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Blood First Edition Paper, prepublished online October 17, 2018; DOI 10.1182/blood-2018-03-785907

How I treat blast phase of Philadelphia-negative myeloproliferative neoplasms

*Olatoyosi Odenike

Associate Professor of Medicine

Department of Medicine

Section of Hematology Oncology

and the University of Chicago Comprehensive Cancer Center

The University of Chicago Medicine

5841 S. Maryland Ave., MC 2115

Chicago, IL. 60637

* Corresponding Author

Copyright © 2018 American Society of Hematology

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Abstract:

The classic Philadelphia chromosome negative myeloproliferative neoplasms (Ph –MPNs) are a

heterogeneous group of hematopoietic stem cell diseases, characterized by activated JAK/STAT

signaling, significant phenotypic mimicry, including a propensity for evolution to myeloid blast

phase disease. Effective therapeutic options are limited for patients with Ph-MPNs in the blast

phase (MPN-BP), and allogeneic stem cell transplant is the only known cure. Our increasing

understanding of the molecular pathogenesis of this group of diseases, coupled with the

increasing availability of targeted agents, has the potential to inform new subset specific

therapeutic approaches. Ultimately, progress in MPN-BP will hinge on prospective clinical and

translational investigation with the goal of generating more effective treatment interventions.

This case based review highlights the molecular and clinical heterogeneity of MPN-BP, and

incorporates a treatment algorithm that underscores the importance of a personalized

approach to this challenging group of diseases.

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Introduction

The classic Philadelphia chromosome negative myeloproliferative neoplasms (Ph-MPNs)

including essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis

(PMF) are a heterogeneous group of hematopoietic stem cell diseases characterized by driver

mutations in JAK2, CALR or MPL genes that result in activation of the JAK/STAT signaling

1-3
pathway . Phenotypically, these diseases share a variable propensity to thrombovascular

complications, constitutional symptoms, overt myelofibrotic (MF) transformation and evolution

4
to a myeloid blast phase . The terms PMF in blast phase, and post-PV/ET myelofibrosis (MF) in

blast phase were coined by the International Working Group for Myelofibrosis Research and

Treatment in recognition of the significant clinical and biologic differences between acute

5
leukemia evolving from the Ph-MPNs and acute myeloid leukemia arising de novo .

Collectively, leukemic transformation from the Ph-MPNs, defined as 20% or more myeloblasts

in the peripheral blood and/or bone marrow in an individual with a preexisting MPN, is often

6
referred to as MPN-blast phase (MPN-BP) .

There is no standard approach to the management of MPN-BP, and outcomes are

generally poor. The median survival is in the 3 to 5 month range in published retrospective

7-11
series, even in the context of intensive induction chemotherapy . Allogeneic stem cell

transplant is the only approach that has been reported to have the potential to significantly

change the natural history of MPN-BP, but applicability has historically been limited by the

refractory nature of these diseases and the older age (median age is in the mid 60s to early 70s)

of patients at the time of presentation.

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Despite these disheartening outcomes, there is reason to evoke a renewed sense of optimism,

based on our increasing understanding of the biological mechanisms that drive these disparate

group of disorders, as well as the increasing availability of new agents and approaches. In this

case based review, I will highlight a few cases that illustrate contemporary therapeutic

strategies and challenges in these otherwise poor prognosis group of diseases.

Who is at the highest risk of transformation to MPN-BP?

Given the historically poor outcomes associated with MPN-BP, identification of patients with

Ph- MPN at high risk of myeloid blast phase transformation could facilitate early intervention

such as allogeneic stem cell transplantation. Risk factors associated with leukemic

12-25
transformation (Table 1), include clinico-pathological and cytogenetic/molecular-genetic

18,26-33
risk factors . The predictive ability of these for evolution to MPN-BP, is variable, and is

limited by the heterogeneity of disease features, coupled with the retrospective nature of

34
several published series .

