosing in the first consolidation, there was
percent at 4 years).657 Thus, in several studies, the early mortality after no improvement in treatment outcomes.677 High-dose cytarabine fre-
allogeneic HSC transplantation and the chemotherapy-induced remis- quently causes conjunctivitis and photophobia, and glucocorticoid eye
sions in patients who relapse following autologous transplantation or drops are usually used every 6 hours until 24 hours after the last dose of

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 Chapter 88: Acute Myelogenous Leukemia 1399

the drug.678 Cerebellar function abnormalities also may occur, and these after high-dose cytarabine plus G-CSF or after G-CSF alone.697 There is
require cessation of drug administration. A 1-hour duration infusion of a plateau in the survival curve after autologous stem cell transplantation
high-dose or reduced-dose (e.g., 2 g/m2) cytarabine may decrease the at about 2.2 years,698 and there is evidence that autologous transplan-
likelihood of severe cerebellar toxicity.678 Older patients and patients tation improves disease-free survival but not overall survival.699 The
with renal insufficiency require dose attenuation (i.e., to 1 to 2 g/m2).679 total number of CD34+ cells infused influences early engraftment, but
durable engraftment is associated more closely with the CD34+/CD38–
Additional Maintenance Therapy subset of cells in the graft.700
Various forms of less-intensive maintenance chemotherapy have been
attempted after completion of intensive consolidation chemotherapy. Chemoradiotherapy Plus Allogeneic Hematopoietic Stem
Many of the regimens consist of monthly chemotherapy, for example, Cell Transplantation for Consolidation Therapy
low-dose 6-thioguanine or cytarabine. Although improved disease-free General Considerations Utilization of allogeneic HSC transplanta-
survival was noted in some studies, no improvement in overall survival tion for AML is increasing in Europe and the United States.701 No strict
has been demonstrated in most studies.680 Some groups are examining upper-age limit for transplantation exists,702 but many centers use age
the role of demethylating agents (e.g., 5-azacytidine or decitabine) as 60 or 65 years for transplantations following ablation of hematopoie-
maintenance therapy.681 sis and 70 to 75 years for transplantations not preceded by ablation of
Autologous Stem Cell Infusion after Myeloablative Chemo- hematopoiesis (nonmyeloablative or reduced-intensity transplants).
therapy or Chemoradiotherapy for Consolidation Removal and Decisions to proceed to allogeneic transplantation should be individual-
cryopreservation of postremission marrow or collection of mobilized ized, and feasibility depends on (1) the availability of a suitable donor, (2)
blood stem cells from patients with AML and reinfusion of these prod- the recipient’s age and health status, and (3) whether AML is in remission.
ucts following intensive chemotherapy and/or radiotherapy is a form of For full-intensity transplantations, the patient is prepared with a
postremission therapy (Chap. 23).682 This approach is loosely referred to regimen that includes total-body irradiation and/or high-dose chemo-
as autologous transplantation but does not cross transplantation barri- therapy, after which the donor stem cells are infused by vein. Patients
ers. Autologous marrow or blood stem cell rescue can be used in patients given allogeneic blood stem cells have more rapid hematopoietic recon-
with AML who achieve a remission, do not have a compatible stem cell stitution than patients given marrow stem cells, but they may have
donor, and are as old as 70 years. With the availability of high-reso- more chronic GVHD and comparable risk of relapse.703,704 Chapter
lution HLA-matched unrelated donors, cord blood and haploidentical 23 describes the indications, procedure, and preparative regimens for
donors, the number of autologous stem cell transplants used in AML allogeneic stem cell transplantation. In general, no single preparative
has diminished. regimen is superior for patients with AML in first remission.705 In one
Various treatment regimens for autologous transplantation in study, cyclophosphamide and total-body irradiation lowered relapse
AML have been used,683 such as busulfan-cyclophosphamide, busulfan- risk, but overall results were comparable to conditioning with chemo-
etoposide-cytarabine, high-dose cytarabine-mitoxantrone plus total- therapy alone.706 Another retrospective study showed outcomes with
body irradiation, melphalan plus total-body irradiation, and cyclo- intravenous busulfan and cyclophosphamide were not different from
phosphamide plus total-body irradiation. A disease-free survival rate of those with cyclophosphamide and total-body irradiation in AML in
approximately 40 percent at 3 years is average after such regimens in remisison.707 A retrospective registry analysis showed that leukemia-free
the age-range treated.684,685 Long-term disease-free survival can occur and overall survivals were better with busulfan and cyclophosphamide,
in patients who undergo this treatment for AML in second remission.686 as compared with total body irradiation in AML in first remission.708
Patients older than age 50 years have inferior outcomes, but no strict Postremission consolidation with cytarabine before allogeneic trans-
upper-age limit for this procedure has been determined.687 Adminis- plantation for AML in first remission does not improve outcome com-
tration of two or more courses of consolidation chemotherapy prior to pared with immediate transplant after successful induction.709 It is
harvest and transplant is associated with decreased relapse rates and unclear that this result will also hold in the setting of reduced-intensity
improved disease-free survival. A marrow nucleated cell dose greater transplants or for transplants performed beyond first remission.710
than 2 × 108/kg improves disease-free survival.688 Chemotherapy agents Related Donors When matched-sibling transplantation is per-
such as 4-hydroperoxycyclophosphamide have been used for purging formed for AML in first remission, approximately half of patients have a
residual leukemic cells in marrow before infusion,689,690 and antisense disease-free survival of 4 years. Small series using T-cell depletion have
agents reportedly diminish leukemic cell contamination.691 Use of reported 4-year disease-free survival of 65 percent.711 Leukemia relapses
marrow grafts purged of residual leukemia cells has not significantly occur in approximately 20 percent of patients who receive an allogeneic
improved the results obtained with unpurged marrow in many stud- transplant. Patients who are alive with good performance status 3 years
ies, suggesting that low proportions of leukemic stem cells may not after transplantation have excellent prospects of long-term survival.711
transplant easily or that they do not survive the freeze–thaw cycle to In the posttransplantation period, approximately one-third of patients
which autologous marrow is subjected as well as do normal HSCs.692 die of severe GVHD, opportunistic infection, or interstitial pneumoni-
In addition, residual leukemia in the patient may contribute to relapse. tis. The outlook for long-term survival is improved if (1) the AML is in
For these reasons, marrow purging is rarely used in AML autograft- remission prior to transplantation, (2) grades III to IV acute GVHD
ing (Chap. 23). In long-term cultures from patients newly diagnosed does not occur, and (3) chronic GVHD is low grade.712,713 For patients
with AML, normal progenitors can be detected, and their numbers with unfavorable cytogenetics, an allogeneic sibling transplantation
are increased by in vitro culture with cytokines.693 In oligoblastic mye- in first remission is often recommended.714 Patients with FLT3/ITD-
logenous leukemia (high-risk myelodysplasia), secondary AML, and positive AML may also benefit from allogeneic HSC transplantation in
therapy-related AML, leukapheresis products obtained after chemo- first remission.715,716 When AML patients in first remission were com-
therapy and growth factor treatment contain normal progenitors,694 pared on a donor versus no donor basis, and more than 80 percent of
indicating mobilized stem cells may be relatively free of leukemic coun- patients with a donor went on to transplantation, patients with a donor
terparts even in the absence of ex vivo purging.695 Early mortality may had a significantly better disease-free survival, although treatment-
be decreased using blood stem cells because they engraft more rapidly, related mortality was higher.717 For patients with intermediate-risk cyto-
but relapse rates may be higher.696 Mobilized stem cells can be collected genetics, where the decision is made to delay transplantation until first

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 1400 Part X: Malignant Myeloid Diseases

relapse and second remission, physicians should identify a source of a donors in AML gave similar rates of leukemia-free survival.740 In a
HSC graft and ensure that careful monitoring of the patient occurs so multivariate analysis, active disease at transplant and development
that transplantation can be instituted as quickly as possible.718 of grades II to IV GVHD after transplantation had a negative impact
In an attempt to decrease the relapse rate after stem cell transplan- on survival in reduced-dose-intensity transplantations.741 Reduced-
tation for advanced acute leukemia,202 I-labeled anti-CD45 antibody to intensity transplantations are feasible in elderly patients with both flu-
deliver radiation to leukemic cells, followed by a standard transplant darabine and low-dose total-body irradiation742and with fludarabine
preparative regimen, has been used. With this regimen, more radiation and IV busulfan743 but donor availability and coexisting medical prob-
can be delivered to hematopoietic tissues compared with liver, lung, or lems often limit its use.744
kidney, which may improve the efficacy of the transplant.719 Use of Transplantation in Relapsed Patients Some form of
Unrelated Donors Approximately 70 percent of all patients with allograft usually is recommended for patients in early first relapse or
AML are older than 50 years of age, and the current mean family size second remission, because long-term survival with chemotherapy alone
in the United States is slightly more than two children per family. Thus, is improbable, whereas histocompatible sibling transplants in these sit-
only approximately 10 to 15 percent of subjects with AML are within uations have a 25 percent survival rate. For patients who lack a sibling
the age-range and have a sibling donor for marrow transplantation. The donor, matched-unrelated donor transplantations can be effective, but
ability to extend the proportion of patients who can be transplanted treatment-related mortality is high, suggesting that patients with unfa-
has led to histocompatible, unrelated donors or HLA type-mismatched vorable cytogenetics should undergo a matched-unrelated donor trans-
sibling or parent (haploidentical) donor transplants.720 More than plantation in first complete remission, if an acceptable donor can be
70 percent of patients of European descent can find a suitable unrelated found.745 However, when transplantation was compared to chemother-
-matched donor in the available donor registries,721 and another study apy for AML in second remission, the 3-year probability of event-free
showed that the majority of patients with AML in first remission for survival was 17 percent with chemotherapy and 16 percent with trans-
whom transplantation is recommended are able to undergo the proce- plantation. Patients younger than 30 years of age who were in remis-
dure; the main barriers to transplantation are relapse of disease while sion for at least 1 year fared best.746 Development of chronic GVHD,
awaiting a donor and poor performance status.722 Molecular matching an unrelated donor, a young age of donor, and blast cell count less than
of classes I and II HLA alleles adds to the clinical success of unrelated 30 percent at transplantation were found in another series to be favor-
donor transplantations, but makes finding a donor more difficult.723 able predictors of survival for transplantations performed in leukemia
Using such typing, studies have demonstrated that use of matched- relapse.747 Another study found that those with a remission duration
unrelated donors as compared with matched-related donors result in of less than 6 months, circulating blasts, donor other than an HLA-
similar survival times in AML.724 Transplantation benefits younger matched sibling, poor-performance status, and poor-risk cytogenetics
adults in first remission, but no difference in outcome between matched- were adverse pretransplantation variables for those in relapse or pri-
related donors and matched unrelated donors.725 HLA-matched or HLA- mary induction failure.748 Patients with extramedullary sites of leukemia
mismatched cord blood stem cells can be used in adults with acute leu- are more likely to relapse after allogeneic transplantation.749
kemia but generally not for patients in first remission.726,727 In adults, the Patients with AML who relapse after allogeneic stem cell trans-
numbers of stem cells available in a single cord product may not result plantation can have a long-term remission, if they undergo retransplan-
in engraftment, which has led to the use of two-cord blood units for tation.750 A second stem cell transplantation can induce 2-year overall
grafting (Chap. 23).728 survival in approximately 25 percent of patients and is effective after
Reduced-Intensity and Nonmyeloablative Transplantation either related or unrelated donor transplantations. A clear advantage
Patients who, based upon comorbidities or performance status, are of changing the donor for the second transplantation has not been
deemed too old or too ill to undergo a full-intensity (myeloablative) demonstrated.751
allogeneic stem cell transplantation may be offered a reduced- The mechanism of benefit of allogeneic stem cell transplantation
intensity transplantation procedure or a nonmyeloablative condition- was thought to result from high-dose ablative chemoradiotherapy fol-
ing regimen, provided a suitable donor is available. Reduced-intensity lowed by marrow “rescue.” The increased relapse rate of AML in patients
transplant results in some degree of myeloablation but in non-ablative transplanted with marrow from identical twins, compared to noniden-
transplants, autologous stem cell recovery would occur in the case of tical siblings, or transplanted with T-lymphocyte–depleted marrow
graft failure.729,730 This type of transplantation for AML and closely has indicated that an immunologic effect of donor lymphocytes may
related hematologic malignancies relies upon the graft-versus-leukemia determine the results of transplantation. This immunologic response,
effect as primary therapy.731–733 These regimens have moderate hema- referred to as graft-versus-leukemia effect, may play a role in preventing
tologic and nonhematologic toxicity, and often can be performed on leukemia relapses.752
an outpatient basis. Engraftment and establishment of complete donor Donor Leukocyte Infusion In an attempt to enhance graft-
chimerism are successful in most patients. GVHD rates have been versus-leukemia effects, adoptive immunotherapy with donor mononu-
variable, and the ultimate risk of acute and chronic GVHD with these clear cell infusions is sometimes used to treat relapse of leukemia after
regimens is unclear. A variety of low-intensity regimens have been allografting.753,754 These infusions have been successful in only a minor-
proposed.734 In AML in first remission, the 1-year progression-free sur- ity of patients with AML, but given the high mortality associated with
vival is approximately 55 percent.735,736 The role of this approach in the alternative procedures such as a second transplantation, the infusions
treatment of AML remains to be defined, and comparative trials with are a reasonable approach for patients who relapse after allogeneic trans-
longer followup are needed. Nonmyeloablative conditioning with unre- plantation.755 GVHD and marrow aplasia are the major complications of
lated donors has been used successfully.737,738 Although randomized this form of treatment.756 The graft-versus-leukemia reaction is thought
trials of ablative versus reduced dose-intensity conditioning regimens to be directed against minor histocompatibility antigens on the cell sur-
for transplantation of AML patients in first remission have not been face of hematopoietic cells, but reactions against leukemia-specific anti-
done, there is evidence that reduced dose intensity is an inferior option gens are possible. Relapses after donor leukocyte infusions for recurring
for disease control, but that disadvantage is offset by the decreased acute leukemia have a higher probability of being extramedullary.757
treatment-related mortality.739 One study found that reduced-intensity con- Donor lymphocyte infusions are most effective in early relapses and in
ditioning compared with myeloablative conditioning using unrelated the absence of extensive of chronic GVHD.758 Some patients also enter a

