How I Treat

How we perform haploidentical stem cell transplantation

with posttransplant cyclophosphamide
Shannon R. McCurdy1,2 and Leo Luznik3,4
1
Abramson Cancer Center and 2Division of Hematology and Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA; and 3Department of Oncology
and 4Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD

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HLA-haploidentical hematopoietic stem cell transplantation is now one of the most commonly employed alternative
donor techniques, with most centers applying T-cell–replete strategies such as that developed by the Baltimore group
using high-dose posttransplant cyclophosphamide. HLA-haploidentical hematopoietic stem cell transplantation using
posttransplant cyclophosphamide is associated with low rates of severe graft-versus-host disease and nonrelapse
mortality and does not require graft manipulation or storage, which results in a low graft acquisition cost. Its re-
markable safety when used with reduced-intensity conditioning has been demonstrated in patients up to 75 years old
with outcomes similar to those of patients in their 50s. Several large, registry-based retrospective studies have
confirmed the efficacy of HLA-haploidentical hematopoietic stem cell transplantation with posttransplant cyclo-
phosphamide, achieving results comparable to those of HLA-matched hematopoietic stem cell transplantation. In this
article, we describe our approach to this rapidly available and clinically simple platform and address some of the key
clinical questions associated with its use. (Blood. 2019;134(21):1802-1810)

Introduction recipient, determining which donor factors influence outcomes

is particularly important in haplo-HSCT. Several studies have
Over the past two and one-half decades, several methods of
been published in the past few years to try to improve donor
facilitating HLA-haploidentical hematopoietic stem cell trans-
selection alogrithms.9-13 One of the most important facets of
plantation (haplo-HSCT) have been developed. The 3 most
donor selection that is unique to HLA-mismatched trans-
frequently used platforms consist of (1) posttransplant cyclo-
plantation are donor-specific antibodies (DSA), which, if present,
phosphamide (PTCy); (2) granulocyte colony-stimulating fac-
can require additional desensitization techniques to mitigate the
tor priming, intensive postgrafting immunosuppression, and
risk of graft failure or may even preclude the use of a given
antithymocyte globulin using combined peripheral blood stem
donor.14,15
cell and bone marrow (BM) allografts; and (3) T-cell depletion
with either “megadose” CD341 cells or selected a/b T-cell
and B-cell depletion. Owing in part to the development of Given its increased use, questions that have previously been
T-cell–replete strategies such as the use of PTCy,1 which has addressed in HLA-matched HSCT are now being asked in haplo-
been associated with survival outcomes comparable to those of HSCT. For instance, the merits of increasing conditioning in-
HLA-matched HSCT,2-6 there has been a rapid expansion in tensity, differing graft sources, and disease status are being
haplo-HSCT. For instance, among centers within the Euro- examined in haplo-HSCT using PTCy, with conclusions mostly
pean Society for Blood and Marrow Transplantation, the use akin to those in HLA-matched HSCT. Although survival out-
of haploidentical donors grew by 291% from 2005 to 2015.7 comes, including relapse, after haplo-HSCT and HLA-matched
A previous review summarized the most often applied HSCT appear to occur at similar rates, it is important to recognize
T-cell–replete and T-cell–depleted haplo-HSCT strategies,8 that a distinct immune mechanism with significant clinical im-
but the present article focuses on PTCy-based haplo-HSCT, plications, called “HLA loss,” occurs in 30% of acute myeloid
which is cost-effective, safe, and easily replicated, leading to leukemia (AML) relapses after haplo-HSCT.16-18 The present
its widespread use. article discusses a complicated case of one patient with AML
to review what we have learned in the last decade of research
An advantage of haplo-HSCT is the rapidity and near-universality and describes the authors’ personal approach to haplo-HSCT
of identifying haploidentical donors and their availability for with PTCy.
subsequent stem cell or lymphocyte donation to treat relapse or
boost engraftment. For instance, at Johns Hopkins Hospital from
2006 to 2011, 96.6% of recipients had one or more haplo- Clinical case
identical donors, with an average of 2.5 donors per candidate. A 58-year-old African American man with insulin-dependent
Given that multiple donors are often available for a given diabetes, hypertension, and depression controlled with a

1802 blood® 21 NOVEMBER 2019 | VOLUME 134, NUMBER 21 © 2019 by The American Society of Hematology
 Father Haplo Mother Haplo

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03:02 DRB1 DRB1 11:02 03:02 DRB1 DRB1 15:03 07:01 DRB1 DRB1 11:02 07:01 DRB1 DRB1 15:03
04:02 DQB1 DQB1 03:01 04:02 DQB1 DQB1 06:02 02:02 DQB1 DQB1 03:01 02:02 DQB1 DQB1 06:02
01:01 DPB1 DPB1 04:01 01:01 DPB1 DPB1 03:01 04:02 DPB1 DPB1 04:01 04:02 DPB1 DPB1 03:01