In general, individuals at high risk of MPN-BP (Table 1) in whom allogeneic transplantation

should be considered include patients with MF who have DIPSS intermediate 2 or high risk

disease (there is an established consensus in this regard), unfavorable karyotype, increasing

35
circulating blasts, transfusion dependency or thrombocytopenia. . Patients with accelerated

phase disease, often simply defined as 10-19% blasts have a median survival of less than 2 years

18,36
and merit consideration of treatment strategies similar to that employed for MPN-BP,

including allogeneic stem cell transplantation.

Evolutionary pathways to MPN-BP

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Recent studies have highlighted the importance of host genetic and environmental factors,

hematopoetic stress and aging in predisposition to clonal hematopoiesis and in facilitating

31,37-39
clonal dominance and emergence of the MPN phenotype . The evolutionary pathways

leading to clonal expansion, including acquisition of additional deleterious mutations (figure 1)

1
that promote clonal evolution and progression towards MPN-BP have recently been reviewed .

The mutational profile of MPN-BP is distinct from that of AML arising de novo, and is

11,26,29,30,40-42
characterized by mutations in IDH1/2, TET2, SRSF2, ASXL1 and TP53 . By contrast,

mutations in NPM1, FLT3 which are typical of AML de novo, are uncommon in MPN-BP.

Retrospective analysis of paired samples obtained from patients with JAK2 V617F mutant MPNs

during the chronic phase and at the time of transformation to MPN-BP has demonstrated the

likelihood of more than one evolutionary pathway to leukemogenesis. In some cases, as

expected, the leukemia blasts demonstrated persistence of the JAK2V617F clone. In other cases

however, JAK2 mutant MPNs evolved to a JAK2 wildtype clone in MPN-BP, suggesting the

presence of a common JAK2-V617F negative ancestral clone, or the possibility that the MPN

43,44
was biclonal from the outset .

Treatment of MPN-BP: Intensive chemotherapy

The therapeutic approaches in MPN-BP have ranged from supportive care to intensive

chemotherapy and allogeneic stem cell transplantation (Table 2). The published series are

retrospective in nature, and there is significant heterogeneity with regards to the patient

population involved, treatment strategies employed, and sample size. There is also a lack of

6
standardization with regard to the criteria employed to evaluate response to therapy . These
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issues pose a significant challenge when trying to evaluate the relative contribution of specific

therapeutic approaches. Patients treated with a supportive care only approach had very short

8,9,11,45
median survivals in the 6 week to 2 month range .

The outcomes reported with intensive chemotherapy have been generally poor (Table 2)

8,9,11,45
. Allogeneic stem cell transplant has the potential to result in long term survival (Table 2)

46-50
, but it is the minority of patients who are able to proceed.

Patient 1

64 year old gentleman who was diagnosed with ET twenty-one years prior, in the context of an

evaluation of signs and symptoms consistent with a transient ischemic attack. He was treated

with hydroxyurea in conjunction with low dose aspirin. Nineteen years later, he presented

with complaints of fatigue and exertional dyspnea. The complete blood count revealed a white

9 9
blood cell count of 6.5 X 10 /L, hemoglobin of 85g/L and platelet count of 613 X 10 /L. The

white blood cell differential revealed 30% circulating blasts. The bone marrow biopsy revealed

a hypercellular marrow with 40% blasts, abundant megakaryocytes and focally increased

fibrosis. Immunophenotyping revealed that the blasts were CD34+, CD33+, HLA-DR+, CD117+.

The bone marrow cytogenetic analysis revealed a complex karyotype : 46, XY[55%]; 42, XY,

ins(2;5)(q31;p13p15), del(4)(q27q35), -5, -6, add(7)(p15), dic(8;19)(p11.1;p12) ,-22,

+der(?)t(/;6)(?;q12)[5%]; clone 2: 41, idem, -16, add(21)(q22)[20%]; clone 3:42, idem,

add(16)9q22)[20%]. Molecular analysis utilizing an institutional Next Generation Sequencing

(NGS) panel (limit of detection 10% mutant alleles), revealed the following pathogenic variants:
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JAK2 V617F, ASXL1 Q910Tfs*14, IDH2 R140Q. The patient had been working full time and

exercising regularly, without any limitations, prior to this presentation.