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 Chapter 88: Acute Myelogenous Leukemia 1401

new remission upon withdrawal of immune suppression. Patients who patients who relapse more than 1 year after the first remission, the orig-
enter remission by donor lymphocyte infusion or cessation of immu- inal remission-induction regimen can be readministered or a combi-
nosuppressive agents have a better survival than those who entered nation salvage chemotherapy regimen can be administered. At relapse,
remission with chemotherapy alone or after a second transplantation.759 cell lineage trees suggest that the leukemic cell sustaining the relapse
Unrelated donor-leukocyte infusions can be used to treat relapsed leu- resembles the leukemic stem cell of origin.770 When primary tumor
kemia after unrelated donor stem cell transplantation.760 Approximately and relapse genomes are compared, two primary patterns of relapse are
40 percent of AML patients enter remission with this treatment. G-CSF discerned: gain of mutations in a founding clone that evolved into the
has been used as an alternative to donor leukocyte infusions after AML relapse clone or a subclone of the founding clone that survived induc-
relapse posttransplantation.761 Donor blood stem cells can be combined tion, gained mutations, and gained ascendancy to become the dominant
with chemotherapy for early relapse of AML after allogeneic stem cell clone at relapse.771
transplantation.762 Strategies with donor leukocyte infusions are antici- Refractory leukemia is defined as leukemia that does not respond
pated to become more effective once the effector cells are identified and to initial induction chemotherapy with cytarabine and an anthracy-
the tumor target antigens better understood.763 cline antibiotic or anthraquinone. Patients with refractory disease are
Other Modalities to Decrease or Treat Relapse after more likely to have disease with adverse cytogenetic findings, a history
Transplant. Killer-cell immunoglobulin-like receptor (KIR) genes of antecedent clonal myeloid disease, adverse immunophenotypic fea-
among HLA-matched potential donors can point to donors with donor tures, and expression of MDR.772
KIR genotype that are associated with enhanced disease-free survival.764 Relapsed leukemia is leukemia that recurs following a remission.
Early cytomegalovirus replication after transplantation is also associ- The duration of remission greatly affects the patient’s prognosis and
ated with decreased relapse risk, possibly because of a virus-versus- response to additional treatment. The wide range of response rates
leukemia effect in AML.765 Hypomethylating agents have been used for may not only reflect the regimen used but may also reflect variability in
the treatment of relapse after allogeneic transplantation with some suc- patient selection, age, and other prognostic factors.772,773
cess and with induction of T-regulatory cells.766,767 Extramedullary sites Chemotherapy regimens can be divided into cytarabine-based,
of relapse are more common after transplant.767 noncytarabine-based, and timed sequential therapy with growth factors
Recurrent Leukemia in Donor Cells or New Leukemia in Recip- and cytotoxic drugs. Table 88–6 lists regimens and their response rates;
ient Cells Recurrence of AML in donor cells has been reported in the duration of response usually is measured in months, and, therefore,
patients who received transplants from healthy siblings. These recur- clinical trials are also recommended for this patient group. The duration
rences in donor cells occurred in approximately one in 18 relapsed of response is difficult to define because many patients go on to other
patients who received marrow from a donor of the opposite sex.768 A therapies, including allogeneic stem cell transplantation.
similar frequency of relapsed AML is observed in recipient cells but In a large patient cohort treated on successive Medical Research
with a different clonal cytogenetic abnormality, suggesting a “new” Council trials, of those patients who relapsed after first remission,
leukemia.768 The frequencies are dependent on the sensitivity and spec- 55 percent entered a second remission. For those with favorable cyto-
ificity of cytogenetic techniques, which have been challenged. AML genetics, 5-year survival was 32 percent; for those with intermediate
developing in a stem cell recipient but of donor cell origin long after cytogenetics, 5-year survival was 17 percent; and for those with adverse
transplantation has been documented in rare cases.768,769 cytogenetic patterns, 5-year survival was 7 percent. In those in a sec-
Summary of Postremission Therapy In younger patients with ond remission who underwent transplant, 42 as compared to 16 per-
favorable cytogenetics (CBF with no mutation of KIT) or with NPM1 cent survived 5 years.774 Results from therapy were better in younger
or double CEBPα mutations in the absence of a FLT3 mutation, there patients, and in those with longer first remissions, longer durations
is no advantage to do an allograft in first remission and four cycles of since last chemotherapy, and better general health. The probability of
high-dose cytarabine is appropriate treatment. Another option would a second remission is approximately 40 percent in younger (ages 15 to
be two cycles of high-dose cytarabine followed by autografting, an 60 years) and approximately 25 percent in older (ages 60 to 80 years)
approach often favored in Europe. In those with intermediate-risk cyto- patients, but the duration of remission is nearly always much shorter
genetics, an allograft should be considered as consolidation, and three than the first remission. An eventual fatal outcome is nearly certain
to four cycles of high-dose cytarabine could be offered if a transplant unless allogeneic HSC transplantation can be performed. Rare patients
donor cannot be found. Those with poor-risk cytogenetics or a FLT3- may have a third (or more) relapse followed by a remission when treated
ITD mutation should be considered for an allograft in first complete with cytotoxic drugs, but each remission is shorter than the preceding
remission. These recommendations may change as transplant mortality one and usually is measured in weeks. For those who have favorable or
improves and subclasses of the “normal” cytogenetics group are better normal karyotype, long second remission, and no previous stem cell
defined such that targeted agents might have an impact on relapse rates. transplantation, intensive chemotherapy can be useful.775 In one study,
After patients complete consolidation therapy, they are generally fol- 21 (approximately 17 percent) of 124 patients had a second remission
lowed with blood counts every 3 months for 2 years, and then every 3 to duration at least 2 months longer than the first remission.776 In patients
6 months for 5 years. Marrow examination is done to confirm continued in relapse treated with the sequential high-dose cytosine arabinoside
remission after consolidation is completed but is rarely pursued regu- and mitoxantrone (S-HAM) regimen, the duration of the first remis-
larly thereafter unless blood counts change. sion was the only factor associated with a successful outcome, and
unfavorable karyotype was the only factor related to duration of sur-
vival.777 Patients who relapse less than 1 year from remission should be
TREATMENT OF RELAPSED OR treated with investigational agents, whereas patients who relapse more
than 1 year later may benefit from standard reinduction therapy.778 No
REFRACTORY PATIENTS standard chemotherapy regimen provides a durable remission of AML
Chemotherapy patients who relapse (Table 88–7),779–789 and all such patients should be
Patients who relapse after remission-induction and postinduction ther- considered for clinical trials if available. For patients not fit for intensive
apy have a decreased probability of entering a subsequent remission, salvage regimens, low-dose cytarabine, hypomethylating agents, or sup-
and the duration of any remission that occurs is usually shorter. In portive or palliative care can be offered.

Kaushansky_chapter 88_p1373-1436.indd 1401 9/21/15 11:02 AM

 1402 Part X: Malignant Myeloid Diseases

TABLE 887. Examples of Chemotherapy Regimens Used for Relapsed or Refractory Patients
Percent of Patients Entering a
Complete Remission (Median
Regimen No. of Patients Duration) Year Reference
Clofarabine 40 mg/m2, IV, days 1–5 163 35.2 (6.6 months) 2012 789
Cytarabine 1 g/m2, IV, days 1-5 163 17.8 (6.3 months) 2012 789
Clofarabine 25 mg/m , IV, daily for 5 days
2
50 46 (9 months) 2011 787
Cytarabine 2 g/m2, IV, daily for 5 days
G-CSF 5 mcg/kg per day subcutaneously daily until ANC
≥2,000/μL
Gemtuzumab ozogamicin 6 mg/m2, IV, days 1 and 13 15 21 (27 weeks) 2003 780
Idarubicin 12 mg/m2, IV, days 2–4
Cytarabine 1.5 g/m2, IV, days 2–5
Mitoxantrone 12 mg/m2, IV, days 1–3 66 36 (5 months) 2003 781
Cytarabine 500 mg/m2, IV, days 1–3
Followed (at blood count recovery) by:
Etoposide 200 mg/m2, IV, days 1–3
Cytarabine 500 mg/m2, IV, days 1–3
Cladribine 5 mg/m2, IV, days 1–5 58 50 (29% disease-free at 1 year) 2003 782
Cytarabine 2 g/m2, IV, days 1–5, 2 h after cladribine
G-CSF 10 mcg/kg subcutaneously, each day, days 1–5
Fludarabine 30 mg/m2, IV, days 1–5 46 52 (13 months) 2003 783
Cytarabine 2 g/m2, IV, days 1–5
Idarubicin 10/m2, IV, days 1–3
G-CSF 5 mcg/kg subcutaneously each day, up to 6 doses
until neutrophil recovery
Gemtuzumab ozogamicin 9 mg/m2, IV, days 1 and 15 43 9 2002 784
Mitoxantrone 4 mg/m2, IV, days 1–3 37 32 1999 785
Etoposide 40 mg/m2, IV, days 1–3
Cytarabine 1 g/m2, IV, days 1–3, ± valspodar (PSC-833)
Fludarabine 30 mg/m2, IV, days 1–5 85 66 1995 786
Cytarabine 2 g/m2, IV, days 1–5±
Idarubicin 12 mg/m2, IV, days 1–3
G-CSF 400 mcg/m2, subcutaneously, daily until complete
remission

ANC, absolute neutrophil count; G-CSF, granulocyte-colony-stimulating factor.

NOTE: The
reader is advised to consult the original reference for details of chemotherapy regimen administration.

Allogeneic Hematopoietic Stem Cell Transplantation or second transplants do not result in consistent durable remissions.794
Allogeneic stem cell transplantation may be the only means to induce For patients who relapse after reduced-intensity allogeneic trans-
a sustained remission in patients with AML who do not enter remis- plantations, median overall survival after relapse was found to be
sion with cytotoxic drug therapy or who relapse after a first remis- 6 months, and no advantage was found for donor leukocyte infusions
sion. Approximately 25 percent of patients with refractory or relapsed or second transplantations as compared with chemotherapy.795 Patients
AML have a sustained remission of at least 3 years.790 Transplant- who relapse after autologous stem cell transplantation can sometimes
related mortality at 3 years is approximately 50 percent. Relapse rates be salvaged with reduced-intensity allogeneic transplantation or with
are higher after sibling than matched-unrelated transplantation.791,792 If full-intensity allogeneic transplantations with high treatment-related
a histocompatible donor is available and the patient is younger than age mortality rates even in younger patients.
50 years, allogeneic stem cell transplantation can be as successful, if it is
performed when the patient is in early relapse compared with in second
remission, but this is often done in the context of a clinical trial.793 OTHER TREATMENT MODALITIES
Relapse after Stem Cell Transplantation For patients who Chemotherapy
relapse after allogeneic stem cell transplantation, the prognosis is Several newer chemotherapeutic agents are being examined for treat-
extremely poor and available chemotherapy, donor leukocyte infusions, ment of AML. For example, liposomal preparations of fixed ratios of

