ASH Hematology Review Series

Myeloproliferative Neoplasms

Presented by Ann Mullally, MD

Disclosures
• Research Funding: Janssen, Actuate Therapeutics
• Consulting: Janssen
• Honoraria: Blueprint Medicines, Roche, Incyte
 ABIM Hematology: MPN topics [= 4.5% exam]

• Chronic myeloid leukemia

• Polycythemia and secondary erythrocytosis
• Essential thrombocythemia
• Primary myelofibrosis
• Mastocytosis
• Chronic neutrophilic leukemia
 Myeloproliferative Neoplasms (MPN)

 Clonal hematopoietic stem cell disorders

 Characterized by proliferation of one or more myeloid lineages
 Preservation of relatively normal hematopoietic differentiation
 Peak frequency in 6th -7th decades of life
 Clinical heterogeneity
 MPN Classification

BCR-ABL positive BCR-ABL negative

Chronic myelogenous leukemia (CML)  Polycythemia vera (PV)
 Essential thrombocythemia (ET)
 Primary myelofibrosis (PMF)
 Mastocytosis
 Chronic neutrophilic leukemia
 Chronic eosinophilic leukemia
Activated JAK-STAT signaling underlies BCR-ABLneg MPN pathogenesis

Jyoti Nangalia, Anthony R. Green, Myeloproliferative neoplasms:

from origins to outcomes, Blood, 2017, Figure 1.
 MPN phenotypic driver mutations

Yellow = ET
Red = PV
Brown = MF
JAK2, CALR, MPL
MPN phenotypic mutations
Typically mutually exclusive

Pontus Lundberg, Axel Karow, Ronny Nienhold, Renate Looser, Hui Hao-Shen, Ina Nissen, Sabine Girsberger,
Thomas Lehmann, Jakob Passweg, Martin Stern, Christian Beisel, Robert Kralovics, Radek C. Skoda, Clonal
evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms, Blood, 2014, Figure 2
 BCR-ABL negative MPN – survival

Ayalew Tefferi, Paola Guglielmelli, Dirk R. Larson, Christy Finke, Emnet A. Wassie, Lisa Pieri, Naseema Gangat, Rajmonda
Fjerza, Alem A. Belachew, Terra L. Lasho, Rhett P. Ketterling, Curtis A. Hanson, Alessandro Rambaldi, Guido Finazzi,
Juergen Thiele, Tiziano Barbui, Animesh Pardanani, Alessandro M. Vannucchi, Long-term survival and blast transformation
in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis, Blood, 2014, Figure 1
 JAK2: structure-function

Edwin Chen, Ann Mullally, How does JAK2V617F contribute to the pathogenesis of myeloproliferative
neoplasms?, Hematology Am Soc Hematol Educ Program, 2014, Figure 1.
 CALR mutations in MPN

• Mutations occur as insertions and/or deletions in exon 9

• ALL mutations cause a +1 bp frame shift leading to:
• loss of the KDEL sequence
• introduction of a novel C-terminal peptide
 CALR mutations in MPN

Michele Ciboddo, Ann Mullally, JAK2 (and other genes) be nimble with MPN diagnosis,
prognosis, and therapy, Hematology Am Soc Hematol Educ Program, 2018, Figure 1.
Mechanism by which mutant CALR causes MPN

Joan How, Gabriela S. Hobbs, Ann Mullally, Mutant calreticulin

in myeloproliferative neoplasms, Blood, 2019,
 MPN Disease-Initiating Stem Cells

Adam J. Mead, Ann Mullally, Myeloproliferative neoplasm stem cells,

Blood, 2017, Figure 2.
 Causes of erythrocytosis

Idiopathic
Primary Secondary
 Causes of secondary erythrocytosis

Congenital:

Acquired:
(EPO-mediated)

Mary Frances McMullin, Idiopathic erythrocytosis: a disappearing entity,

Hematology Am Soc Hematol Educ Program, 2009, Table 1.
 WHO Diagnostic criteria for Polycythemia Vera

MAJOR CRITERIA:
• Hemoglobin > 16.5g/dL in men, >16.0g/dL in women OR
• HCT > 49% in men, >48% in women OR
• Increased red cell mass (RCM) > 25% above mean normal predicted value

• Hypercellular bone marrow with panmyelosis

• Presence of JAK2V617F mutation or other functionally similar mutation (e.g. JAK2 exon 12)
MINOR CRITERIA:
• Serum erythropoietin below reference range for normal
* All 3 major or first 2 major plus minor criteria to make diagnosis
 Diagnostic work-up of erythrocytosis

SN = subnormal
Alessandro M. Vannucchi,
N/I – normal/increased
How I treat polycythemia vera,
Blood, 2014, Figure 1
 Clinical Presentation of Polycythemia Vera

❑ Presenting symptoms: ❑ Presenting signs:

➢ Fatigue, dyspnea ➢ Splenomegaly
➢ Headaches, dizziness, visual ➢ Plethora
changes, vertigo
➢ Systemic hypertension
➢ Pruritus
➢ Hepatomegaly
➢ Erythromelalgia
➢ Gout
➢ Arterial or venous thrombosis
➢ Cutaneous ulcers
➢ Epistaxis, GI bleeding
Clinical Management of Polycythemia Vera

Brady L. Stein, Karlyn Martin,

From Budd-Chiari syndrome to
acquired von Willebrand syndrome:
thrombosis and bleeding
complications in the
myeloproliferative neoplasms,
Hematology Am Soc Hematol Educ
Program, 2019, Figure 3.
 Clinical Management of Polycythemia Vera – Summary

❑ Therapeutic Phlebotomy (goal HCT < 45%)

❑ Prevention of Thrombosis
➢ Low dose ASA
➢ Anticoagulation in the setting of thrombosis
❑ Cytoreductive therapy
➢ Hydroxyurea (HU)
➢ Interferon (particularly if age < 40 years)
➢ Ruxolitinib (JAK2 inhibitor) if HU intolerant/resistant
Causes of secondary thrombocytosis

❑ Iron deficiency
❑ Infection / Inflammatory state
❑ Connective tissue disease
❑ Malignancy
❑ Post-splenectomy
❑ Surgery
 WHO Diagnostic criteria for Essential Thrombocythemia
MAJOR CRITERIA:
• Sustained platelet count > 450 x 109/L
• Megakaryocytic hyperplasia on bone marrow biopsy (enlarged, mature megakaryocytes)
• Not meeting WHO criteria for another myeloid neoplasm e.g. PV, PMF, CML, MDS
• Presence of JAK2, CALR or MPL mutation

MINOR CRITERIA:
• Presence of a clonal marker or absence of evidence for reactive thrombocytosis

* All 4 major criteria or the first 3 major criteria plus the minor criterion required for diagnosis
 Diagnostic work-up of thrombocytosis

Elisa Rumi, Mario Cazzola,

How I treat essential
thrombocythemia,
Blood, 2016, Figure 1.
 Clinical Presentation of Essential Thrombocythemia

❑ Presenting symptoms:
➢ Headaches, dizziness, visual changes, vertigo, seizures
➢ Erythromelalgia
➢ Paresthesias
➢ Arterial > venous thrombosis
➢ GI or mucosal bleeding, epistaxis (acquired vWD)
➢ First trimester spontaneous abortion

❑ Presenting signs:
➢ Splenomegaly (25%)
➢ Cutaneous ulcers
 International Prognostic Score of Thrombosis in ET (IPSET)

Tiziano Barbui, Guido Finazzi, Alessandra Carobbio, Juergen Thiele, Francesco Passamonti, Elisa Rumi, Marco Ruggeri,
Francesco Rodeghiero, Maria Luigia Randi, Irene Bertozzi, Heinz Gisslinger, Veronika Buxhofer-Ausch, Valerio De Stefano,
Silvia Betti, Alessandro Rambaldi, Alessandro M. Vannucchi, Ayalew Tefferi, Development and validation of an
International Prognostic Score of thrombosis in World Health Organization–essential thrombocythemia
(IPSET-thrombosis), Blood, 2012, Table 2
Clinical Management of Essential Thrombocythemia

Brady Stein, Karlyn Martin,

From Budd-Chiari
syndrome to acquired von
Willebrand syndrome:
thrombosis and bleeding
complications in the
myeloproliferative
neoplasms, Hematology Am
Soc Hematol Educ Program,
2019, Figure 2.
 WHO Diagnostic criteria for Primary Myelofibrosis
MAJOR CRITERIA:
• Megakaryocytic proliferation with reticulin/collagen fibrosis (grade 2/3)
• Not meeting WHO criteria for another myeloid neoplasm e.g. PV, CML, MDS
• Presence of JAK2, CALR or MPL mutation or in the absence if these mutations, presence of
another clonal marker, or absence of reactive myelofibrosis
MINOR CRITERIA:
• Anemia not attributed to a co-morbid condition
• Leukocytosis >/= 11 x 10^9/L
• Palpable splenomegaly
• LDH increased to above upper normal limit of reference range
• Leukoerythroblastosis
* All 3 major plus at least 1 minor criteria required to make diagnosis
 Clinical Features of Myelofibrosis

❑ Symptoms: ❑ Signs:
➢ Constitutional: fever, sweats, ➢ Splenomegaly (85-100%)
weight loss ➢ Hepatomegaly, extra-medullary
➢ Fatigue hematopoiesis (EMH)
➢ Abdominal pain, early satiety ➢ Cachexia
➢ Splenic infarct ➢ Gout
➢ GI bleeding, bruising ➢ Portal HTN/ascites
 Myelofibrosis – peripheral blood – myelophthisis

Image ID: 1183

Authors: Peter Maslak

Copyright © 2020 American Society of Hematology. Copyright restrictions may apply.