Brother 1: Haplo donor Patient Brother 2: Disparate Sister: Haplo

Figure 1. Family pedigree of the patient in the clinical case. An HLA-haploidentical donor has inherited one HLA haplotype in common with the recipient and is mismatched for
anywhere between 0 and 5 HLA genes on the unshared haplotype. Biological parents and biological children always share an HLA haplotype with the recipient, unless a rare
genetic rearrangement has occurred. In this pedigree analysis, the patient has 3 siblings, none of whom are HLA-matched, but 2 are partially matched related (haploidentical)
donors, whereas 1 brother is disparate. Other potential HLA-haploidentical donors include half-siblings, aunts, uncles, nieces, nephews, cousins, or grandchildren.

selective serotonin reuptake inhibitor was diagnosed with AML and underrepresentation in donor registries. There is also a
with a complex karyotype after presenting with leukocytosis, sense of urgency for patients with high-risk acute leukemia,
anemia, and thrombocytopenia. He underwent initial manage- which may preclude the time required to identify an unrelated
ment with fluids, hydroxyurea, and allopurinol, then initiation of donor in the registry. Over recent years, haploidentical donors
induction chemotherapy with cytarabine and daunorubicin (7 1 have increasingly been adopted as a valid, immediately avail-
3). His clinical course was complicated by neutropenic fever that able donor source when an HLA-matched sibling donor (MSD)
resolved with cefepime. A day 14 BM biopsy showed no residual is unavailable. However, there are certain clinical scenarios
AML. On his recovery bone marrow biopsy, he achieved a in which a MUD or an HLA-mismatched unrelated donor (MMUD)
morphologic complete remission (CR), but with residual cyto- is preferred. These include recipients with familial genetic syn-
genetic abnormalities. At the time of count recovery, he was dromes; very high levels of DSA to family members; or those
referred for discussion of HSCT. His HSCT-specific comorbidity who lack living relatives, are estranged from their families, or are
index score was 2. The patient’s immediate family included an adopted and have no children.
88-year-old father, an 85-year-old mother, 2 brothers aged 60
and 52 years old, and 1 sister who was 65 years old. He did not In the absence of a definitive indication for an unrelated donor
have any biological children. Both parents shared one HLA search, is waiting for an unrelated donor beneficial? Data are
haplotype with the patient; the younger brother and his sister growing on the similarity in outcomes between haplo-HSCT and
also shared one HLA haplotype; and the older brother was both MUD-HSCT and MSD-HSCT. In one of the earliest studies
disparate (Figure 1). Class I and class II screens for DSA were comparing HLA-matched HSCT with haploidentical bone mar-
negative. A preliminary unrelated donor search showed 3 po- row transplantation (haplo-BMT) employing PTCy, we used the
tential donors who had a low probability of being a 10/10 Disease Risk Index to show risk-stratified outcomes. In that study,
HLA match. 3-year overall survival (OS) rates were 70% and 73% in low-risk
disease, 47% and 49% in intermediate-risk disease, and 25% and
37% in high/vs high-risk disease in HLA-matched and haplo-
HSCT, respectively.2 Later that year, in a large Center for In-
Questions ternational Blood and Marrow Transplant Research (CIBMTR)
Is there benefit in waiting for a completed matched analysis, Ciurea et al showed that, among patients with AML
unrelated donor search vs proceeding directly with in complete remission (CR), there was no significant differ-
a haploidentical donor? ence in 3-year probability of OS after MUD with calcineurin
Identifying fully HLA-matched unrelated donors (MUDs) is dif- inhibitor–based prophylaxis and haplo-HSCT with PTCy with
ficult for some ethnic groups, reflecting both their HLA diversity either myeloablative conditioning (MAC) or reduced-intensity