Kaushansky_chapter 88_p1373-1436.indd 1402 9/21/15 11:02 AM

 Chapter 88: Acute Myelogenous Leukemia 1403

daunorubicin and cytarabine have entered trials.796 This has shown of patients with AML. Several small-molecule FLT3 tyrosine kinase
some responses in older adults with secondary leukemia. inhibitors have been formulated, but none have yet received regula-
tory approval.826–831 Myeloblast differentiation may occur, including a
Epigenetic Modulation syndrome with neutrophilic dermatosis wherein the neutrophils are
Methylation of DNA at critical sites can cause transcriptional inactiva- FLT3-positive.832 FLT3-mutant allelic burden may predict response
tion of genes or chromosomal instability. In AML, aberrant methyla- to such inhibitors.833 These agents are in phase I and phase II trials,
tion, especially preferential methylation of chromosome 11, has been in which they have induced a decline in blood blast cells, but rarely
described.797 Epigenetic gene silencing caused by DNA methylation is result in complete remissions.834,835 Newer-generation FLT3 inhib-
a target for presumptive demethylating agents such as 5-azacytidine or itors have been developed in an attempt to improve their effects.836
decitabine, and silencing mediated by histone deacetylation is a target Crenolanib may inhibit both ITD and TKD mutations.837 Quizartinib
for histone deacetylases.798 Decitabine, a potent agent, can cause mat- (previously AC220) showed activity in a phase I study in relapsed/refrac-
uration and growth arrest of AML cells.799–801 5-Azacytidine also has tory AML, especially in patients with FLT3-ITD mutations.838 Trials are
activity in AML, and it is being studied in an oral formulation.802 These now under way to examine inhibitors such as midostaurin (PKC412)839
agents, singly or in combination, have resulted in response rates of 25 to and sorafenib840 in combination with cytostatic drugs for AML.
60 percent.803 Methylome analysis may be useful as a pharmacodynamic Kit Tyrosine Kinase Inhibitors: Imatinib Mesylate Activation of
end point in those treated with decitabine,804 and higher levels of miR- the KIT tyrosine kinase by somatic mutation has been documented in a
29b are associated with responses to decitabine.805 Histone deacetylase small minority of AML cases. Paracrine or autocrine activation of KIT
inhibitors can restore retinoic acid-dependent transcriptional activation may occur in AML cells.841 Imatinib mesylate has induced a complete
and maturation in AML blasts.806 Depsipeptide can promote histone remission in refractory secondary AML,842 but this is a very uncommon
acetylation and gene transcription in RUNX1/ETO-positive leukemic result of its use.843 Dasatinib has been studied in CBF leukemias with
cells.807 Depsipeptide (romidepsin),808 LBH589,809 vorinostat (suberoy- a KIT mutation in conjunction with chemotherapy, but final results of
lanilide hydroxamic acid [SAHA]),810 and MGCD0103811 have each studies are awaited.844
been studied in early phase trials in leukemia. Combination therapy of Nuclear Factor-Kappa B Inhibitors AML leukemia stem cells
these agents with other targeted therapies is being explored,812 and com- have activated NF-κB, unlike normal HSCs.845 Proteasome inhibitors
bination therapy with hypomethylating agents and histone deacetylase such as bortezomib inhibit NF-κB and have been examined in AML.
inhibitors has been reported.813 They have been found to increase sensitivity to chemotherapy agents in
NPM1-mutated AML.846 Bortezomib is also being combined with che-
Inhibitors of DOT1L, Isocitric Dehydrogenase, and MDM2
motherapy agents in AML patients.847 Other inhibitors more specific to
The histone methyltransferase DOT1L is necessary for sustaining
the NF-κB family have been proposed for study in AML.848
MLL-rearranged, AML. EPZ-5676, an aminonucleoside inhibitor of
Other Signal Transduction and Tyrosine Kinase Inhibitors
DOT1L histone methyltransferase activity is under clinical investiga-
Numerous inhibitors of activated tyrosine kinases have been examined
tion in MLL-rearranged leukemias.814 Other DOLT1L inhibitors are
for AML therapy.849,850 These include mammalian target of rapamycin
being explored in IDH1/2 mutated AML.815 AGI-6780 has been iden-
(mTOR) inhibitors,851,852 phosphoinositol 3′-kinase inhibitors,853,854 AKT
tified as an IDH2 R140Q inhibitor with potential for differentiation.816
inhibitors, such as perifosine,855 small-molecule mitogen-activated
Inhibitors of MDM2, a regulator of p53 and p53-specific E3 ubiquitin
protein kinase (MEK) kinase inhibitors,856 Aurora kinase inhibitors,857
ligase have also entered trials.817
and heat-shock protein inhibitors.858 None of these agents have had an
Antibodies to CD33 impact on AML survival as single agents, but using a combination of
The CD33 antigen is expressed on approximately 90 percent of AML agents that target multiple pathways or using multitargeted tyrosine
blasts and is a target for antibody-mediated destruction. Gemtuzumab kinase inhibitors may hold promise for incremental improvements in
ozogamicin is a recombinant humanized anti-CD33 monoclonal AML therapy.859 There is some indication that extramedullary disease
immunoglobulin G4 antibody conjugated to the cytotoxin calicheami- may increase in incidence in cases treated with signal transduction
cin.818 The conjugated antibody is rapidly internalized and causes agents alone.860
subsequent cell apoptosis.819 Hyperbilirubinemia and transaminase Other Inhibitors of Signal Transduction and Apoptosis
elevations can occur. Although it results in similar survival rates as Pathways Many malignancies overexpress antiapoptotic proteins, such
standard chemotherapy reinduction, its use was associated with fewer as BCL-2 and BCL-xL.861 Small-molecule BCL-2 homology domain-3
days of hospitalization.820 In patients who relapsed between 3 and 11 (BH3) mimetics such as ABT-737862 and GX15–070 (obatoclax)863
months, gemtuzumab ozogamicin resulted in higher remission rates inhibit BCL-2. CDDO-Me, a triterpenoid, studied in vitro induces apop-
compared to regimens containing high-dose cytarabine in different tri- tosis and differentiation in AML cells through activation of caspase-8
als. However, in patients who had prolonged first remissions of greater and caspase-3 and induction of mitochondrial cytochrome c release.864
than 19 months, cytarabine resulted in superior remission rates.821 Prior Prenylation Inhibitors: Farnesyltransferase inhibitors (FTIs)865–868
gemtuzumab ozogamicin exposure may increase the risk of venoocclu- and geranylgeranyltransferase-1 inhibitors (GTIs), such as statins, have
sive disease in patients who later undergo myeloablative allogeneic HSC been examined as therapy in AML. Examples of responses of AML to
transplantation procedures.822 Gemtuzumab ozogamicin was approved lovastatin have been reported.869 Simvastatin adds to the effect of cyta-
by the FDA in 2000, but withdrawn from the market in 2010. Studies in rabine’s inhibition of AML cell lines.870 Other studies suggest that the
Europe are examining its role in induction treatment coupled with stan- statins may mediate antileukemic effects independent of Ras/Rho pre-
dard chemotherapy, in postremission therapy, and in the treatment of nylation through blockade of cholesterol responses to cellular injury.871
APL.823–825 In those studies, it did not alter remission rates but appeared Effectiveness of either FTIs or GTIs as single agents has been minimal
to decrease relapse rate or improve relapse-free survival. in untreated AML patients.865–868
Maturation Therapies Several analogues of vitamin D inhibit
Therapies Targeted to Signal Transduction Mediators AML cells by inducing inhibition of cyclin-dependent kinases.872 In
Tyrosine Kinase Inhibitors: FLT3 Inhibitors Constitutively activating general, AML cells have not responded to retinoids. Single-strand con-
FLT3 receptor mutations have been found in approximately 30 percent formational polymorphism analysis and DNA sequencing of leukemic

Kaushansky_chapter 88_p1373-1436.indd 1403 9/21/15 11:02 AM

 1404 Part X: Malignant Myeloid Diseases

cells from AML, other than APL, have not found mutations of RAR- The immunomodulatory drug lenalidomide has also been exam-
α.873 Nevertheless, combinations of retinoids, growth factors, and che- ined in AML and has some activity in high doses in relapsed or refrac-
motherapeutic agents are being examined for therapeutic potential in tory AML.907,908
AML.874 Leukemias with 11q, –5, and –7 chromosome abnormalities The IL-3 receptor α (CD123) is overexpressed in AML as compared
have high telomerase activity, which can be inhibited by maturation- with normal HSCs, so it has been proposed as a target for chimeric anti-
inducing agents.875 In one study, addition of ATRA to chemotherapy did gen receptors (CARS) as a bridge to allogeneic HSC transplantation.909,910
not improve patient outcome but did result in a 25 percent increase in
apoptosis in AML marrow cells in vitro.876 ATRA has induced a com-
plete remission in a patient with acute myelomonocytic leukemia.877,878 SPECIAL THERAPEUTIC CONSIDERATIONS
Arsenic trioxide induces apoptosis and cytotoxic effects in blasts from Acute Promyelocytic Leukemia
patients with AML other than APL, and it is not influenced by permea- General Consideration in Therapy Because of the early induction
bility glycoprotein (P-gp) expression.879,880 mortality in APL, patients who are suspected based on morphology
and presence of coagulopathy should begin ATRA without waiting for
Antiangiogenesis Agents and Agents That Inhibit Microenvi- definitive FISH or molecular confirmation. There is now an International
ronmental Interactions Consortium on APL, the goal is to improve outcomes through educa-
Targeting the increased vascular density of marrow noted in AML tion and guidelines formulaton.911 While many trials with variations in
or cytokines secreted by marrow endothelium has been examined as the induction, consolidation, and maintenance phases are published,
means to inhibit AML cell growth. Amifostine,881 thalidomide,880 suni- the clinician is urged to consider clinical trials and to follow one proto-
tinib,881 and other agents that target VEGF and interleukin (IL)-8,882 as col plan through all the phases of therapy.
well as of the angiopoietin signaling pathway,883 are potential antiangio- Induction Treatment ATRA has become a standard component of
genic agents in the treatment of AML. Lenalidomide, which also has induction therapy for APL. Used alone, ATRA can induce a short-term
antiangiogenic properties, is used to treat deletion 5q– AML.884 Antago- remission in at least 80 percent of patients.912 However, ATRA should be
nists of the chemokine receptor CXCR4, which plays a role in retention combined with an anthracycline such as idarubicin or with arsenic tri-
of hematopoietic cells in marrow and of integrins or selectins, have been oxide during induction treatment for most benefit and to prevent drug
proposed as therapeutic agents to overcome stromal-mediated resis- resistance.913 Idarubicin by itself can induce remission in approximately
tance and to enhance chemotherapy-induced cell death.885,886 75 percent of patients.914 A typical induction regimen for APL is ATRA
45 mg/m2 daily in divided doses with idarubicin at standard induction
Modulation of Drug Resistance doses (e.g., 12 mg/m2 on days 1 to 3).915,916 Although cytarabine has been
Numerous mechanisms of drug resistance occur in AML,887 and several largely abandoned as part of induction, some studies show a high degree
attempts to overcome this resistance have been instituted, but none of of efficacy of high-dose cytarabine combined with ATRA.917 There is evi-
the agents used, such as cyclosporine or PSC-833, have had a significant dence that in patients who present with a white cell count of 10 × 109/L
impact on AML outcomes to date. P-gp, MDR protein-1 (MRP-1), and or greater, the complete remission rate and overall survival may be supe-
breast cancer resistance protein (BCRP) expression all have been found rior when cytarabine is added to induction or consolidation regimens,
in AML.888 especially if arsenic trioxide is not part of the induction regimen.918,919
The addition of arsenic trioxide to ATRA and idarubicin in induction
Other Immunotherapy and Antisense DNA Approaches regimens results in approximately 95 percent complete remission rates.
Culture of AML blasts upregulates costimulatory molecules, and the This approach allows reduction in anthracycline usage and excellent
role of dendritic cells in antileukemia therapy is being examined.889–891 overall survival (93 percent).920 In low- to intermediate-risk APL (WBC
Other approaches to generating autologous T-cell antileukemic activity <10 × 109/L), the combination of ATRA and arsenic trioxide was found
include vaccination with AML-specific peptides, immunization with equal to, or possibly superior to, an ATRA plus chemotherapy regi-
AML blasts exhibiting dendritic cell phenotype and function,892,893 and men.921,922 Also, there was less hematologic toxicity and fewer infections
pulsing normal dendritic cells with AML-specific peptide sequences.894 with that combination of drugs. Older patients generally tolerate a com-
Natural killer cells may mediate antileukemia effects.895 Low doses bination of ATRA and an anthracycline.923 Combinations that include
of IL-2 have been used in the maintenance phase of AML, and some gemtuzumab ozogamicin are being examined for their effectiveness in
patients have remained on this regimen for 10 or more years without APL induction therapy, but this antibody is no longer marketed in the
significant side effects.896 However, low-dose IL-2 does not improve out- United States.924 The combination of ATRA and arsenic trioxide results
comes when used as maintenance treatment in older AML patients.897 in more rapid remissions and lower PML-RAR-α transcript levels than
The WT gene WT1 is expressed on AML blasts, and a WT1 vaccine either agent alone.925 Despite the high remission rates and frequency
may elicit cytotoxic T-cell responses against this protein.898 Peptides of long-term event-free survival achieved in this disease, controversies
derived from the mutated nucleophosmin I gene can elicit in vitro remain regarding therapy because of the 5 to 10 percent of patients who
CD4 and CD8 T-cell responses.129 Other proteins against which such die as a result of fatal intracranial hemorrhage.926 This relatively high
humoral responses have been elicited include minor HLA antigens and early death rate (17.3 percent) persisted despite use of ATRA in induc-
proteinase-3.899 Coinhibitory molecule signaling can hamper benefit tion therapy.927 Thus, there are several induction regimens that can be
of immune therapies, so efforts to modulate coinhibitory networks are chosen to treat APL based on WBC at diagnosis and, to a lesser extent,
underway in leukemias.900 Small interfering RNA (siRNA) targeting of patient age and ability to tolerate anthracyclines. For those with low-risk
transcription factors901 and GTI-2040, an antisense to ribonucleotide disease, a combination of ATRA plus arsenic trioxide, ATRA plus idaru-
reductase, have been used in AML therapy.902 In addition to CD33, bicin alone, or ATRA plus daunorubicin plus cytarabine can be used. In
CD45, CD66, and CD38 have been examined as targets for immuno- high-risk patients, ATRA plus daunorubicin and cytarabine, ATRA plus
therapy of AML.903,904 Immunotoxin conjugates are being examined in idarubicin, or ATRA and arsenic trioxide with idarubicin (dose-adjusted
AML as well to increase potency of naked monoclonal antibodies.905 based on age) can be used.928 Table 88–8 lists APL induction regimens.
Alloreactive haploidentical KIR ligand-mismatched natural killer cells All-Trans Retinoic Acid: Dose and Mechanism of Action ATRA,
are also being examined in high-risk elderly AML cases.906 an analogue of vitamin A, has been used to initiate the therapy of APL