Based on the patient’s overall fitness level and the intent to move to an allogeneic SCT as

soon as disease control was achieved, induction chemotherapy was initiated with high dose

cytarabine (3gm/2, on days 1 and 5) and mitoxantrone (30mg/m2 on days 1 and 5) according to

51,52
a regimen commonly utilized at our institution for high risk acute myeloid leukemia . The

nadir bone marrow biopsy at day 14 showed persistent leukemia. His performance status

remained excellent, and a second induction attempt with high dose cytarabine and etoposide

was administered. The subsequent bone marrow at day 14 of the second induction also

showed persistent leukemia (40% cellular, 50% blasts) .

At this point, given the presence of the IDH2 R140Q, and the availability of a clinical trial

focused on patients with late stage AML harboring an IDH2 mutation, participation in the

clinical trial was recommended. The patient was subsequently enrolled on a clinical trial of

enasidenib for late stage AML, and was randomized to the experimental arm of the study.

Therapy with enasidenib was initiated at 100mg/day administered orally, in 28 day cycles. His

bone marrow biopsy after 2 cycles showed a hypercellular marrow with a decline in blasts to

9%. The bone marrow cytogenetic analysis revealed a reversion to a normal male karyotype.

The most recent bone marrow biopsy at the 2 year time-point was mildly hypercellular (50-60%

cellular), with increased granulopoiesis and markedly atypical megakaryocytic proliferation,

with a marginal increase in blasts, at 3 to 4%. His recent blood counts revealed the following-

9 9
WBC-15X10 /L, 89% neutrophils, 2% blasts, hemoglobin 139g/L, platelet count 200X10 /L.
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Interestingly, recent NGS analysis revealed the following pathogenic variants: JAK2 V617F,

ASXL1 Q910Tfs*14. The IDH2 mutation was not detected (level of sensitivity of NGS assay

utilized was 10% mutant alleles).

Status: The patient is two and half years out from the original diagnosis of MPN-BP and is

working full time. His performance status is excellent and he is exercising on a near daily basis.

He remains on enasidenib 100mg daily and low dose aspirin 81mg daily. An allogeneic stem cell

transplant evaluation has been recommended, but the patient has elected not to proceed with

a transplant at this time.

Comments about Patient 1

Late Stage MPN-BP associated with IDH1/2 mutations

The advent of therapeutic agents targeted to mutant IDH1/2 enzymes has provided a new

treatment approach for patients with high risk myeloid neoplasms associated with IDH2

mutations. IDH2 mutations are present at a low frequency, in the 2 to 4% range in the chronic

32,41,53
phase of Ph-MPNs .The incidence increases with evolution to MPN-BP, and is in the 13-

11,26,40,41
31% range, in published retrospective series . Wildtype IDH1/2 enzymes catalyze the

conversion of isocitrate to αketoglutarate. Mutant IDH1/2 result in conversion of isocitrate to

R-2-hydoxyglutarate (2-HG), an oncometabolite which competitively inhibits αketoglutarate

dependent enzymes including TET2 and the Jumanji enzymes, resulting in DNA and histone

54
hypermethylation, epigenetic dysregulation and differentiation block .
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Enasidenib (AG-221) and ivosidenib (AG-120) are small molecule inhibitors of mutant IDH2

and IDH1 respectively, which bind the catalytically active sites, preventing conversion of

isocitrate to 2-HG, reversing the epigenetic dysregulation and facilitating cellular

differentiation. These agents were associated with significant clinical activity in early phase

55-57
trials of relapsed or refractory IDH1/2 mutant AML . 2-HG levels were uniformly

downregulated and served as a useful pharmacodynamic marker in early phase development of

these agents, but decline in 2HG levels did not correlate with response. The overall response

rate with enasidenib in relapsed refractory AML was 40% (CR/CRi rate of approximately 26%),

and over half of the patients enrolled had received 2 or more prior AML-directed regimens. The

median overall survival was 9.3 months, but in those who had a CR or PR, the median survival

was 19.7 months. The agent was well tolerated, with the most frequent adverse events being

58
indirect hyperbilirubinemia and IDH differentiation syndrome .