HOW I MANAGE PATIENTS UNDERGOING haplo-HSCT blood® 21 NOVEMBER 2019 | VOLUME 134, NUMBER 21 1803
conditioning (RIC).3 In another CIBMTR study, there were no Given the data showing that younger donor age improved
significant differences in grades II to IV acute graft-versus- outcomes in recipients of MUD allografts,34-36 donor age is of
host disease (aGVHD), relapse, nonrelapse mortality (NRM), keen interest in haplo-HSCT, where multiple donors are often
or OS for AML in CR1 after MSD- and haplo-HSCT, but there available. Understanding the impact of donor age on outcomes
was less chronic graft-versus-host disease (cGVHD) in recip- in haplo-HSCT is difficult, not only because of the correlation
ients of haploidentical grafts, regardless of conditioning or between donor and recipient age, but also because of the
graft source, owing to the use of PTCy.19 For poor-risk AML in correlation of recipient age and donor relationship inherent to
CR, when all graft sources were compared, MSD-, MUD-, and haploidentical related donors; that is, older recipients are more
haplo-HSCT did not significantly differ with regard to OS, but likely to have children or sibling donors, whereas younger re-
cord blood transplantation and 9/10 MUD were associated cipients are more likely to have sibling or parent donors. For
with inferior survival.20 instance, in a CIBMTR analysis, mortality risk was higher when
donors were 30 years or older; however, when patient age,
In an analysis of patients with AML aged 60 years and older, which negatively impacts outcomes, was entered into the
haplo-HSCT with PTCy and MUD-HSCT were not associated model, the effect of donor age was negated.10 In that study,
with significant differences in OS and leukemia-free survival although donor age did not affect outcomes, parent donors

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(LFS), but MUD-HSCT was associated with a higher incidence of were associated with more graft failure (14% compared with 6%
extensive cGVHD.21 In contrast, in 2 studies in older recipients, to 7% with siblings and offspring), but this had no effect on
survival when using MUD donors younger than age 4022 or using survival.10 In a subsequent study by the European Society for
an MSD23 was improved when compared with haploidentical Blood and Marrow Transplantation in patients with acute leu-
donors, owing to less relapse.22 The authors concluded that this kemia over the age of 40 years, donors over 40 years old were
difference may be due to a greater use of peripheral blood stem associated with higher NRM and inferior OS and LFS.37 However,
cell transplantation (PBSCT) in recipients of both MSD-HSCT23 in recipients under 40 years old, donor age did not influence
and MUD-HSCT22 in those studies, which has been associated outcomes.37 Recently, we have demonstrated the safety of
with less relapse24,25 and improved survival25 in these platforms. second-degree relative haplo-HSCT with PTCy using pre-
In a single-center study comparing haplo-PBSCT with PTCy with dominantly nephews, nieces, and grandchildren.38 These data raise
MUD-PBSCT, there were no significant differences in survival the following yet unanswered questions:
outcomes.26 1. In older recipients without children, should we use younger
second-degree donors (nieces or nephews) rather than
Given the many studies showing equivalency between HLA- haploidentical sibling donors?
matched HSCT and haplo-HSCT, 5 our practice is to not 2. For recipients with children over 40 years old, should we use
routinely formalize a MUD search unless contraindications to grandchildren rather than offspring donors?
haplo-HSCT exist or no eligible physically and psychologically fit
haploidentical donors are identified. However, a currently en- Although the data are preliminary, our practice is to avoid parent
rolling Bone Marrow Transplant Clinical Trials Network (BMT donors and choose the youngest eligible donor when multiple
CTN 1702) study is asking whether the strength of the pre- haploidentical donors are available.
liminary MUD search can be used to decide whether awaiting a
MUD or proceeding with an alternative donor results in better Does conditioning intensity matter?
outcomes. The vast majority of data demonstrating the efficacy of haplo-
HSCT with PTCy is associated with the widely accepted RIC
approach that consists of fludarabine/cyclophosphamide and
Donor selection: do donor relationship, low-dose total body irradiation (TBI), with recent interest in in-
cytomegalovirus serostatus, and age matter? creasing the intensity of TBI from 200 cGy to 400 cGy to further
One of the unique aspects of haplo-HSCT with PTCy is that there reduce relapse and graft failure. However, far less consensus
is no need to minimize the extent of mismatch between donor exists with regard to the preferred MAC regimen for haplo-HSCT
and recipient.27 Although we do not currently use the number of with PTCy. This is in part due to a wide range of conditioning
mismatches to choose between haploidentical donors, this may platforms used, including busulfan/cyclophosphamide, fludar-
change as our understanding of the immune effects of each abine/TBI, fludarabine/busulfan and thiotepa, fludarabine/
individual HLA allele expands. For instance, certain preliminary melphalan and thiotepa, or fludarabine/busulfan, each of which
studies have demonstrated improved progression-free survival has been studied in relatively small patient populations with
with class II mismatching in HLA-DRB1 and HLA-DPB1.13,28,29 In encouraging results. For instance, fludarabine/busulfan and
the absence of a negative effect of increasing HLA mismatch on thiotepa haplo-BMT with PTCy39 and fludarabine/TBI haplo-
outcomes,9,12,13 other donor selection criteria have gained more PBSCT with PTCy40 were associated with a cumulative incidence
attention.11 A traditional risk factor for poor outcomes with HLA- of relapse of 24% at 4 years39 and 2 years,40 respectively, with low
matched HSCT has been mismatched donor–recipient cyto- associated NRMs.
megalovirus (CMV) serostatus. However, 2 haplo-HSCT studies
showed that donor CMV serostatus was not associated with A recurring question in HSCT is whether the intensity of the
outcomes.30,31 This may be due to the high rate of CMV reac- preparative regimen impacts outcomes. In haplo-HSCT, several
tivation in all CMV-positive recipients undergoing haplo-HSCT, studies have sought to examine this question. For instance, when
which has led to interest in escalating antiviral prophylaxis to we compared PTCy platforms including MAC MSD, MAC MUD,
prevent CMV in this population32 as well as the need to in- and RIC haplo-HSCT, we found that composite GVHD-free and
vestigate more active agents such as letermovir.33 relapse-free survival endpoints were not significantly different.6