Kaushansky_chapter 88_p1373-1436.indd 1404 9/21/15 11:02 AM

 Chapter 88: Acute Myelogenous Leukemia 1405

vitro responsiveness to ATRA.933 The t(11;17) variant of APL, in which

TABLE 888. Examples of Treatment Protocols for Acute
the promyelocytic leukemia zinc finger (PLZF) gene is fused to RAR-α,
Promyelocytic Leukemia
does not respond to ATRA.934 Other nonpromyelocytic leukemia sub-
Induction Consolidation Reference types of AML have not responded to ATRA therapy. ATRA is benefi-
HIGH-RISK PATIENT cial in APL during the induction and maintenance phases of disease,935
and improved outcome with ATRA is reflected in the 5-year survival
ATRA 45 mg/m2 PO in 1st Cycle: Daunorubicin 60 922
rates of 75 to 80 percent.936 Additional cytogenetic changes do not influ-
divided doses mg/m2 IV for 3 days; Cyta-
rabine 200 mg/m2 IV for 7 ence treatment outcomes with ATRA plus an anthracycline.937 ATRA
Daunorubicin 60 mg/ induction therapy can result in favorable results without blood product
m2 IV for 3 days days
support.938
Cytarabine 200 mg/m2 2nd Cycle: Cytarabine 2 g/
m2 (or 1.5 g/m2 in older Toxic Effects of All-Trans Retinoic Acid ATRA therapy is asso-
IV for 7 days ciated with dryness of the skin and lips, occasionally leading to mild
patients) IV, every 12 hours
for 5 days plus daunoru- exfoliation, nausea, headache, arthralgia, and bone pain. The white cell
bicin 45 mg/m2 IV for 3 days count may rise dramatically in the first week or two of therapy. Serum
glutamic-pyruvate transaminase and triglyceride concentrations often
ATRA 45 mg/m2 PO 1st Cycle: ATRA 45 mg/m2 928
(days 1–36 in divided PO in divided doses for 28 increase. Leukemic promyelocytes disappear from the blood in 2 to
doses) days; arsenic trioxide 0.15 4 weeks, and a normal marrow aspirate may be obtained in 4 to 10
mg/kg IV per day for 28 weeks. Anemia improves gradually. The majority of patients become
Idarubicin (6–12 mg/
m2 based on age) IV on days PML-RAR-α–negative by PCR after the second consolidation therapy
days 2, 4, 6, and 8 2nd Cycle: ATRA 45 mg/m2 in conjunction with ATRA.939 ATRA has been used successfully to treat
PO for 7 days every 2 weeks APL diagnosed during pregnancy.940 ATRA has been used from week 3
Arsenic trioxide 0.15
mg/kg IV (days 9–26) × 3. Arsenic trioxide 0.15 of gestation, but may result in fetal malformations when it is used dur-
mg/kg per day × 5 days IV ing the first trimester.941
for 5 weeks Differentiation Syndrome A rapid increase in the total blood
LOW-RISK PATIENT leukocyte count to as high as 80 × 109/L in the first several weeks of
therapy, referred to as the differentiation syndrome (previously called
ATRA 45 mg/m2 PO in Arsenic trioxide 0.15 mg/kg 921
the retinoic acid syndrome), is a potential cause of early death during
divided doses daily IV per day, 5 days per week
until remission; arsenic for 4 weeks every 8 weeks therapy.942–944 The median time of onset is 11 days, but the syndrome has
trioxide 0.15 mg/kg IV for 4 cycles occurred up to 47 days after therapy starts.944 Two approaches to treat-
daily until remission ment of this phenomenon have been suggested: early use of cytotoxic
ATRA 45 mg/m2 PO per day
for 2 weeks every 4 weeks chemotherapy945,946 and glucocorticoid administration.947,948 The syn-
for 7 cycles drome consists of fever, weight gain, dependent edema, pleural or peri-
cardial effusion, and bouts of hypotension. Respiratory distress is the
ATRA 45 mg/m2 PO 1st Cycle: ATRA 45 mg/m2 919 key feature. In fatal cases, pulmonary interstitial infiltration with matur-
in divided doses until PO for 15 days; idarubicin 5
ing granulocytes is prominent. Once respiratory distress is evident, the
clinical remission; Ida- mg/m2 IV for 4 days
rubicin 12 mg/m2 IV on patient should receive dexamethasone 10 mg IV every 12 hours for sev-
2nd Cycle: ATRA 45 mg/ eral days. Because the syndrome may occur at relatively low total white
days 2, 4, 6, and 8 m2 PO for 15 days; mitox-
cell counts and its onset is unpredictable, high-dose glucocorticoid
antrone 10 mg/m2 IV for 5
days therapy should be instituted if respiratory symptoms develop even in
the absence of pulmonary infiltrates or an elevated white cell count.942,946
3rd Cycle: ATRA 45 mg/m2
ATRA can be continued or resumed with glucocorticoids or with con-
PO for 15 days; idarubicin
12 mg/m2 IV for 1 dose current cytotoxic chemotherapy, but the syndrome may recur.942 This
syndrome is not observed during maintenance therapy. It may also
NOTE: The reader is advised to consult the original reference for details occur with arsenic trioxide therapy, and some recommend prophylactic
of the administration of the chemotherapy regimens. “High risk” is glucocorticoids in those with a WBC greater than 10 × 109/L or in those
defined as a white cell count at diagnosis ≥10 × 109/L. “Low risk” is receiving both ATRA and arsenic trioxide.943
defined as a white cell count at diagnosis <10 × 109/L. Treatment of Coagulopathy Reducing the risk of early death
from hemorrhage as a result of the coagulopathy accompanying APL
requires use of fresh-frozen plasma, platelet replacement, and fibrino-
gen replacement.489,490,949 Targeted levels for platelet counts are usually
since 1987 in the United States. ATRA induces complete remissions in 30 to 50 × 109/L928 and for fibrinogen levels 1.5 g/L or higher, but these
approximately 80 percent of previously untreated patients.929 In vitro, levels are often difficult to achieve in patients with active hemorrhage.950
ATRA is 10 times more potent in inducing maturation of leukemic pro- Heparin treatment was used during induction chemotherapy in the past
myelocytes to neutrophils than 13-cis retinoic acid, the other naturally to prevent onset of disseminated intravascular coagulopathy during
occurring isomer.930 ATRA induces maturation of the leukemic cells treatment, but rarely is used now.951 ATRA may have some corrective
and their apoptosis results in the reappearance of normal polyclonal effect on coagulation disorders in APL.952 However, a reduction of 5 to
hematopoiesis and a remission in most cases.931 ATRA may induce 10 percent of fatal hemorrhages has not been significant with ATRA
synthesis of a protein that selectively degrades PML-RAR-α. ATRA can used early during treatment. Paradoxically, hypercoagulable clotting
overcome the recruitment of histone deacetylase activity by the PML- tendency may occur in patients during the first months of ATRA ther-
RAR-α fusion gene through interference with a nuclear corepressor.932 apy.931 In the coagulopathy of APL, the blasts overexpress annexin II,
STAT1 is induced and activated by ATRA. Promyelocytic leukemia cells and there is evidence that the effects of annexin II can be reversed by
with PML-RAR-α break-fusion sites in PML exon 6 have decreased in l-methionine administration.953

Kaushansky_chapter 88_p1373-1436.indd 1405 9/21/15 11:02 AM

 1406 Part X: Malignant Myeloid Diseases

Chemotherapy Induction of remission with ATRA alone is fol- Maintenance Therapy After consolidation phases of therapy are
lowed by relapse in weeks to months unless intensive chemotherapy is complete, patients should be in a molecular remission, that is, PCR-
used concomitantly.954 At relapse, cells show high levels of a cytosolic negative for PML-RAR-α. ATRA maintenance with chemotherapy is
retinoic-acid-binding protein not detected prior to ATRA therapy.932 recommended based on the APL 93 trial, which showed that relapse-
The mechanism of retinoid resistance in leukemic cells may involve free survival was superior with ATRA versus no ATRA, and that the
cytochrome P450 and P-gp because of induction of various enzymes best results were achieved when ATRA was combined with 6-mercap-
that may alter ATRA metabolism.955 ATRA, whether administered as topurine and methotrexate.969 The 10-year cumulative relapse rates were
part of induction therapy or as maintenance therapy, confers a disease- 43 percent with no maintenance, 33 percent with ATRA alone, 23 per-
free survival advantage. More than 70 percent of patients receiving cent with chemotherapy alone, and 13 percent with ATRA and chemo-
ATRA at any point were in continuous remission at 2.5 years versus less therapy.970 Maintenance is usually recommended for 2 years, and studies
than 20 percent of patients who never received ATRA.936 The acquired to examine whether maintenance is beneficial in low-risk disease are
in vivo resistance that occurs rapidly to ATRA as a single agent requires ongoing.928 During maintenance, PCR monitoring on blood samples is
consolidation of ATRA-induced complete remission with intensive recommended.928 If the PCR is positive in blood, a marrow examination
chemotherapy using an anthracycline antibiotic. Customary treatment should be done.
today involves simultaneous administration of ATRA and an anthracy- Treatment for Relapsed Acute Promyelocytic Leukemia Con-
cline and/or arsenic trioxide. Some therapists have returned to combin- ventional chemotherapy can be effective after relapse. Arsenic trioxide
ing an anthracycline antibiotic with cytarabine in an effort to decrease has been used in those who do not achieve molecular remission at com-
CNS relapse, especially in patients younger than 60 years of age with pletion of consolidation or who subsequently demonstrate molecular
white counts greater than 10 × 109/L at presentation.956 Maintenance relapse and can generate high molecular remission rates in more than 80
therapy with ATRA alone or in combination with mercaptopurine or percent of patients alone or when combined with chemotherapy.971 It is
methotrexate has been recommended. This additional therapy has not still uncertain whether ATRA has benefit in patients previously exposed
been examined in a randomized trial of ATRA dosing and scheduling, to ATRA. Patients younger than age 70 years should be considered for
but ATRA usually is given in an interrupted fashion. Intensified main- allogeneic or autologous HSC transplantation after they have achieved a
tenance therapy may have a negative impact on those patients who have second remission or for allogeneic transplantation if a second remission
become negative for the PML-RAR-α fusion transcript after induc- cannot be induced.972 Other treatments for patients in relapse include
tion plus consolidation therapy.957 Some therapists have proposed that the combination of ATRA, arsenic trioxide, and gemtuzumab ozogami-
elderly patients can be treated with ATRA and arsenic trioxide without cin. This combination has resulted in durable remissions.973 Transplan-
chemotherapy and with addition of gemtuzumab ozogamicin in the tation generally is not recommended for patients with APL in first
event of an elevated white count at the time of diagnosis.958 remission given the prolonged remissions after standard treatments.
Arsenic Trioxide Arsenic trioxide can trigger apoptosis of APL Allogeneic stem cell transplant is best used in advanced APL, especially
cells at high concentrations and maturation at low concentrations. in patients with persistent disease by PCR.974 The outcome of autologous
The presence of PML-RAR-α is important for the response. Apoptosis stem cell transplantation in second complete remission is excellent if the
may occur through induction of activation of caspase-1 and caspase-3 stem cells used are negative for PML-RAR-α.941 High-dose cytarabine
after changes in the mitochondrial membrane potential with increase can be used for stem cell mobilization which will also treat CNS relapse,
in H2O2.959,960 It also may function through NF-κB inhibition.961 Death- and when a second molecular remission is followed by an autograft, the
associated protein 5 also contributes to arsenic trioxide–induced 5-year disease-free survival is approximately 75 percent. This result is
apoptosis in APL.962 Arsenic trioxide given at 0.06 to 0.12 mg/kg body superior to survival after allografting, but a direct comparison of autol-
weight per day until leukemic cells were eliminated from the marrow ogous transplantation, allogeneic transplantation, and arsenic trioxide
induced remission within 12 to 89 days in 11 of 12 patients.963 Suppres- or ATRA with standard chemotherapy has not been made in patients
sion of hematopoiesis did not occur. Rash, light-headedness, fatigue, with APL in a second remission after relapse.975 For patients in a second
and musculoskeletal pain were the main side effects. Arsenic trioxide remission who are not candidates for allogeneic stem cell transplant, up
can be combined with idarubicin in relapsed patients; it also has been to six cycles of arsenic can be used.
used with ATRA.921,964,965 A retinoic acid–like syndrome (see “All-Trans- Many cases of extramedullary relapse in APL have been reported.976
Retinoic Acid: Dose and Mechanism of Action” above) has been Many of the relapses occur in patients who received ATRA and who
described in patients with APL treated with arsenic trioxide.966 Torsade initially were diagnosed with hyperleukocytosis,977 and many of the
de pointes, an uncommon variant of ventricular tachycardia in which patients are in marrow remission. Relapses occurring more than 5 years
the underlying etiology and management are different from those of the after diagnosis have been reported, some at extramedullary sites such
usual variety of ventricular tachycardia, has been described with arsenic as in the mastoid bone.978 Early detection of relapse is important as
trioxide use,967 and monitoring of electrocardiographic QTc intervals those with molecular relapse before hematologic relapse has occurred
and electrolyte levels during therapy is recommended.968 fare best.979 Patients should be monitored with PCR every 3 months for
Consolidation Therapy Consolidation therapy is required in 2 years after remission induction, especially those with intermediate- or
APL to achieve a durable molecular remission. Consolidation typically high-risk disease.928
consists of anthracycline plus ATRA, but in high-risk patients, the addi- MDS can occur in patients in remission with APL, usually
tion of cytarabine or use of arsenic trioxide can be used to diminish the 24 months or more after diagnosis. The complication results from a sec-
rate of relapse. Almost every induction regimen described in APL has ond (drug-induced) clonal disease in long-term responders.980–992 Cases
a distinct consolidation regimen attached to it, dependent on disease of therapy-related APL have been described.983 Patients with APL who
stratification. To achieve uniformly good responses, it is recommended are FLT3-ITD–positive generally have worse overall outcomes than do
that one follow a given protocol’s induction, consolidation, and mainte- those persons who present with elevated white cell counts and older
nance regimen. Table 88–8 provides examples of paired induction and age.984 There is also evidence that mutations in the ATRA-targeted ligand
consolidation regimens. Excellent results can be achieved with all of binding domain of PML-RAR-α and additional chromosome abnormal-
these regimens, if treatment plans are executed faithfully. ities may be associated with reduced postrelapse survival in those on

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 Chapter 88: Acute Myelogenous Leukemia 1407