Based on these encouraging results, enasidenib and ivosidenib were recently approved in

the United States by the Food and Drug Administration (FDA) for relapsed or refractory AML

associated with an IDH2 or and IDH1 mutation respectively. Enasidenib and ivosidenib are

therefore potential options for patients with MPN-BP associated with IDH1/2 mutations who

are refractory to or have relapsed after prior therapy. There is a paucity of information however

55-57
with regard to both clinical trial and real world experience with these agents in MPN-BP.

Enrollment on studies that aim to validate the potential promise of this approach in MPN-BP,

remains the preferred option. Currently, there are ongoing trials in which enasidenib and

ivosidenib are being combined with azacitidine or intensive induction chemotherapy in the

frontline setting in AML, including AML arising from prior Ph-MPN. Interestingly, in a murine
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10

model of combined JAK2/IDH2 mutant MPN, the combination of JAK inhibition with ruxolitinib

and IDH2 inhibition with enasidenib reduced disease burden to a greater extent than was seen

with JAK inhibition alone. Similar cooperativity with combined JAK/IDH2 inhibition was seen in

primary cells from MPN patients with both mutations, suggesting the potential promise of this

59
approach . Such combinations require validation in the context of prospective clinical trials.

Patient 2

MPN-BP associated with TP53 mutations

77 year old gentleman who was diagnosed with polycythemia vera nine years ago. Phlebotomy

and low dose aspirin were initiated, followed by hydroxyurea, in line with treatment

60
recommendations for upfront therapy of high risk polycythemia vera .

Eight years after the original diagnosis of PV, he presented with significant fatigue. His

performance status had declined significantly to ECOG performance status of 3. CBC revealed

9 9
platelet count of 110X10 /L , WBC-6.7X10 /L and hemoglobin 104g/L. Peripheral blood smear

was notable for leukoerythroblastosis, occasional hypogranular neutrophils and 15% circulating

blasts. Bone marrow biopsy revealed a hypercellular marrow with panmyelosis and marked

reticulin and collagen fibrosis (MF-3), with CD34+ blasts comprising 20-30% of the overall

cellularity (Figure 2). Cytogenetic analysis performed on the peripheral blood revealed a

complex karyotype including abnormalities of chromosomes 5 and 7, and trisomy 8. Pathogenic

Variants detected on NGS analysis included JAK2 V617F, TP53 H168R and TP53 S215G. Serum

LDH was significantly elevated at 2930IU/L.

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11

Comments about Patient 2 continued

Hypomethylating agent therapy in MPN-BP

Therapy with a hypomethylating agent was recommended in this case. TP53 mutant acute

61,62
myeloid leukemia is relatively chemoresistant . This issue, coupled with the patient’s older

age and poor performance status, made an intensive chemotherapy approach a less attractive

option.

Studies evaluating clonal evolution and clonal architecture in the MPNs have revealed that TP53

mutations or abnormalities of the TP53 pathway are common in leukemic blasts in MPN-BP

29,30,42
. It has been demonstrated that in some cases TP53 mutations may be present at a low

variant allele frequency in the chronic phase of the MPN, and that with loss of heterozygosity

there is rapid expansion of the mutant clone associated with transformation to acute

30
leukemia .

There is an accumulating body of evidence supporting the use of hypomethylating agents

(HMA) decitabine or azacitidine in advanced myelofibrosis, including accelerated/blast phase

63
Ph-MPN . Most are summaries of retrospective experience and only a few reports are focused

64-67
particularly on accelerated/blast phase disease (Table2). Myelosuppression is the dose

limiting toxicity with the use of these agents, and there is a relative paucity of non-hematologic

side effects. There are no prospective randomized studies comparing HMA based approaches

with intensive chemotherapy in MPN-BP. Most retrospective series (Table 2) have not shown

any significant survival advantage in favor of HMA use, compared with intensive chemotherapy.