1804 blood® 21 NOVEMBER 2019 | VOLUME 134, NUMBER 21 McCURDY and LUZNIK
Similarly to HLA-matched HSCT, there was less relapse with Do DSA matter?
MAC but more GVHD and NRM, leading to comparable com- Presence of circulating anti-HLA DSA in the recipient before
posite outcomes. However, this analysis compared intensity in transplantation increases the risk of primary graft failure.53 The
differing donor sources, and the haploidentical cohort received incidence of DSA is highest in parous women, occurring in 52%
mycophenolate mofetil (MMF) and tacrolimus as GVHD pro- (vs 31% in nulliparous females and 11% in males), but DSA can
phylaxis in addition to PTCy. In a propensity score–adjusted also be elicited in patients with high transfusion burden.14 The
analysis of only haplo-HSCT, when compared with MAC HSCT, titer of DSA also influences outcomes, with mean fluorescence
RIC HSCT was associated with no significant differences in OS intensity (MFI) .2000 being associated with graft dysfunction,54
or disease-free survival, but it was associated with higher MFI .500015 being associated with graft failure, and MFI
relapse and less NRM.41 Rates of aGVHD and cGVHD were .10 000 being associated with very high incidence of graft
not different by intensity of conditioning.41 In patients over failure.54 In the study by Ciurea et al, MFI .1500 was associated
60 years old, Santoro et al showed no significant difference in 25% engraftment compared with 95% for patients without
NRM, relapse, OS, or LFS in patients treated with MAC or RIC DSA53; however, other data suggest that MFI ,300055 or ,5000
haplo-HSCT with PTCy. 21 Although data comparing MAC to HLA-A, HLA-B, and HLA-DR does not affect engraftment.56 In
vs RIC exclusively in younger patients does not exist, we our current practice, we do not attempt desensitization if the