ATRA.985 Oral arsenic trioxide and tamibarotene, a synthetic retinoid, are associated with an increased risk of AML.1004,1005 In patients with non-
are being examined in relapsed APL.986,987 Children older than 4 years Hodgkin lymphoma, up to 10 percent of patients treated with either
and adolescents have outcomes with ATRA-treated APL equivalent to conventional chemotherapy or high-dose therapy developed secondary
that of adults, but younger children have more frequent relapses.988 AML within 10 years.1006 Secondary leukemia is seen after autologous
marrow or blood stem cell transplants involving high-dose chemother-
apy and/or radiotherapy. In a study of 83 patients after autografting, 12
SECONDARY ACUTE MYELOGENOUS
had nonclonal cytogenetic abnormalities and 10 had clonal abnormal-
LEUKEMIA ities, five of whom developed secondary AML. Onset occurred 12 to
Secondary leukemias arise after treatment of another malignancy or an 48 months after autografting. The relative contribution of the underlying
autoimmune disease with cytotoxic chemotherapy or radiation. Second- disease and the conditioning therapy is uncertain.1007 Clonality analysis
ary AML responds more poorly to chemotherapy and allogeneic stem using an X chromosome gene, based on methylation of the human andro-
cell transplantation than does de novo AML. Secondary AML accounts gen receptor locus in cell samples in patients with lymphoma, found a
for approximately 5 to 10 percent of all AML cases, although this per- clonal marrow cell population 6 months after autologous transplantation
centage is increasing.980,990 The leukemogenic risk of treatment regimens at a time when no morphologic or clinical evidence of AML was pres-
depends on the agents used. Future development of agents with lower ent. AML appeared later in some patients.1008 More than 10 percent of
risk of inducing AML is an important goal.991 patients with non-Hodgkin lymphoma who underwent stem cell rescue
after total body irradiation and cyclophosphamide developed AML at a
Effect of Topoisomerase II Inhibitors median followup of 6 years.1009 Using a triple FISH assay to detect loss of
Exposure to topoisomerase II inhibitors (e.g., etoposide, mitoxantrone, chromosomal material from 5q31, 7q22, or 13q14, abnormal cells were
amsacrine) can lead to AML with MLL gene rearrangements on chro- detected before high-dose therapy was given to non-Hodgkin lymphoma
mosome 11q32.992 Inversion 16 is an uncommon aberration in sec- patients.1010 Thus, some patients are at increased risk for developing sec-
ondary AML and, like balanced translocations of chromosome bands ondary AML based on pretreatment chromosome studies.
11q32, 21q22, and t(15;17), is associated with prior chemotherapy
with topoisomerase II inhibitors when seen in the setting of treatment- Treatment of Secondary Leukemia
induced leukemias. The site of breakpoints within the MYH11 gene Secondary leukemia generally is treated similarly to de novo leukemia.
involved in inversion 16 may vary between therapy-induced AML and However, given the lower response rates and remission durations of
AML occurring de novo.993 The latency period for development of AML secondary leukemia, patients can be treated in clinical trials examining
after topoisomerase II inhibitors is approximately 2 years. No relation- new therapies or treated initially with chemotherapy regimens used for
ship with higher cumulative dose has been identified. Studies of single refractory disease.1011 Some patients may benefit from early allogeneic
nucleotide polymorphisms to ascertain genetic predisposition are ongo- HSC transplantation.1012 Autologous transplant can be successful if stem
ing.994 Polymorphisms in detoxification genes and in genes involved in cells are harvested prior to the development of secondary AML.1013 In
DNA repair pathways might be involved.995 Even the use of low-dose or those who have low blood blast counts, allogeneic stem cell transplan-
oral etoposide can be associated with development of secondary AML. tation as initial therapy may be superior to induction chemotherapy
followed by transplantation, but this remains an area of controversy.1014
Effect of Alkylating Agents and Cisplatin Although patients may have a response rate of approximately 50 percent
Alkylating agents cause secondary AML, often preceded by myelodys- to standard induction chemotherapy, most soon relapse, and long-term
plasia. The mean latency period after onset of treatment is approximately survival is approximately 10 percent.1015 Secondary AML more often has
6 years. Deletions of all or part of chromosome 5 or 7 are the most com- unfavorable cytogenetic features compared to de novo leukemia.1016
mon cytogenetic changes. The risk is related to cumulative alkylating
agent dose. Germline aberrancies of NFI and p53 may increase the risk
TREATMENT OF Ph CHROMOSOME–POSITIVE
of AML. Cisplatin used for treatment of ovarian cancer also increases
the risk of secondary leukemia.996 AML
This cytogenetic variant of acute leukemia is characterized by extraor-
Other Cytotoxic Agents dinary drug resistance. Imatinib mesylate in doses of 600 to 800 mg/day
Other drugs that may increase the risk of secondary leukemias include may produce a hematologic remission in a small proportion of patients
low-dose weekly methotrexate for rheumatoid arthritis,997 etanercept with Ph chromosome–positive AML, based on the response in patients
therapy,998 temozolamide,999 growth hormone administration,1000 and with CML who go on to a myeloid blast crisis. No formal studies of
G-CSF given to patients with congenital, but not idiopathic or cyclic the response to imatinib mesylate of de novo Ph chromosome–positive
neutropenia.1001 In the latter cases, a cause-and-effect relationship AML have been performed. In myeloid blast crisis of CML, the uncom-
between MDS/AML and G-CSF therapy has not been established. mon full hematologic response (blood and marrow) usually is short
Improved survival duration with G-CSF may allow expression of an lived, measured in weeks or a few months. This outcome also seems to
underlying leukemic predisposition. be the case when therapy with other drugs (e.g., cytarabine, etoposide,
anthracycline antibiotics) is included. Occasional cases in which che-
Other Settings for Secondary Leukemia motherapy has induced remission in Ph chromosome–positive AML
Patients with APL in remission may develop a new MDS (oligoblastic and imatinib mesylate has appeared to help induce and sustain the
leukemia), presumably secondary to therapy.1002 Series of children with remission have been reported.1017 Thus, in Ph chromosome–positive
treatment-related myelodysplasia or AML have the same latency period AML, a matched-related or matched-unrelated donor stem cell trans-
as do adults treated with alkylating agents or topoisomerase II inhibitors plant should be considered if the patient is younger than age 50 years.
for AML.1003 Breast cancer patients receiving doxorubicin and cyclophos- This approach may have the highest probability of a long-term remis-
phamide regimens of such intensity that they required G-CSF support sion. There is little information about the use of second generation BCR-
had increased rates of posttherapy AML. Breast and prostate radiotherapy ABL inhibitors in this setting.

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 1408 Part X: Malignant Myeloid Diseases

TREATMENT OF OLDER PATIENTS cytarabine with etoposide and G-CSF.1041 Temozolomide has been used
in this age group,1042 and clofarabine is also being tested in patients
Biologic Features age 60 years and older.1043 In one study of clofarabine in older patients
Approximately 65 percent of patients with AML are older than age
who were deemed unfit for 7-plus-3 chemotherapy, a 5-day clofarabine
60 years at the time of diagnosis.1018 The disease in this age group is
regimen resulted in a 48 percent response rate, and 18 percent died
less responsive to therapy, and this age group has a higher propor-
within 30 days.1044 Another study in those older than 60 years showed a
tion of patients who have oligoblastic myelogenous leukemia (MDS);
response rate of 46 percent and an overall median survival of 41 weeks
an antecedent clonal myeloid disease; prior chemotherapy for cancer
and a 30-day all-cause mortality of approximately 10 percent.1045 Several
of another site; and comorbid conditions that decrease the tolerance
investigational therapies, including 5-azacytidine, decitabine, clore-
to intensive chemotherapy programs.1019–1022 The AML cells of elderly
tazine, and depsipeptide, are also being studied. There are also several
patients often have more CD34 expression, suggesting origin from a
reports concerning addition of other agents to standard chemotherapy
more primitive multipotential (? stem) cell. This finding is thought to
to improve responses. These include bevacizumab,1046 sorafenib,1047 and
contribute to longer duration of postchemotherapy aplasia and to the
gemtuzumab ozogamicin.1048,1049 Thus far, none of these drugs have
increased risk of induction deaths in this age group.1023 Patients older
resulted in improvement in overall survival.
than age 60 years also have a high frequency of unfavorable cytogenetic
findings (32 percent) and higher MDR1 expression (71 percent) and
functional drug efflux (58 percent).1024,1025
Autologous Stem Cell Infusion or Nonmyeloablative Alloge-
neic Transplantation
Autologous stem cell transplantation has been used in fit patients older
Chemotherapy than age 60 years.1050 The incidence of relapse is lower when marrow
The therapist and patient determine whether a standard regimen, a stan- stem cells are used compared to blood stem cells. Some patients older
dard regimen with dose reductions, or a special regimen is used.1026,1027 than age 60 years may be eligible for reduced-intensity allogeneic stem
Decisions based on chronologic age should be supplanted by mea- cell transplantation from related or unrelated donors, but more data
surements of cognitive, neurologic, and physical fitness used by geri- regarding outcomes are needed.1051 In a large registry study, examin-
atricians to evaluate the wisdom of considering intensive treatment.1028 ing reduced-intensity allogeneic HSC transplantation for older patients
These are often not well-validated in geriatric AML populations, but with AML and MDS in first remission, older age was not found to affect
there is evidence that assessments focused on cognition and objective 2-year nonrelapse mortality, disease-free or overall survival.1052
measures of physical function may predict for overall survival in those
older than age 60 years who undergo standard induction chemother- Postremission Therapy in Older Patients
apy.1029 In patients older than age 60 years who are fit and otherwise are No consensus exists regarding the best regimen or the number of treat-
considered good candidates, standard two-drug therapy can be used: ment cycles for postremission therapy in older adults. Regardless of the
cytarabine and an anthracycline antibiotic, and on some occasions the consolidation regimen, the duration of the leukemia-free survival is
addition of a third drug, etoposide. Remission rates of approximately longer with high-dose cytarabine and autologous stem cell transplanta-
35 to 45 percent can be achieved. Based on case studies, those who are tion, just as it is in younger patients,1042 but fewer older patients can tol-
able to receive induction chemotherapy may have a median survival erate this degree of therapeutic intensity. Higher-dose cytarabine can be
slightly better than those who receive supportive care alone,1030,1031 but used in older adults with AML, but usually at a reduced dose.1053 Older
there are no randomized trials that address this issue.1032 Patients older patients treated with attenuated high-dose cytarabine at 750 mg/m2
than 70 years (median: 74; range: 70 to 88) may not have much ben- intravenously for 12 doses and then consolidated with four to six doses
efit from intensive chemotherapy with an 8-week mortality of greater had an approximately 50 percent remission rate with a median duration
than 30 percent and a median survival of less than 6 months.1033 Some of remission of 326 days.1054 Fifty-one percent of 110 patients older than
investigators have proposed waiting for cytogenetic information before 60 years of age had a 9-month median remission duration when con-
therapy decisions are made in older patients. Those with unfavorable solidated with high-dose cytarabine.1055 Older patients are at higher risk
cytogenetics and two or more other criteria including age older than for relapse despite successfully completing intensive consolidation ther-
75 years, poor performance status, and WBC greater than 50 × 109/L apy, regardless of whether other adverse prognostic features are present.
were found not to benefit from chemotherapy.1034 Chemotherapy has Cytarabine as maintenance therapy may prolong disease-free survival
been combined with growth factor support to accelerate neutrophil but does not improve overall survival.1056 Decitabine and 5-azacytidine
recovery in older patients.1035 In a study in which patients older than age are also being examined for maintenance therapy. In one randomized
55 years were randomized to receive either placebo or G-CSF after study, those receiving consolidation therapies had more hospitalizations
induction therapy, no reduction in the duration of hospitalization, sur- and more transfusion requirements.1057
vival prolongation, or cost of supportive care was noted.1036 In previously Patients older than 80 years of age do not tolerate treatments well.
untreated elderly patients with AML, mitoxantrone induction therapy Remission rates are approximately 30 percent, but the median survival
produces a slightly higher remission rate than did daunorubicin, but of treated patients is approximately 1 month. Less than 10 percent of
had no significant effect on remission duration and survival.1037 Oral patients survive for 1 year.1058
idarubicin alone has been used with success.1038 Unlike the case in younger patients, the treatment outcomes for
Attenuated standard regimens can be used in older patients. An older patients have not improved over the last two decades.1059 Treat-
example of an attenuated regimen is cytarabine 100 mg/m2 subcutane- ment options in older patients include (1) no treatment, (2) supportive
ously every 12 hours for 10 doses on days 1 through 5 and daunorubicin care, (3) palliative low-dose chemotherapy, (4) attenuated induction
30 mg/m2 IV on days 1 through 3 of treatment. One induction regimen chemotherapy, or (5) high-dose chemotherapy regimens. Investigative
is not superior to another in older patients. Outcomes achieved with agents should also be given strong consideration in this population.1060
cytarabine and daunorubicin are comparable to results with mitox- Comorbidities are independent predictors of complete remission and
antrone and etoposide.1039 Other regimens for older patients include should be taken into account during decision making,1061 as should
lower total doses of idarubicin, etoposide, and cytarabine (DIVA performance status.1062 Some argue that the approximately 15 percent
regimen)1040 and a combination of continuous infusion low-dose rate of death in those older than 60 years of age in the first month after

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 Chapter 88: Acute Myelogenous Leukemia 1409