 Myelofibrosis – bone marrow – reticulin stain

Image ID: 3930

Authors: Hussein Said Baden

Copyright © 2020 American Society of Hematology. Copyright restrictions may apply.

 Myelofibrosis – massive splenomegaly

Image ID: 60983

Authors: Omer Hassan Jamy; Victor Lin

Copyright © 2020 American Society of Hematology. Copyright restrictions may apply.

 Dynamic International Prognostic Scoring System-plus (DIPSS-plus)

Ayalew Tefferi,
How I treat myelofibrosis,
Blood, 2011, Figure 1

**Constitutional symptoms = weight loss > 10% of baseline in year preceding diagnosis, unexplained fever, or excessive sweats for > 1 month.
***Unfavorable karyotype = complex karyotype or sole or 2 abnormalities that include +8, −7/7q−, i(17q), inv(3), −5/5q− 12p−, or 11q23
 MIPSS70: Mutation Enhanced IPSS for Myelofibrosis

HMR* = ASXL1, EZH2, SRSF2 or IDH 1/2 mutation

Unfavorable karyotype** = any karyotype that is NOT normal, 20q-, 13q-, 9+, chromosome 1 translocation/duplication,
Y- OR a sex chromosome abnormality other than Y-
 Treatment of Myelofibrosis
• Low / Int-1 risk:
- Observation if asymptomatic
- Erythropoiesis stimulating agents (ESA) if anemic
- Lenalidomide if del (5q)
- Hydroxyurea if symptomatic splenomegaly
• Int-2 / High risk:
- Allogeneic stem cell transplant
- Ruxolitinib or fedratinib (JAK2 kinase inhibitors)
- Investigational

*Splenomegaly: hydroxyurea/JAK2i/splenectomy/splenic XRT

*Portal HTN: Transjugular intrahepatic portosystemic shunt (TIPS)
 Ruxolitinib – summary
❑Ruxolitinib is an oral JAK1/JAK2 inhibitor
❑First ever FDA approved drug for MF (approved in 2011)
❑Approved for intermediate/ high risk MF regardless of JAK2 mutational status
(not JAK2V617F-mutant specific)
❑Subsequently approved for PV patients who are intolerant of or refractory to hydroxyurea
❑Reduces splenomegaly and constitutional symptoms in MF
❑Not clonally selective (doesn’t preferentially kill JAK2V617F cells)
❑Despite this overall survival appears to be improved in MF
❑Anemia is a dose-limiting toxicity
❑Fedratinib (JAK2 inhibitor) approved in 2019 for MF (first line or ruxolitinib refractory)
❑In rare cases fedratinib is associated with Wernicke’s encephalopathy (boxed warning)

FDA = Food and Drug Administration

 Diagnosis of systemic mastocytosis

William Shomali, Jason Gotlib,

The new tool “KIT” in advanced
systemic mastocytosis,
Hematology Am Soc Hematol Educ
Program, 2018, Figure 1.
 KIT D816V mutation in systemic mastocytosis

KIT D816V:
Imatinib resistant
Midostaurin sensitive (FDA-approved)
Avapritinib sensitive (investigational)

ISM = indolent systemic mastocytosis

Andreas Reiter, Tracy I. George, Jason Gotlib, New SSM = smoldering systemic mastocytosis
developments in diagnosis, prognostication, and ASM = advanced systemic mastocytosis
treatment of advanced systemic mastocytosis, AHN = associated hematological neoplasm
Blood, 2020, Figure 2. MCL = mast cell leukemia
 WHO Diagnostic criteria for Chronic Neutrophilic Leukemia

• Peripheral blood WBC > / = 25 x 109/L (neutrophilia)

• Hypercellular bone marrow (< 5% blasts, mature neutrophil predominance)
• Not meeting WHO criteria for another myeloid neoplasm e.g. CML, PV, ET or PMF
• No rearrangement of PDGFRA, PDGFRB, FGFR1 or PCM1-JAK2
• Presence of CSF3R T618I or other activating CSF3R mutation

OR
• In the absence of a CSF3R mutation, persistent neutrophilia (min. 3 months), splenomegaly
and no identifiable cause of reactive neutrophilia including no plasma cell neoplasm or, if
present, demonstration of clonality of myeloid cells by cytogenetic or molecular studies
CSF3R mutations in chronic neutrophilic leukemia (CNL)

In 2020, a Phase 2 clinical trial of

ruxolitinib in CNL was completed

Julia E. Maxson, Jeffrey W. Tyner, Genomics of chronic

neutrophilic leukemia, Blood, 2017, Figure 1.
 Affiliations and Acknowledgements

mullallylab.bwh.harvard.edu
@MullallyLab