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typically reserve MAC conditioning for very fit younger recipient has anti–donor HLA antibodies of sufficient strength to
candidates in whom we anticipate the risk of NRM will be result in a positive complement-dependent cytotoxicity assay
exceedingly low. result (associated with DSA on phenotype panels with MFI
.10 000).14 Although what constitutes a prohibitive DSA level is
unclear, we generally consider antibody levels to be weak to low
Does graft source matter?
with phenotype panel MFI values from 1000 to 3000, moderate
In the original studies of haploidentical donor transplantation,
from 3000 to 5000, and strong when .5000. Moderate to strong
BM was the graft source used.1,42 However, some centers prefer
DSA levels are more frequently directed against familial haplo-
PBSCT, which does not require anesthesia and also avoids
identical donors rather than MMUDs,14 which makes exploring
the logistics of obtaining operating room time and harvesters.
MMUDs particularly important in cases of high DSA levels.
Given that PBSCT has been associated with less graft failure25,43
Importantly, MFI values can differ between laboratories, and
and quicker engraftment in multiple studies of HLA-matched
each institution should define their own MFI thresholds for
HSCT,44-48 there has been clinical interest in using PBSCT for
graft failure risk.
diseases that are associated with difficult engraftment, such as
myeloproliferative neoplasms and myelodysplastic syndrome. In
Our desensitization process consists of tacrolimus and MMF
haplo-HSCT with PTCy, neutrophil engraftment is, on average,
starting 2 weeks before conditioning with every-other-day
1 to 2 days earlier with PBSCT, but rates of graft failure seem
therapeutic plasma exchange (TPE) with post-TPE/IV immuno-
to be similar between the sources.24,49,50 However, a comparison
globulin (IVIG). The number of TPE/IVIG treatments is influenced
of graft sources for myeloproliferative neoplasms and myelo-
by the strength of DSA and cross-matching, being 3 to 4 for weak
dysplastic syndrome has not been performed.
to moderately positive and 5 to 6 for patients with a strongly
positive flow cross-match or a cross-match positive because of
In one of the earliest studies to compare graft sources after the presence of class II antibodies. Under that protocol, 15
RIC haplo-HSCT with PTCy, Castagna et al demonstrated in patients underwent desensitization for high DSA. Fourteen
69 patients that there were no significant differences in survival patients achieved DSA levels below that consistent with a
outcomes.49 In 2017, a CIBMTR study including a variety of positive flow cross-match, all of whom engrafted after HSCT.57
hematologic malignancies enriched for RIC cases found that Other desensitization platforms have been similarly successful.
although OS was not different, aGVHD and cGVHD risk was For instance, Ciurea et al employed a desensitization technique
greater and relapse risk was less with peripheral blood than with that included administration of an irradiated “buffy coat” pre-
BM grafts.24 In another analysis in patients with AML in CR1, pared from 1 unit of blood and administered to the recipient on
there were no differences in 2-year OS, 2-year LFS, cGVHD, the day before transplantation as a method to sop up the DSA.15
relapse, or NRM, but grades III to IV aGVHD incidence was less However, this method has not been approved by the U.S. Food
with BM grafts than with PBSCT.51 In a small study by Bradstock and Drug Administration, and therefore its use is not currently
et al, survival was significantly improved with PBSCT when available outside of a clinical trial.15,58 Regardless of the platform,
compared with BM, but with significant differences between the the goal of desensitizatoin is to reduce DSA to MFI ,3000 on
cohorts; BM recipients received only 1 dose of PTCy, and PBSCT phenotype panels, to achieve a negative flow cross-match,56
recipients received 2.50 In addition, CD341 dose was doubled in or to become C1q testing negative through the clearance
patients receiving PBSCT compared with BM,50 which could of complement-binding antibodies.15 Presence and strength of
have contributed to the inferior outcomes. When using BM DSA are the most important aspects of haploidentical donor
grafts, higher nucleated cell graft dose has been associated with selection, with our practice being to choose the donor with the
improved progression-free survival and OS in haplo-HSCT with least DSA above all other factors and, if necessary, to use a
PTCy.52 Thus, at centers with less experienced harvesters, there MMUD59 rather than a haploidentical related donor for patients
may be an advantage to using PBSCT, which typically has less with prohibitive levels of DSA to relatives.
potential for yielding low-dose grafts. Given the CIBMTR data
showing less relapse with PBSCT,24 we typically choose PBSCT Do MRD and active disease matter?
for patients with good functional status but high-risk hemato- Many studies in HLA-matched HSCT have shown the negative
logic malignancies, including those with minimal residual impact of the presence of MRD in the pretransplantation BM.
disease (MRD). Not surprisingly, pretransplantation MRD was also a risk factor

HOW I MANAGE PATIENTS UNDERGOING haplo-HSCT blood® 21 NOVEMBER 2019 | VOLUME 134, NUMBER 21 1805
for relapse after haplo-HSCT with PTCy, with a 2-year relapse 44% after RIC haploidentical, and 84% after MAC haploidentical),
incidence of 37% compared with 16% in patients who were but with these early fevers having no effect on survival.65 In contrast
MRD-negative before transplant.60 In a study of patients with to BM grafts, haplo-PBSCT has also been associated with CRS,
active AML, patients who underwent haplo-HSCT, MUD-HSCT, with 87% of early febrile patients meeting criteria, 12% of whom
or 9/10 HLA-MUD-HSCT were compared, and there was no experienced grade 3 or 4 CRS.66 Transplantation-related mortality
significant difference in OS, LFS, relapse, or NRM between the also rose in patients with grade 3 or 4 CRS, but symptoms could be
groups.61 In all, the 2-year LFS was 25% in patients with active alleviated with administration of tocilizumab.66 In the absence of
AML at the time of HSCT.61 Whether additional therapy to severe CRS, diagnostic and supportive measures that include
achieve MRD negativity before HSCT improves outcomes or cultures and antipyretics are employed, and because of the dif-
whether it is a function of disease biology that cannot be ficulty of distinguishing sepsis and CRS in real time, broad-
overcome with further treatment remains to be seen. As such, spectrum antibiotics are routinely administered. If grade 3 or
for patients with MRD in whom additional pretransplantation 4 CRS develops before administration of PTCy, we would rec-
therapy is not pursued, we prefer allografting with PBSCTs ommend administering tocilizumab if available and corticosteroids
and/or for early cessation of immunosuppression, which was if tocilizumab is unavailable. Routine administration of cortico-
associated with less relapse in a small study of BM allografts.62 In steroids before PTCy is generally avoided because it could the-