standard induction chemotherapy is unacceptable given the less than newborn usually is normal after intensive chemotherapy for AML dur-
1 year median survival expected.1063 Lower-dose regimens can also be ing pregnancy, if therapy is started after the first trimester.1072,1077,1078
toxic and can lead to severe cytopenias. Use of colony-stimulating fac- Vaginal delivery should be used whenever possible. Pregnant women
tor permits older patients to tolerate full-dose induction therapy. The with AML who enter remission have little difficulty with childbirth or
Medical Research Council of the United Kingdom observed remis- postparturition. The remission rates of AML are approximately the rates
sion rates of 80 percent in children, 70 percent in adults younger than expected for the age group, and long-term remissions can occur with
50 years of age, 68 percent in adults 50 to 59 years old, 53 percent in current therapy. Leukemic infiltrates can be found on the maternal side
adults 60 to 69 years old, 39 percent in adults 70 to 75 years old, and of the placenta, but usually not in the villi. One case of maternal-to-fetal
22 percent in adults older than 75 years of age.1064 In one study of transmission of AML has been documented.1080 Transmission of AML
patients older than 60 years of age, the 2-, 5-, and 10-year survivals were from one identical twin to another through a shared placental circula-
22, 11, and 8 percent, respectively.1065,1066 The older patients who remain tion accounts for the dual occurrence in twins in the first several years
free of leukemia beyond 1 year have a reasonable quality of life.1067,1068 of life.177 There are reports of the use of ATRA for APL treatment during
The National Cancer Institute 5-year relative survival rates for patients pregnancy, but use during the first trimester is discouraged, and data
with AML are 11 percent for adults ages 65 to 74 years and 1.8 percent are sparse.941,1081,1082
for adults ages 75 years and older.1069
Even though t(8;21) and inversion 16 are rare in older AML
patients, remission rates are high with these favorable prognostic chro- TREATMENT OF CHILDREN
mosome changes, so induction chemotherapy is often recommended, AML represents approximately 15 percent of the acute leukemias in
although rates of relapse remain high.1070 In parallel, elderly patients children (younger than 20 years of age) in the United States. APL is
with unfavorable cytogenetics have a dismal prognosis, and those who treated as in adults, with ATRA and an anthracycline antibiotic. In other
have a monosomal karyotype have low complete remission and overall phenotypes of AML, intensive treatment—including initial therapy
survival rates; 37 versus 64 percent and 8 versus 28 percent, respectively, with cytarabine and daunomycin or doxorubicin and a third drug such
in those with and without monosomal karyotype.1071 as mitoxantrone or 6-thioguanine, followed by intensive multidrug con-
solidation therapy including additional agents such as etoposide, and
intrathecal cytarabine—has resulted in remission in approximately 80
TREATMENT OF PREGNANT PATIENTS percent of children and 5-year relapse-free remissions in approximately
Leukemia (AML, ALL, CML) is the second most common malignancy 50 percent of treated children.1083–1086 Most of the children in long-term
of women in the childbearing age group and is expected to occur in remission are considered cured.
approximately 1 in 75,000 to 100,000 pregnancies.1072,1073 No systematic Monocytic leukemia and hyperleukocytic (>100 × 109/L) myel-
studies of the (1) effects of leukemia on pregnancy or delivery, (2) effects ogenous leukemia are unfavorable phenotypes. In children, FLT3-ITD
of the leukemia or its treatment on the fetus, or (3) postnatal devel- mutations are approximately half as common (15 percent) as in adults
opment of the offspring exposed to maternal chemotherapy in utero (30 percent), but are a very poor prognostic indicator.1087 Therapy can
have been performed. A recent literature review led to the conclusion be adjusted for children based on the presence of poor prognostic vari-
that treatment during the second and third trimesters resulted in fewer ables, which include age younger than 2 years or older than 10 years;
complications to the fetus, but delaying treatment adversely affected the abnormalities of chromosome 3, 5, or 7, complex karyotypes, FLT3
outcome of mothers. Remission rates were comparable to that of non- mutations, elevated white cell count of 50 × 109/L or greater, male gen-
pregnant patients.1074 Folic acid inhibitors, purine, pyrimidine, or retin- der; and, perhaps, most importantly, because it reflects the effect of all
oid analogues given during the first trimester of pregnancy increase the factors, the presence of greater than 15 percent blast cells in the marrow
probability of major congenital malformations. In a French study of 37 examined 14 days after onset of treatment.1088,1089 The presence of resid-
patients with acute leukemia during pregnancy, 34 patients achieved ual blast cells detected by flow cytometry after induction therapy is a
remission, and disease-free survival appeared equivalent to that of very poor prognostic finding.1090 The duration of first remission predicts
patients who were not treated during pregnancy.1075 In another study the subsequent remission rate and long-term survival in children with
from Saudi Arabia, of 21 pregnant patients with acute leukemia, 10 were relapse.
given chemotherapy with seven livebirths and three spontaneous abor- Translocations 8;21, 15;17, or inv16 are good prognostic markers.
tions without any teratogenetic or congenital malformations. In the 11 Loss of a sex chromosome in the t(8;21) group is especially favorable.
not given chemotherapy until after 34 weeks of gestation, three had nor- Monosomy 7 and abnormalities of chromosomes 3 or 5 are poor prog-
mal births and eight had an abortion before starting chemotherapy.1076 nostic features.1091 Pediatric AML with t(8;16)(p11;p13) has been found
If the pregnancy is not terminated, leukapheresis might be use- to be a distinct clinical entity, and in a subset of neonatal cases, spon-
ful in the first trimester, when chemotherapy poses a high risk to the taneous remissions can occur.1092 In childhood 11p23/MLL AML, there
embryo. Intensive chemotherapy given to women in the second and are large differences in outcome based on translocation partners that
third trimesters of pregnancy does not present an inordinate risk to are independent prognostic markers as assessed in a large international
fetal or neonatal development,1077,1078 although an increased frequency study.1093 When gene mutations were examined in childhood leukemia,
of premature delivery, higher perinatal mortality, and lower birthwei- FLT3-ITD was most frequent, and 29 percent had more than one gene
ght for gestational age are observed, especially if the fetus is exposed to mutation. Mutated epigenetic regulators were less than in adults, but
chemotherapy. were often seen with other mutations.1094
Cytarabine is highly teratogenic in animal models and malfor- In the United Kingdom Medical Research Council Trial 12,
mations have been described in women who were treated in the first completed in 2002, using daunorubicin, mitoxantrone cytarabine,
trimester of pregnancy. Doxorubicin is the preferred anthracycline etoposide, and asparaginase in different combinations, approximately
antibiotic to treat pregnant women as it has lower transplacental trans- 90 percent of children with AML had a remission, 60 percent of chil-
fer. Doxorubicin is considered relatively safe when used in pregnant dren had a 5-year disease-free survival, and most were considered
women.1079 Newborn infants may be transiently cytopenic if the mother cured.1091 Approximately 4 percent of children are drug resistant with
receives chemotherapy near the time of delivery. Development of the this program and approximately 4 percent die during induction and

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 1410 Part X: Malignant Myeloid Diseases

intensification therapy. Studies are under way to examine the effects of in serious ventricular and valvular disturbances years after therapy in
using fludarabine in the regimen (Medical Research Council 15 Trial). some patients. Periodic evaluation of cardiac status by ultrasonography
Autologous stem cell transplantation has not improved outcome should be undertaken in long-term survivors.1106 Cardiomyopathy and
compared to current intensive chemotherapy treatment regimens.1095 heart failure can occur 10 to 15 years after therapy. Two approaches that
Allogeneic stem cell transplantation from a histocompatible sibling may ameliorate the cardiomyopathic effect of anthracycline antibiotics
should be considered in children in first remission with a donor and are the use of these agents in liposome encapsulated preparations1107 and
poor prognostic indicators or in children who relapse.1095 Trials have the use of dexrazoxane. Either approach may reduce the cardiotoxicity
shown good results of allogeneic transplantation in first remission; of anthracycline antibiotics.1108
event-free survival was better in childhood AML with those allografted
than with those who underwent autografting.1096 Children younger than Hepatitis
age 2 years previously had a very poor prognosis. They tend to present Hepatitis may occur in multiply transfused patients and usually is mild,
with myelomonocytic or monocytic leukemia with high blast counts but persistent hepatitis can develop, although hepatitis viruses A and B
and CNS involvement. The t(9;11) abnormality has a more favorable infection are not increased above the expected incidence in the general
prognosis. Intensive multidrug regimens have resulted in 3-year surviv- population. Hepatitis caused by type A virus is nearly nonexistent early
als approaching 70 percent of all infants treated. Thus, most infants can in the course of AML. Cases of type B hepatitis can occur infrequently
be successfully treated with intensive chemotherapy or allogeneic stem in patients who are carriers of the B virus and in whom chemother-
cell transplantation.1097,1098 Cord blood may be a suitable allograft option apy and transient immunosuppression reactivate the virus.1109–1111 These
for children with AML who lack an acceptably matched unrelated mar- rare cases of fibrosing cholestatic hepatitis can be fulminant. Screening
row donor.1099 blood products for hepatitis virus C has markedly decreased the risk of
Growth failure, neurocognitive abnormalities, endocrine deficien- hepatitis C.1112 Reactivation of carriers of the C virus after chemotherapy
cies, and cardiac abnormalities are found in children treated at a young is unusual.1113 Medication induced chemical hepatitis or cholestasis can
age.1100 The occurrence of a second malignancy in cured children is occur but is usually reversible. Iron overload in the multiply transfused
approximately 10-fold greater than expected in a matched population survival may lead to later liver abnormalities.
by age.1101 Indefinite followup of children in remission or believed to
be cured is important to assess developmental and intellectual progress Systemic Candidiasis Syndrome
and to evaluate long-term adverse events. The syndrome is manifested by fever, abdominal pain, and hepatomegaly.
Increased serum alkaline phosphatase activity often is noted. Blood
cultures are often negative. Abdominal ultrasonography, computed
NONHEMATOPOIETIC ADVERSE EFFECTS OF tomography, and MRI show characteristic hepatic lesions: circular
TREATMENT areas of decreased attenuation of liver and often spleen, kidney, lung,
or paraspinal muscles by imaging.1114 Ultrasonography reveals multiple
Skin Rashes hypoechogenic areas with a bull’s-eye appearance. Laparoscopic-guided
More than 50 percent of patients with AML develop skin lesions dur- liver biopsy reveals yellow nodules on the liver surface, which on micro-
ing remission-induction or remission-consolidation therapy. The rash scopic examination are large granulomas with Candida and pseudohy-
may be on the trunk and extremities. The rash usually is maculopapu- phae. Cure of this infection is possible with long-term (2 to 10 months)
lar initially but can become hemorrhagic in patients who have throm- antifungals. Hepatosplenic candidiasis is seen much less frequently
bocytopenia. Allopurinol, trimethoprim-sulfamethoxazole, and other when azoles are used for fungal prophylaxis.
β-lactam antibiotics are commonly implicated causes. Use of multi-
ple drugs enhances the probability of skin reactivity of patients.1102
Neutropenic Enterocolitis
Cytostatic therapy coupled with the effects of leukemia predisposes
Necrotizing inflammation of the cecum with secondary infection can
patients to an increased frequency of allergic dermatitis.
occur in patients with acute leukemia on intensive chemotherapy.233
Bacteremia may occur. Right lower abdominal pain and fever can sim-
Cardiac Toxicity ulate appendicitis. The diagnosis can be confirmed by sonography or
Alterations in cardiac function, especially left ventricular and intraven- computerized tomographic scanning in which a characteristic mucosal
tricular septal diastolic wall motion abnormalities, occur frequently in thickening and polypoid appearance are evident.1115,1116 Management
patients after they are exposed to the anthracycline antibiotics, daunoru- includes bowel rest, nasogastric suction, fluids, and antibiotics. Par-
bicin, or doxorubicin.1103 The risk of serious cardiac effects is correlated enteral alimentation is sometimes used but is generally not helpful.1117
with increasing dose of anthracycline antibiotic, increasing patient age, Restoration of the neutrophil count after chemotherapy is an important
and presence of underlying heart disease. Adverse effects include elec- feature of resolution. In the absence of resolution, right hemicolectomy
trocardiographic changes, such as prolonged QT interval, myocarditis, should be considered but is a last resort in neutropenic patients, usually
pericarditis, myocardial infarction, and congestive heart failure. The imposed if hemodynamic stability is lost.233
incidence of congestive heart failure is dose related and ranges from
approximately 5 percent at doses of 550 mg/m2 to greater than 30 per- Thromboembolic Disease
cent at doses of 600 mg/m2.1104 The frequency and long-term sequelae Although bleeding is associated with AML, thrombotic complications
increase as anthracycline dose increases. However, even lower doses of can also occur; up to 10 percent in APL and up to 3 percent in other
these agents exert negative effects on cardiac myocytes. Measurement AML subtypes.1118 Management can be difficult because of thrombocy-
of heart wall behavior, valvular competence, and ejection fraction by topenia. Central lines may contribute to this incidence.1119 Thrombotic
ultrasonography can assist in assessing the risk of proceeding with thrombocytopenic purpura has also been reported in patients in remis-
anthracycline treatment in patients with or without pretreatment heart sion of AML during consolidation chemotherapy.1120 Patients with AML
disease.1105,1106 In younger patients, transient abnormalities, although undergoing allogeneic stem cell transplantation also may develop post-
frequent, often improve after therapy is completed. Increased long- transplantation thrombotic thrombocytopenic purpura, which rarely
term remissions in children and younger adults have led to an increase responds to plasmapheresis.

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 Chapter 88: Acute Myelogenous Leukemia 1411

Fertility and Gonadal Function cytogenetic abnormalities at morphologic remission after induction
Patients treated for AML, especially patients undergoing condition- therapy predicts for a significantly shorter relapse-free survival and
ing for allogeneic stem cell transplantation, have decreased gonadal overall survival, for example.1135
function.1121–1123 Men may develop oligospermia. Women may develop
ovarian dysfunction and very high gonadotropin levels.1124 Men recover Rates of Remission
gonadal function more often and sooner than do women. Recovery of Remission rates have improved dramatically in the last 60 years, but
ovarian function in women is partly dependent on a younger age at the remission, relative 5-year survival, and cure rates are most dependent
time of treatment. In survivors of childhood AML treated only with on the patient’s age when AML occurs.1136,1137 Initial remission rates now
chemotherapy and not transplantation, normal pubertal development approach 90 percent in children, 70 percent in young adults, 60 percent
and fertility are found, but antimüllerian hormone was low in some in middle-aged patients, and 40 percent in older patients. Within age
women.1125 Women in remission following treatment for AML with groups, remission is related to other variables such as cytogenetic risk
allogeneic transplantation can become pregnant and deliver healthy category and expression of MDR genes in leukemic cells, but these vari-
infants1126,1127; however, this preservation of fertility is rare.1128 Histologic ables also are correlated with age at onset. For example, the more favor-
studies of the testes show marked suppression of spermatogenesis as a able cytogenetic patterns t(8;21), t(15;17), inv16, or t(16;16) are present
function of duration of treatment for AML and not of the specific agents in approximately 30 percent of patients between 10 and 39 years old,
used or the patient’s age. Residual spermatogenesis in intensively treated 15 percent of patients between 40 and 59 years old, and 5 percent of
patients enables recovery of reproductive function in males.1129 Males patients 60 to 90 years old (Table 88–9).1137 Other factors, such as AML
receiving intensive daunorubicin, cytosine arabinoside, or 6-thiogua- evolving from a prior clonal myeloid disease or developing as a result
nine treatment for AML have conceived children during therapy.1130 of cytotoxic treatment for another cancer or immune disorder, can
Banking of sperm should be offered, and cryopreservation of ova can decrease the expected remission and survival rates for the age group. In
be attempted prior to institution of cytotoxic therapy, but often nei- one study, treatment-related AML was an adverse prognostic factor for
ther is logistically possible or successful in patients with AML who are death in remission for younger patients and for relapse in remission in
acutely ill at presentation and require urgent chemotherapy.1121 Banking older patients.1138 Age-related comorbid conditions may limit the appro-
of sperm or ova-ovarian tissue should be considered before myeloabla- priateness or tolerance of intensive therapy, decreasing the opportunity
tive conditioning regimens for transplantation are administered. Many for remission. The expected increase in the proportion of old and old-
AML survivors report they were not, or not fully, informed about fertility- old individuals in the population may decrease remission rates and their
related issues.1131 duration unless counteracting improvements in treatment approaches
are developed. In one study of 1069 consecutive AML patients in first
CR treated between 1991 and 2003, the yearly risk of treatment failure
COURSE AND PROGNOSIS was 69.1 in the first year, 37.7 in the second year, 17 in the third year,
7.6 in the fourth year, and 6.6 in the fifth year. The effects of cytogenetics
RESULTS OF TREATMENT remained constant during the first 3 years, but the effect of age increased
Definition of Remission with time. The probability of relapse-free survival at 6 years was 84 percent
Complete remission (CR) after AML therapy is defined as neu- for those in remission at 3 years, but for the group older than 60 years
trophil count greater than 1000/μL and platelet count greater than old, it was only 56 percent, suggesting that different variables contribute
100,000/μL1132 with less than 5 percent blasts morphologically in mar- differently over time to overall outcomes.1139
row and the absence of extramedullary AML, although this definition Early death can occur during induction chemotherapy, and per-
has been called into question.1133 Remission with incomplete platelet formance status and age are the most important predictors of treatment
recovery CRplatelets (CRp) has all these requirements but the platelet related mortality. Age may be primarily a surrogate for other factors
count does not reach 100 × 109/L. In a large cooperative group study, which also predict treatment related mortality.1140
at least 94 percent of patients receiving cytarabine-based therapy who
survived more than 3 or 5 years achieved a remission. Three- and 5-year Clonal Remissions
survivals with CRp were less frequent.1134 With residual leukemic cell A small proportion of patients who enter remission have apparently
detection now possible by flow cytometry, cytogenetic, and molecular normal hematopoiesis supported by a single clone rather than the
methodologies, definitions of remission may change. Persistence of expected polyclonal hematopoiesis. Evidence points to this clone being

TABLE 889. Frequency of Cytogenetic Findings with a More Favorable Prognosis by Age Group
Favorable
No. of Cases t(8;21) (No. of t(15;17) (No. of Inv16/t(16;16) Total (No. of Karyotypes (% of
Age (Years) Studied Cases) Cases) (No. of Cases) Cases) All Cases)
10–39 307 27 38 33 98 32
40–59 584 36 28 28 92 16
60–69 579 18 24 21 63 11
70–79 381 5 7 5 17 4.5
>80 45 1 2 0 3 6.6
Total 1896 87 99 87 273 22

These observations were made in Germany by Claudia Schoch and colleagues and kindly provided to the authors. (See also Schoch C, Kern W,
Krawitz P, et al: Dependence of age-specific incidence of acute myeloid leukemia on karyotype. Blood 98:3500, 2001.)