Limitations to these studies include the relatively small sample sizes, heterogeneity of the
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12

disease features and non-randomized nature of the study designs. The relative tolerability

profile of HMA therapy however, has made this approach an increasingly attractive option,

particularly in the older patient with a borderline or poor performance status, or with a

molecular or cytogenetic risk profile that would predict chemoresistance.

Alternative schedules (10 day regimens) of azanucleoside therapy in high risk myeloid

68-70
neoplasms including MDS and AML have been explored . In a single arm Phase II trial in

which older adults with previously untreated AML were treated with a 10 day regimen of

decitabine in the frontline setting, the CR/CRi rate was 64%, including a CR rate of 50% in those

68
patients with complex karyotypes . A recent intriguing report, incorporating enhanced exome

sequencing of samples from individuals with AML or MDS treated with the 10 day decitabine

regimen, revealed that clinical responses were highly correlated with the presence of TP53

71
mutations in the founding clone .The median survival was 12.7 months in the TP53 mutant

cohort, and the receipt of an allogeneic stem cell transplant for consolidation had the largest

impact on survival.

Patient 2 continued:

The patient received decitabine administered at 20mg/m2/day given on a 10 day schedule, with

cycles repeated every 28 days. His second cycle of therapy was complicated by culture negative

febrile neutropenia.

His most recent bone marrow biopsy after 2 cycles of decitabine revealed a 30% cellular

bone marrow without an overt increase in blasts, but with marked proliferation of erythroid

precursors, as well as megakaryocytes with clustering and atypia, reminiscent of the patient’s
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13

underlying myeloproliferative neoplasm (Figure 2). Cytogenetic analysis revealed reversion to a

normal male karyotype. FISH analysis (400 cells) was negative for a deletion or loss of

chromosomes 5 and 7, and was disomy for chromosome 8. NGS analysis revealed the JAK2

V617F as the sole pathogenic variant. The mutations in TP53 were no longer detectable (assay

sensitivity 10% mutant alleles). Serum LDH was within normal limits-214U/L.

Status: The patient has just completed his fifth cycle of decitabine. Given the myelosuppressive

effect of the 10 day schedule and the fact that his bone marrow no longer shows an excess of

blasts, he is currently receiving decitabine on a 5 day (maintenance) schedule. His performance

status has improved considerably. Complete blood count at this point is significant only for

mild anemia, with a hemoglobin of 11g/dL. He has been HLA typed and has several potential

matched unrelated (MUD) donors in the National Bone Marrow Donor Registry. He has recently

been referred for a transplant consultation to evaluate candidacy for an allogeneic stem cell

transplant.

Patient 3:

60y/o woman who was diagnosed with ET twenty three years prior. At that time, she had

9 9
presented with a WBC of 8X10 /L, hemoglobin of 128g/L and a platelet count of 900 X10 /L.

Thirteen years after the original diagnosis of ET, she developed splenomegaly (the spleen was

palpable at 4cm below the costal margin) on physical examination. CBC at the time was notable

9
for WBC 12.9X10 /L with a left shift, 3% circulating blasts, hemoglobin of 118g/L and platelet

9
count of 382 X10 /L. She had a leucoerythroblastic picture on the peripheral blood smear and

tear drop red cells. Her bone marrow biopsy was hypercellular with moderate reticulin fibrosis
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14

and osteosclerosis, associated with increased numbers of atypical megakaryocytes, granulocytic

proliferation and prominent intrasinusoidal hematopoiesis consistent with evolution to post ET

myelofibrosis. There was no increase in bone marrow blasts and bone marrow cytogenetic

analysis at the time revealed a normal karyotype. Five years later, she presented with

complaints of abdominal discomfort, night sweats, pruritus and weight loss. There was no prior

history of cytoreductive therapy. The spleen was noted to be massively enlarged, 23 cm below

9
the costal margin and extending into the pelvis. CBC revealed WBC 14 X10 /L , hemoglobin of

9
950g/L, platelet count of 331 X10 /L. Serum LDH was significantly elevated at 2130IU/L. The

peripheral blood smear showed leukocytosis with dyspoietic cells and 24% circulating blasts

(Figure 2). The marrow biopsy was fibrotic (Figure 2) with few hematopoietic cells.