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addition, a clinical trial using maintenance therapies (eg, ena- oretically decrease the efficacy of PTCy by preventing proliferation
sidenib, ivosidenib, idelalisib, gilteritinib, blinatumomab, ven- of alloreactive T cells, which leads them to be susceptible to PTCy
etoclax, and APR-246) or prophylactic posttransplantation and comprises one of PTCy’s several mechanisms of GVHD pre-
immunotherapy (donor lymphocyte or natural killer cell infusion) vention.67 The management of CRS after haplo-HSCT is still a work in
to prevent relapse should be considered in these high-risk progress, with our suggestions merely reflecting our current clinical
patients. practice.

How long do we continue postgrafting

Clinical case continued immunosuppression?
In the original haplo-BMT PTCy study, MMF was administered
The patient discussed above received 1 cycle of high-dose
3 times daily for 35 days, and tacrolimus was administered
cytarabine consolidation that was uncomplicated. His pre-
to maintain a level of 5 to 10 mg/L through day 180 and
transplant BM showed CR without MRD. Sixty days from the start
stopped without a taper.1,42 However, a prolonged duration
of consolidation, he began conditioning consisting of fludar-
of postgrafting immunosuppression has the potential to in-
abine, cyclophosphamide, and TBI followed by haploidentical
crease infectious complications and calcineurin inhibitor–
BM graft with a total nucleated cell count of 2.9 3 107 total
associated side effects and to impede graft-versus-leukemia
nucleated cells per kilogram from his brother, the donor.
responses. Emerging data in the HLA-matched setting sug-
Postgrafting GVHD prophylaxis included PTCy on days 3 and 4,
gest that total immunosuppression burden after PTCy may be
followed on day 5 by initiation of MMF and tacrolimus. He
less than with other strategies.68 As such, we are currently
tolerated the procedure well, with his main complication being
exploring in clinical trials whether we can reduce the duration
high fevers with hemodynamic stability from the time of graft
of tacrolimus after haplo-HSCT with PTCy. In a recent pub-
infusion until after completion of PTCy on day 4, which was
lication, after haplo-BM allografting with PTCy, tacrolimus
attributed to cytokine release syndrome (CRS) secondary to the
could be stopped as early as day 60 after transplantation.62
HLA mismatches between donor and recipient. He had nausea
Clinical trials are ongoing in patients who have under-
and diarrhea during the first month. Neutrophil engraftment
gone allografting using haplo-PBSCT with PTCy to examine
occurred on day 15, with platelet recovery occurring on day 19.
whether immunosuppression can safely be discontinued on
The MMF was discontinued on day 35, and the patient’s
day 90.
gastrointestinal symptoms resolved shortly thereafter. He
developed grade 1 overall acute GVHD after tacrolimus
was discontinued on day 180 that improved with topical
steroids. Days 90 and 180 BM biopsies showed remission with
Clinical case continued
At 8 months after HSCT, our patient had 100% donor chimerism
normal cytogenetics and 100% donor engraftment in both
in the peripheral blood and BM, but he developed isolated
CD31 and CD331 cells.
testicular relapse that was treated with surgery, radiation, and
prophylactic intrathecal chemotherapy. At 13 months after
HSCT, he developed systemic relapse, with BM biopsy re-
Questions continued vealing 63% myeloblasts with 49% recipient DNA. Karyotype
How common is CRS after haploidentical graft analysis at the time of relapse showed a complex karyotype. A
infusion, and how is it treated? small-nucleotide polymorphism array was performed on the
Noninfectious fevers occur in 80% to 90% of haplo-PBSCT re- BM and revealed a clonal 38.2-MB region of copy neutral loss
cipients between days 0 and 6 after transplantation. They typ- of heterozygosity on the short arm of chromosome 6. The
ically resolve soon after completion of PTCy on day 4 and often region of copy neutral loss of heterozygosity included the
do not require administration of steroids.63,64 These early fevers region where the recipient and donor haplotypes differed.
are associated with class II mismatching and higher CD31 graft Further molecular studies confirmed HLA loss.17 The patient
cell dose.65 Although the highest incidence of early fever has underwent salvage chemotherapy with mitoxantrone, eto-
been demonstrated in haplo-PBSCT, haplo-BM allografts have poside, and cytarabine and achieved a second CR with MRD
also been associated with a higher incidence than HLA-matched negativity by flow cytometry. During salvage chemotherapy,
BM allografts (13% after MAC MSD, 23% after MAC MUD, we inquired regarding the availability of second-degree