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 1412 Part X: Malignant Myeloid Diseases

a preleukemic cell rather than a normal stem cell.1141–1144 This finding groups, and the proportion of AML patients receiving transplantation
is in keeping with previous hypotheses about the possible patterns of is very small.1136,1158–1161 Abnormalities of chromosomes 17p and –5/5q–
remission and relapse in AML1145–1148 and has implications for minimal have negative impact on outcomes after allogeneic transplant. 1162,1163
residual disease detection. In contrast to other AML subtypes, APL has had an increased
incidence as well as improved survival since the introduction of ATRA.
Spontaneous Remissions In one large study, relative survival rates were 0.18 for the period 1975
Spontaneous disappearance of AML has been reported for more than to 1990, with increase to 0.64 from 2000 to 2008. Age did remain an
100 years; however, most cases reported before 1960 had poor doc- important predictor of survival; 0.38 in those older than age 60 years
umentation of the diagnosis. Bona fide cases of AML patients who and 0.73 for those 20 to 29 years old.1164
entered CR, usually after or concurrent with an infection, occur but are Relapse (or a new leukemic event) in long-term survivors occur-
very rare.1148–1151 The occurrence of spontaneous remission with infec- ring as late as 8 years after remission has been reported in adults1153,1154
tion is consistent with the observation that the antibody response to and after more than 16 years in children.1153,1154 Relapse in long-term
Pseudomonas vaccine1152 correlates with improved probability of che- survivors nearly always occurs in the marrow in adults and usually in the
motherapy-induced remission. Spontaneous remissions often are short marrow in children, with occasional childhood cases of CNS or gonadal
lived but have lasted up to 3 years in adults and more than 9 years in relapses occurring initially, followed by relapse in the marrow.1159 Stud-
children.1153 A particularly notable case of remission for more than 60 ies of long-term survivors of AML show that most can return to work
years has been documented following “treatment” prior to the intro- and that, at a median followup of 9 years, no increased risk of secondary
duction of chemotherapeutic drugs. The regimen included arsenic.1154 invasive cancer or secondary AML had occurred.1160,1161 An exception
to this finding is the occasional report of myelodysplasia or presumably
secondary AML in long-term survivors of APL. Health-related quality
LONG-TERM SURVIVAL
of life in long-term survivors appears to recover completely as related to
Prior to the introduction of chemotherapy for AML 60 years ago, the physical, psychological, and emotional well-being, but continued sexual
median survival of patients was approximately 6 weeks,1155 the 1-year dysfunction has been reported.1165 The quality of life at the time of diag-
survival was approximately 3 percent, and longer survival occurred nosis and during the course of therapy usually is poor.1165,1166
in less than 1 percent of patients. Five-year relative survival rates of
patients in the United States from 2004 to 2010, based on the Surveil-
lance, Epidemiology, and End Results Program of the National Can- FEATURES INFLUENCING OUTCOME OF
cer Institute, are 56 percent for patients younger than age 45 years,
THERAPY IN ACUTE MYELOGENOUS LEUKEMIA
39 percent for patients 45 to 54 years old, 27 percent for patients 55
to 64 years old, 11 percent for patients 65 to 74 years old, and 1.8 Numerous features are related to outcome of AML treatment. Older
percent for patients older than age 75 years at the time of diagnosis age and less-favorable cytogenetic risk group are the two most com-
(Table 88–10).1069 Considering that the median age at disease onset is pelling determinants of a poor outcome. Even with multivariate anal-
approximately 70 years and that 75 percent of patients are older than 45 ysis, dissecting which other features are themselves important or are
years, the overall median survival is approximately 12 months. A study associations that segregate with another prognostic factor is difficult
of the cost of care of older AML patients using Medicare data found that (Table 88–11).1167–1264 As noted previously, prognostic models of AML
in adults older than age 65 years who were diagnosed between 1991 and that rely solely on molecular mutations have been proposed.105
1996, the median survival was 2 months and the 2-year survival was Determining useful prognostic variables in patients with AML is
6 percent.1156 Very similar results were found in a study of nearly 10,000 imprecise because negative prognostic factors may be eliminated by
patients in Sweden.1157 Better survival has been reported for younger better treatment protocols. Moreover, several prognostic factors are
patients who have received allogeneic stem cell transplantation in first significant only when AML is stratified by age or by morphologic phe-
remission, but the confidence limits for remission duration and survival notype. Conflicting findings are common among studies. In addition,
are overlapping for drug-treated and drug- and transplantation-treated although a prognostic variable may be correlated significantly with a
favorable outcome, the lack of a very strong statistical correlation with
the outcome of treatment makes the variable’s presence or absence of
TABLE 8810. Acute Myelogenous Leukemia: Five-Year little prognostic value in an individual patient. If a stem cell donor is
Percent Relative Survival Rates (2004–2010) available, unfavorable prognostic factors could influence the therapist to
use allogeneic stem cell transplantation as a means of remission main-
Acute Myelogenous tenance in patients entering remission. The impact of prognostic factors
Age (Years) Leukemia* may change in patients treated with allogeneic stem cell transplantation
<45 56 compared with conventional cytotoxic treatment.1265,1266
45–54 39
55–64 27 DETECTION OF MINIMAL RESIDUAL DISEASE
65–74 11 General Considerations
>75 1.8 The tumor cell burden in acute leukemia at presentation is approx-
imately one trillion (1012) cells. Apparent marrow aplasia followed by
<65 43 restitution of normal hematopoiesis can occur with at least a three-log
>65 6.0 reduction in leukemic cell numbers, which represents a residual tumor
cell burden of approximately one billion cells. Intensification therapy is
*Percent rounded to nearest integer. intended to decrease further the residual cell numbers. With the advent
Data from SEER Cancer Statistics. Table 13.6. National Cancer Institute, of specific monoclonal antibodies for leukemic cell antigens and FISH
Washington, DC. Available at: http://seer.cancer.gov/csr/1975_2011/ coupled with flow cytometry and DNA amplification by PCR, resid-
browse_csr.php?sectionSEL=13&pageSEL=sect_13_table.16.html ual leukemic cell populations at or below the level of one billion cells,

Kaushansky_chapter 88_p1373-1436.indd 1412 9/21/15 11:02 AM

 Chapter 88: Acute Myelogenous Leukemia 1413

TABLE 8811. Prognostic Factors in Acute Myelogenous Leukemia

Better prognosis than average of all patients hemopathy may relapse as a smoldering leukemia. It then
reverts to AML but can be treated with remissions lasting several
Early blast clearance during remission induction therapy1167,1168
years1199–1203
Leukemic cells contain t(8;21), t(15;17), inv(16) t(16;16), trisomy
Higher white cell count: Count >30 × 109/L or a blast cell count
21282,284,1169
>15 × 109/L1204–1206
CEBPA mutations in cytogenetically normal AML1170
Very low platelet count (<30 × 109/L)1205
Absence of exaggerated dysmyelopoiesis1170
High serum lactic dehydrogenase1207
Residual normal metaphases admixed with clonal cytogenetic
High stem cell mobilizing capacity during complete remission
abnormalities1172
predicts for relapse risk1208
High telomerase activity levels1173
Another medical disorder: extreme obesity, diabetes mellitus,
Low levels of TdT expression by flow cytometry (<5%)1172 chronic renal disease.
High BAX expression1175 and high BAX/BCL-2 ratios1176 Low serum albumin or prealbumin
High expression of integrin CD11b1177 Need for intubation or ventilator support during induction
Absence of VLA-4 expression on AML blast cells1178 therapy1209
High levels of soluble VCAM-1 binding to AML blast cells1179 Autonomous clonal growth of leukemic blast cells1210
High levels of caspase-31180 High BCL-2 expression1211,1212
Mutant CEBPA expression1181 High MCL-1 expression: Elevated at the time of leukemic relapse.
NPM1 gene expression in adults or children (usually present in Suggests prognostic importance or that chemotherapeutic reg-
cytogenetically normal cases)1182 imen selects for leukemia cells with elevated levels of apoptosis
inhibitors1213
Higher neutrophil and higher platelet counts at time of com-
plete remission1183 Low expression of retinoblastoma gene1214
<5% blasts on day 14 marrow predicts for complete remission High levels of WAF/Cip1 protein: This is a regulator at the G1
but not for overall survival1184 checkpoint of cell cycle1215
MiR-181a expression in NK AML1185 High CD34 expression: High CD34 antigen expression often in
AML subtypes M0, M1, and M4.1216 Remission rate of 61% vs.
High methylation levels of polycomb group genes1186 to 88% in AML not expressing CD34. Correlation is stronger
Poorer prognosis than average of all patients between high-intensity expression of CD34 and lower remission
rate.1216–1217 CD34 expression in APL1218
Older age: Age at the time of diagnosis has the greatest impact
on the probability of remission and on duration of survival. Chil- GATA-1 expression1219
dren in the first 15 years of life, exclusive of the neonatal period, Neural cell adhesion molecule (CD56) expression1220
have the highest rate of remission and longest relapse-free remis- Elevated soluble L-selectin: Seen especially in extramedullary
sion; patients older than age 60 years have only half the chance disease1221
of a young adult to enter remission and less likelihood of a long
relapse-free remission.1137 There is a gradient of poor response to Higher expression of interleukin (IL)-1β gene1222
treatment through adulthood, with the largest decrease after the Low FMS expression1222
sixth decade of life Expression of the thrombopoietin receptor (c-MPL) mRNA1223
Unfavorable karyotypes: The cytogenetic pattern of leukemic FLT3 mutations1224,1225
blast cells influences outcome, but the relationship is com-
Increased angiogenesis/vascular endothelial growth factor
plex.212–284 The presence of –5, –7, 5q–, 7q–, or of exaggerated
levels1226
hyperdiploidy (>47 chromosomes), trisomy 8, t(6;9), trisomy 11,
and multiple chromosomal abnormalities in leukemic cells are High β2-microglobulin levels in adults younger than 60 years
poor prognostic signs. old1227
Multidrug resistance phenotype: Leukemic cells expressing P- MN1 (meningioma 1) gene overexpression in AML patients with
glycoprotein, a unidirectional drug efflux pump, encoded by the normal cytogenetics1228
MDR1.1187 Expression of this gene product can result in decreased Young adults with the genotype WT1(mutation)/FLT3-ITD(pos-
accumulation of anthracyclines, amsacrine, mitoxantrone, and itive) have a lower complete remission rate and an inferior
etoposide. Expression of P-glycoprotein does not influence out- relapse-free and overall survival compared to those with the
come of treatment, but if rhodamine-123 efflux also is increased, genotype WT1(mutation)/FLT3-ITD(negative)1229
relapse is more common.1188–1191 Frequently observed in AML cells WT1 gene mutations in patients with AML and a normal
after relapse. Associated with CD34 expression and chromosome karyotype1230,1231
7 abnormalities.1190 Alternative non–MDR1-mediated drug efflux
mechanisms are important also.1191–1194 MDR1 expression is low in Patients with AML with a large number of AML stem cells
favorable prognosis subtypes of AML1195 Elevated expression of IL-3Rα1232
Presence of mutated KIT with t(8;21): Associated with higher MLL tandem duplications1233 and 11p23/MLL abnormalities1234
relapse risk and poorer overall survival1196 CD56 expression in APL.1235 High incidence of CNS involvement,
Prior clonal hemopathy: Chemotherapy or radiotherapy remis- especially with CD7 expression.1236 Also contributes to poorer
sion rates are one-third to one-half that of de novo AML in the outcomes in t(8;21) cases1237
same age group. Remission duration is shorter with remissions P15 methylation1238
>3 years very uncommon.1197–1198 AML developing from the clonal
(continued)

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 1414 Part X: Malignant Myeloid Diseases

TABLE 8811. Prognostic Factors in Acute Myelogenous Leukemia (Continued)