1806 blood® 21 NOVEMBER 2019 | VOLUME 134, NUMBER 21 McCURDY and LUZNIK
 a a c
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A A 30:01 A A 02:01
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42:01 49:01
DRB1 DRB1 03:02 DRB1 DRB1 15:03
03:02 15:03
DQB1 DQB1 04:02 DQB1 DQB1 06:02
04:02 06:02
DPB1 DPB1 01:01 DPB1 DPB1 03:01
01:01 03:01

Leukemic blasts
at diagnosis
Patient

a d a c
c e

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30:01 A A 03:01 30:01 A A

HLA loss
17:01 Cw Cw 06:02 Cw Cw
17:01 02:01 A A 01:01
42:01 B B 58:02 B B
42:01 07:01 Cw Cw 07:01
03:02 DRB1 DRB1 11:02 DRB1 DRB1
04:02 DQB1 DQB1 03:01
03:02 Allorecognition 49:01 B B 08:01
04:02 DQB1 DQB1 15:03 DRB1 DRB1 03:01
01:01 DPB1 DPB1 04:01 01:01 DPB1 DPB1 Preserved 06:02 DQB1 DQB1 02:01
03:01 DPB1 DPB1 04:01
Immune Pressure

Allorecognition
First Haploidentical Lost Second Haploidentical
Leukemic blasts at
Donor Donor
HLA loss relapse

Figure 2. Rationale for using an alternative donor for second allogeneic transplantation. The patient’s 2 HLA haplotypes are shown in blue and red. The first donor shares a
common blue haplotype with the recipient and a distinct yellow haplotype. At relapse, the leukemic blasts lose the mismatched red haplotype, which results in loss of cell surface
expression of that mismatched HLA molecule. After relapse and subsequent chemotherapy to induce a remission, a second haploidentical donor is selected because they share
the red haplotype with the patient, but lack the blue haplotype. This will allow the second donor’s immune system to recognize these disparate HLA molecules on the leukemic
blasts to potentially elicit graft-versus-leukemic effects. Figure concept was influenced by two prior publications.8,73

relatives. The patient had 5 nieces and nephews. We typed with a 31.3% CR rate in this disease.69 The incidences of
the children of the recipient’s haploidentical sister because grades II to IV and grades III to IV aGVHD after DLI are 20%
these nieces and nephews also have a 50% chance of being and 15%, respectively, in the absence of GVHD prophylaxis.69
haploidentical to the recipient. Importantly, the sister was HLA- Patients with overt leukemia should receive reinduction che-
disparate from the recipient’s original haploidentical brother motherapy, whereas in cases of low disease burden, it is rea-
donor, but she had medical problems preclusive of donation. sonable to try hypomethylating agents before DLI. We suggest a
Two of the recipient’s nieces were found to be haploidentical. starting dose of DLI of 106 CD31 T cells per kilogram with es-
The patient underwent a second fludarabine/cyclophospha- calation in nonresponders who do not develop GVHD to a
mide/TBI haplo-PBSCT PTCy using a niece with a haplotype maximum of 107 CD31 T cells per kilogram.69,70
mismatch distinct from the original donor and received MMF
and sirolimus prophylaxis. He experienced stage III aGVHD of With the development of less toxic conditioning regimens and
the skin only, overall grade II aGVHD, that required systemic acceptable NRM, second allogeneic HSCTs have become a
steroids started on day 65 posttransplant. Steroids were feasible option for patients experiencing disease relapse after
successfully tapered after 3 months, and sirolimus was a first HSCT. In the HLA-matched setting, several retrospective
stopped 1 month after steroid discontinuation. He was alive studies have shown that “medically fit” patients who relapse
and in remission at last follow-up, approximately 14 months $6 months after the first HSCT may benefit from a second HSCT
after HSCT. and achieve long-term disease-free survival that is at least
proportional to the experience with DLI. Thus, a second
haplo-HSCT from a relative who is HLA-mismatched to the
Questions continued original donor (and thus to the retained HLA) is a reasonable
How do we treat relapse after haplo-HSCT? choice. Our early clinical data suggest that second HSCT is
Leukemia relapse represents the most common cause of treat- associated with a 4-year OS of 40%; however, longer survival
ment failure and death in patients after HSCT, regardless of was demonstrated when the second donor had a distinct
donor source. The approach for patients who relapse after haplotype mismatch from the initial HSCT donor.71 Our
haplo-HSCT is challenging, and there are no clear guidelines. practice is to try DLI first, especially for early relapses, which
Similar to HLA-matched HSCT, relapses occurring ,6 months could potentially be related to insufficient graft dose or in-
from HSCT are associated with poor outcomes,6 whereas later complete immune reconstitution and reserve second HSCT
relapses can be successfully treated with additional chemo- for cases for DLI failure. However, we avoid DLI altogether
therapy followed by donor lymphocyte infusion (DLI), clinical and pursue a second HSCT if at the time of relapse there is no
trial, or second allogeneic transplantation. DLI is capable of significant CD31 donor chimerism or there is suspected HLA
inducing sustained remissions in relapse after haplo-HSCT, loss (discussed in more detail below).

HOW I MANAGE PATIENTS UNDERGOING haplo-HSCT blood® 21 NOVEMBER 2019 | VOLUME 134, NUMBER 21 1807
What are the unique aspects of relapse after appealing and safe and may make donor selection even more
haplo-HSCT? complex in the future. A significant barrier to haplo-HSCT is the
New insights into the biology of relapse have demonstrated that high incidence of DSA in parous females, which can preclude
genomic HLA loss and downregulation of HLA are mechanisms familial haploidentical donors. Thus, clinical investigation of new
frequently employed by leukemic cells to evade immune control desensitization platforms for patients with the highest levels
(Figure 2).16,17 Loss of expression of the mismatched HLA hap- of DSA (positive for either flow cross-match or complement
lotype has been described to occur in as many as 33% of patients dependent cytotoxicity) is warranted. In addition, in patients
with relapsed AML after haplo-HSCT, but it has also been lacking a MUD, DSA are often lower to MMUD than to haplo-
demonstrated in myelodysplastic syndrome and myelofibrosis identical relatives. Data supporting the safety of MMUD-BMT
relapses.16-18 DLI is not anticipated to be effective in treating HLA with PTCy suggest that this may be a viable alternative in this
loss relapse, but it still carries a risk of GVHD. Thus, in the case of patient population. Finally, as with all HSCT, relapse remains the
confirmed HLA loss or HLA downregulation, DLI should be biggest barrier to successful haplo-HSCT and novel strategies to
avoided. The same applies for performing a second HSCT from reduce relapse should be the focus of future investigation.
the original stem cell donor. We are currently exploring in pa-
tients who relapse after HSCT whether an HLA-mismatched

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second donor might actually be a better choice. When using Acknowledgments
a different haplotype-mismatched donor, the second donor’s S.R.M. has received grant support from an American Cancer Society
T cells would be alloreactive to the mismatched HLA molecules Institutional Research Grant. L.L. is supported by National Institutes of
retained on the leukemic blasts (Figure 2). Besides genomic loss Health/National Cancer Institute grant 1P01CA225618.
of mismatched HLA alleles, downregulation of HLA class II
molecules and upregulation of inhibitory T-cell ligands are likely
important mechanisms of posttransplant relapse after haplo- Authorship
HSCT.72 More work needs to be done to better understand Contribution: L.L. and S.R.M. conceptualized and wrote the paper.
the biology underlying graft-versus-tumor effects and post-
transplant relapse and represents the next frontier. This work Conflict-of-interest disclosure: L.L. receives research support from
should also be complemented with a deeper understanding of Genentech and Merck, serves on a speaker’s bureau for Merck, serves as
consultant and on advisory boards for AbbVie, and is a patent holder for
how PTCy modulates alloreactivity and immune reconstitution, WindMIL Therapeutics. S.R.M. declares no competing financial interests.
which represents an insight essential to the safe and effective Off-label drug use: None disclosed.
integration of the growing immunological armamentarium, in-
cluding cellular therapies, into haplo-HSCT. Correspondence: Leo Luznik, Johns Hopkins University, Cancer Research
Building I, Room 2M88, 1650 Orleans St, Baltimore, MD 21231; e-mail:
[email protected].
Conclusions
Haplo-HSCT with PTCy is an increasingly used platform, given its
advantages of rapid identification of donors, low cost relative to Footnotes
other alternative donor strategies, simplicity of applying PTCy Submitted 26 April 2019; accepted 9 September 2019. Prepublished
clinically, and comparability to HLA-matched HSCT. One of the online as Blood First Edition paper, 20 November 2019; DOI 10.1182/
most complex issues with haplo-HSCT is donor selection, given blood.2019001323.
that multiple haploidentical donors are often available for a
This article was selected by the Blood and Hematology 2019 American
given recipient. No studies have prospectively compared first- Society of Hematology Education Program editors for concurrent sub-
degree relative haplo-HSCT with second-degree relative haplo- mission to Blood and Hematology 2019. It is reprinted in Hematology Am
HSCT; however, the use of PTCy has made the latter approach Soc Hematol Educ Program. 2019;2019:513-521.

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