Microsatellite instability1239 (may not be independent of age and High Nrf2 and high ROS expression1254,1255
t-AML) Overexpression of IL-1 receptor accessory
AC133 expression (shorter remissions and disease-free protein1256
survival)1240 Survivin expression in CD34+CD38– cells1257
Constitutive activity of signal transducer and activator of tran- High TRAIL-R3 (tumor necrosis factor [TNF]-related apoptosis-
scription 3 protein (shorter disease-free survival)1241 inducing ligand) expression1258
BAALC gene expression1242 PICALM-MLLT10 fusion gene expression302
High S-phase activity in cells surviving after 7 days of induction1243 Factors with no or uncertain prognostic findings
High EVI1 expression1244,1245 Complex karyotype or secondary aberrations in patients with
Overexpression of CXCR41246 t(8;21), inv(16) t(16;16), or t(9;11)1259
Increased marrow angiogenesis as measured by magnetic reso- Myeloid antigens: CD11b expression may be predictive of shorter
nance imaging1247 survival1260
The presence of the CTLA4 CT60 A/G genotype adult patients Detection of the WT1 (Wilms tumor) transcript1261
with AML1248 FLT3-ITD or Asp835 mutations in APL1262
miR 155 upregulaation1249 Levels of initiator caspase1263
ERG expression1250 Persistent thrombocytopenia after remission induction1264
EVI1 expression in MLL_rearranged AML1251 Lung resistance protein: Functional test is needed to assess
Clonal heterogeneity by metaphase karyotyping1252 activity.1265 Expression may predict poor outcome in de novo
Abnormal expression of FLI1 protein1253 AML1193,1266

which are undetectable by light microscopy of stained marrow films, be useful because these two markers are expressed on leukemic cells
can be quantified.1267 When real-time PCR is used to quantify PML- in the majority of AML patients and these markers are rare in normal
RAR-α, RUNX1/ETO, or CBF-β/MYH11, risk for treatment failure can marrow cells.1280,1281 In other cases, aberrant combinations of surface
be determined by the levels of the fusion gene at diagnosis and after antigens1280,1282 or increased expression of various surface antigens,
the first 3 to 4 months of therapy.1268 Sampling remains an important such as CD34, are seen.1283 Immunophenotype may change at relapse
problem because marrow aspiration contains approximately 1/10,000 of and has implications for MRD detection.1284 Five-color staining has
the marrow cell population, and variation among sites of aspiration is been reported to improve the percentage of AML cases in which a
well documented. In addition, the markers of the leukemic cell used leukemia-associated aberrant immunophenotype can be identified.1285
for detection can change during the course of the disease. For example, Various markers, such as CLL-1 (C-type lectin-like molecule-1) and
persistence of circulating cells containing t(8;21) in patients with AML other lineage markers and marker combinations, have been found aber-
despite long-term remission has been established using PCR.1269 rantly expressed on leukemic CD34+CD38–, cells allowing residual
There are many other pitfalls when interpreting these studies, disease detection at the stem cell level.1286 Other methods for detect-
including timing of sampling in relationship to therapy, sensitivity of the ing MRD include MRI; fluorescence DNA in FISH1287,1288; reverse tran-
PCR reaction for target genes, interlaboratory standardization, selection scriptase (RT)-PCR to detect amplification of abnormal fusion genes,
of patients, and retrospective or prospective design of the study.1270 There such as t(15;17), t(8;21), inversion 16, and 11q23; and DNA PCR for
is emerging evidence, however, that detection of minimal residual disease mutations in the RAS coding regions.1267 Quantitative assessment of
(MRD) by multiparameter flow cytometry has prognostic relevance in WT1 expression1289 or presence of a FLT3 mutation1290 can also be eval-
older patients,1271 in children with de novo AML,1272 and in adults younger uated for MDR monitoring. Real-time quantitative PCR can be used
than age 60 years.1273 Pretransplantation, detection of MRD by flow to quantitate MDR more precisely than other methods, but this test
cytometry has negative impact on outcome in patients with AML in either requires standardized criteria and is not widely available clinically.1291
first or second remission. Even MRD levels less than 0.1 percent have an Multiparameter flow cytometry is applicable to most AML cases,
adverse correlation with outcome.1274 Detection of MRD in the after allo- whereas real-time quantitative PCR is applicable in just above half the
geneic stem cell transplantation is also important. Sensitive chimerism cases when NPM1 and FLT3 mutations are examined in addition to
assays have been developed using PCR-based technology to detect short fusion oncogenes.1292 Gene profiling of CD34+CD38– cells, a fraction
tandem-repeat polymorphisms. Whether these will have impact on man- that contains both normal and leukemic stem cells, might be important
agement of posttransplantation relapses is still undetermined.1275,1276 in MRD measurement, but 34 percent of genes modulated in AML stem
Marrow examinations are not needed in the majority of AML cells are shared with normal stem cells.1293
patients in first CR.1277 Because of increased myeloid precursors in
regenerating marrow, detection of residual disease may be difficult early Detecting Inversion 16
after a given therapeutic modality.1278 Cytogenetic followup usually is Minimal residual disease in acute myelomonocytic leukemia with
not helpful. Emergence of a karyotypically unrelated clone of AML inversion 16 can be detected by nested PCR with allele-specific ampli-
cells, especially containing chromosome 7, can occur. Studies using fications (CBF-β on 16q and MYH11 on 16p).1294,1295 This fusion tran-
multiparameter flow cytometry to identify leukemic cells by aberrant script occurs not only in the majority of cases of acute myelomonocytic
antigen expression have a high positive predictive value in identifying leukemia with marrow eosinophilia (M4Eo), but also in 10 percent of
relapse.1279 Detection of residual disease in AML patients using double acute myelomonocytic leukemia M4 without eosinophilic abnormali-
immunologic marker analysis for TdT and myeloid CD antigens can ties, a much higher incidence than suggested by the sporadic reports of

Kaushansky_chapter 88_p1373-1436.indd 1414 9/21/15 11:02 AM

 Chapter 88: Acute Myelogenous Leukemia 1415

chromosome 16 abnormalities in AML. Following completion of che- REFERENCES

motherapy (induction and consolidation), patients who had a CBF-β/
1. Friedreich N: Ein neuer Fall von Leukämie. Arch Pathol 12:37, 1857.
MYH11 fusion transcript copy number greater than 10 had a shorter
2. Ebstein W: Ueber die acute Leukämie und Pseudoleukämie. Dtsch Arch Klin Med
remission duration and higher risk for relapse than did patients with 44:343, 1889.
a copy number less than 10.1295 Evidence indicates transcript ratios of 3. Fraenkel A: Ueber acute Leukämie. Dtsch Med Wochenschr 21:639, 1895.
samples may have utility in establishing thresholds for curability and for 4. Neumann E: Ueber myelogene leukäemie. Berl Klin Wochenschr 15:69, 1878.
5. Ehrlich P: Farbenanolytische Untersuchungen zur Histologie und Klinik des Blutes.
relapse risk in standard clinical CR states in the future.1296 Hirschwald, Berlin, 1891.
6. Naegeli O: Ueber rothes Knochenmark und Myeloblasten. Dtsch Med Wochenschr
Detecting t(8;21) 26:287, 1900.
Translocation 8;21 is one of the most common translocations in AML, 7. Hirschfield H: Zur Kenntnis der Histogenese der granulirten Knochenmarkzellen.
Arch Pathol 153:335, 1898.
especially in younger patients (see Table 88–9). This translocation fuses 8. Hsu TC: Human and Mammalian Cytogenetics: An Historical Perspective. Springer-
the RUNX1 gene on chromosome 21p to RUNXIT1 (ETO) on chromo- Verlag, New York, 1979.
some 8p to produce the fusion gene.1297,1298 The fusion has been detected 9. Subramanian G, Adams MD, Venter JC, Broder S: Implications of the human genome
for understanding human biology and medicine. JAMA 286:2296, 2001.
in the majority of patients in remission. One study found its persistence 10. Ellison RR, Holland JF, Weil M, et al: Arabinosyl cytosine: A useful agent in the treat-
in all patients with t(8;21) after chemotherapy or autologous marrow ment of acute leukemia in adults. Blood 33:507, 1968.
transplantation.1299–1301 Quantitation of the amount of the fusion tran- 11. Yates JW, Wallace HJ, Ellison RR, Holland JF: Cytosine arabinoside and daunorubicin
therapy in acute non-lymphocytic leukemia. Cancer Chemother Rep 52:485, 1973.
script during remission may be more predictive of cure or relapse than a
12. Lichtman MA: A historical perspective on the development of the cytarabine (7 days)
simple qualitative assessment.1302,1303 Real-time quantitative RT-PCR can and daunorubicin (3 days) treatment regimen for acute myelogenous leukemia: 2013
be used for this purpose. the 40th anniversary of 7+3. Blood Cells Mol Dis 50:119, 2013.
In general, CBF leukemias lend themselves to MRD monitoring 13. Thomas ED, Buckner CD, Banaji M, et al: One hundred patients with acute leukemia
treated by chemotherapy, total body irradiation, and allogeneic bone marrow trans-
by quantitative RT-PCR. In a trial from the Medical Research Coun- plantation. Blood 49:511, 1977.
cil, in 163 patients with t(8;21) and 115 with inv(16), quantitative PCR 14. Preston DL, Kusumi S, Tomonaga M, et al: Cancer incidence in atomic bomb survi-
transcripts at end of induction and end of consolidation course three vors. Part III. Leukemia, lymphoma and multiple myeloma, 1950–1987. Radiat Res
137(2 Suppl):S68, 1994.
were informative for relapse. Rising MRD levels in blood also predicted 15. Tsushima H, Iwanaga M, Miyazaki Y. Late effect of atomic bomb radiation on myeloid
relapse.1304 Another study showed that a three-log reduction in MRD disorders: Leukemia and myelodysplastic syndromes. Int J Hematol 95:232, 2012.
after one consolidation had prognostic value whereas expression of KIT 16. Rinsky RA, Smith AB, Hornung R, et al: Benzene and leukemia. An epidemiologic
and FLT3 mutations did not.1305 risk assessment. N Engl J Med 316:1044, 1987.
17. Johnson GT, Harbison SC, McCluskey JD, Harbison RD: Characterization of cancer
risk from airborne benzene exposure. Regul Toxicol Pharmacol 55:361, 2009.
Detecting t(15;17) 18. Pyatt D: Benzene and hematopoietic malignancies. Clin Occup Environ Med 4:529, 2004.
Unlike AML with the fusion transcript t(8;21), in APL the t(15;17) 19. Lichtman MA: Cigarette smoking, cytogenetic abnormalities, and acute myelogenous
leukemia. Leukemia 21:1137, 2007.
fusion transcript usually disappears after intensive therapy.1306 At least
20. Rund D, Ben-Yehuda D: Therapy-related leukemia and myelodysplasia: Evolving con-
one in 100,000 cells with the PML-RAR-α transcript can be detected by cepts of pathogenesis and treatment. Hematology 9:179, 2004.
RT-PCR.1306 FISH also can be used.1307 Molecular monitoring has shown 21. Larson RA, Le Beau MM: Therapy-related myeloid leukaemia: A model for leukemo-
treatment is capable of achieving a molecular remission (negative genesis in humans. Chem Biol Interact 153–154:187, 2005.
22. Yeasmin S, Nakayama K, Ishibashi M, et al: Therapy-related myelodysplasia and
RT-PCR).1308 Nested PCR can be used to determine the need for addi- acute myeloid leukemia following paclitaxel- and carboplatin-based chemotherapy in
tional treatment at the end of consolidation, to determine the advisabil- an ovarian cancer patient: A case report and literature review. Int J Gynecol Cancer
ity of autologous stem cell transplantation in second remission, and to 18:1371, 2008.
23. Visfeldt J, Anderson M: Pathoanatomical aspects of malignant haematological disor-
predict relapse after transplantation.1309 Real-time quantitative RT-PCR ders among Danish patients exposed to thorium dioxide. APMIS 103:29, 1995.
may improve the predictive value of MDR assessment and aid in labo- 24. Brownson RC, Novotny TE, Perry MC: Cigarette smoking and adult leukemia: A
ratory standardization.1310 meta-analysis. Arch Intern Med 153:469, 1993.
25. Stewart SL, Cardinez CJ, Richardson LC, et al: Surveillance for cancers associated with
tobacco use—United States, 1999–2004. MMWR Surveill Summ 57:1, 2008.
Detecting NPM-1 and FLT3 Mutations 26. Rhomberg LR, Bailey LA, Goodman JE, et al: Is exposure to formaldehyde in air caus-
In AML patients who have normal cytogenetics, mutational status of ally associated with leukemia?—A hypothesis-based weight-of-evidence analysis. Crit
NPM1, FLT3, CEPBA, MLL, and RAS have implications for treatment Rev Toxicol 41:555, 2011.
27. Checkoway H, Boffetta P, Mundt DJ, et al: Critical review and synthesis of the epi-
outcomes and prognosis.1311 Whether detection of these mutations as a
demiologic evidence on formaldehyde exposure and risk of leukemia and other lym-
reflection of MRD will have implications for relapse and therapy remains phohematopoietic malignancies. Cancer Causes Control 23:1747, 2012.
undetermined. Cumulative incidence of relapse is higher in those who 28. Lichtman MA: Obesity and the risk for a hematological malignancy: Leukemia, lym-
remain positive using real-time quantitative PCR consolidation.1312 There phoma, or myeloma. Oncologist 15:1083, 2010.
29. Swolin B, Rödjer S, Westin J: Therapy-related patterns of cytogenetic abnormalities
is evidence in NPM1-mutated cases, relapse was accompanied by an in acute myeloid leukemia and myelodysplastic syndrome post polycythemia vera:
increase of mutant gene copy numbers; it has been concluded that quan- Single center experience and review of literature. Ann Hematol 87:467, 2008.
titative PCR monitoring may have prognostic impact in such patients.1313 29a. Xie M, Lu C, Wang J, et al: Age-related mutations associated with clonal hematopoi-
etic expansion and malignancies. Nat Med 20:1472, 2014.
The technology to detect MRD has increased in sensitivity and 30. Wiernik P: Leukemias and plasma cell myeloma. Cancer Chemother Biol Response
availability. Detection of MRD to determine a patient’s treatment or Modif 17:390, 1997.
prognosis remains an evolving area of investigation. The role that pro- 31. Luca DC, Almanaseer IY: Simultaneous presentation of multiple myeloma and acute
teomic1314,1315 and microRNA profiles1316–1319 will play in MRD detection monocytic leukemia. Arch Pathol Lab Med 127:1506, 2003.
32. Pulik M, Genet P, Jary L, et al: Acute myeloid leukemias, multiple myelomas, and
is under study. chronic leukemias in the setting of HIV infection. AIDS Patient Care STDS 12:913, 1998.
33. Yohe SL, Chenault CB, Torlakovic EE, et al: Langerhans cell histiocytosis in acute
leukemias of ambiguous or myeloid lineage in adult patients: Support for a possible
clonal relationship. Mod Pathol 27:651, 2014.
34. Edelbroek JR, Vermeer MH, Jansen PM, et al: Langerhans cell histiocytosis first
Marshall A. Lichtman has been an expert witness on behalf of defen- presenting in the skin in adults: Frequent association with a second haematological
malignancy. Br J Dermatol Dermatology 167:1287, 2012.
dants in toxic tort cases involving occupational exposure to chemicals, 35. Moskowitz C, Dutcher JP, Wiernik PH: Association of thyroid disease with acute leu-
including benzene. kemia. Am J Hematol 39:102, 1992.

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