Immunohistochemistry showed focal clusters of CD34+ blasts, the overall blast percentage was

difficult to estimate. Bone marrow cytogenetic analysis was uninformative given the marked

fibrosis. Cytogenetic analysis on the peripheral blood revealed a tetraploid clone 92,

XXX[4]/46,XX[16]. Institutional NGS panel was not yet available at that time. Molecular studies

performed on the peripheral blood included evaluation for mutations in JAK2, NPM1, FLT3 and

CEBPA mutation, all of which were negative. RT-PCR for BCR/ABL was also negative.

Given the presence of constitutional symptoms and massive splenomegaly, the patient inquired

about treatment with the JAK inhibitor, ruxolitinib. The potential for ruxolitinib to cause

amelioration of symptomatic splenomegaly and constitutional symptoms in advanced

myelofibrosis is well established, and the agent is FDA approved in MF based on its significant

72-74
activity in this context . The potential utility of ruxolitinib in improving performance status

prior to proceeding with allogeneic stem cell transplant in myelofibrosis, especially in those
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15

with significant debilitating symptoms and massive splenomegaly has been documented in

75,76
retrospective series .

The available evidence however (Table 2) does not support the use of single agent ruxolitinib as

an effective strategy in MPN-BP. In one prospective trial of ruxolitinib in relapsed refractory

leukemias, 3 of 18 patients with MPN-BP responded, and responses were relatively slow to

77
occur . In a subsequent trial utlilizing high doses of the agent, at a dose range of 50-200mg

twice daily, only one patient responded, and infectious complications were frequent, occurring

78
in more than half of patients treated . Investigational approaches evaluating the combination

79,80
of ruxolitinib and hypomethylating agents including decitabine in MPN-BP are ongoing ,

based in part on preclinical evidence of synergy observed between these agents in a murine

42
model of MPN BP .

Comments about Patient 3 continued.

The patient was treated with low dose subcutaneous decitabine (0.1mg/kg/day for 10 days-

given on days 1-5, and days 8-12, with cycles repeated every 4 to 6 weeks), according to a

regimen investigated in a prospective clinical trial in advanced myelofibrosis at our

81
institution .The second cycle of decitabine was complicated by neutropenic fever and

streptococcal mitis bacteremia. After 3 cycles of decitabine, her splenomegaly improved, with

the spleen now being palpable at about 10cm below the costal margin. Her performance status,

improved and her constitutional symptoms were also considerably improved. CBC after 3

9 9
cycles revealed- WBC-2.4X10 /L, hb-96g/L, platelet count 306X10 /L, absolute neutrophil count

9
0.9X10 /L, with 5% circulating blasts. Serum LDH also declined significantly to 376IU/L. Bone
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16

marrow biopsy demonstrated persistent, extensive fibrosis, blasts did not appear to be

obviously increased, but hematopoietic elements were sparse. At this point, a matched

unrelated donor was available, the patient’s performance status was excellent and she had no

significant comorbidities. By the consensus criteria proposed for the assessment of response in

6
MPN-BP , this patient would be judged to have a partial response-defined as a decrease in

leukemic burden (greater than 50% reduction in blasts) without complete resolution of

peripheral blood or bone marrow blasts and with residual MPN features. The question arose

regarding the optimal timing of allogeneic stem cell transplant in this situation.

Comments about Patient 3 continued:

Optimal timing of allogeneic stem cell transplant and choice of conditioning regimen in MPN-
BP?
There is lack of a consensus regarding the depth of response required to be able to successfully

proceed to an allogeneic stem cell after treatment of MPN-BP. Patients who proceeded to

transplant in most of the published retrospective series had achieved a CR, CRi or return to

second chronic phase. As expected, achievement of a response prior to allogeneic stem cell

46-48
transplant was associated with a trend towards an improved outcome . A subset of patients

with refractory disease however, may still enjoy long term survival post allogeneic stem cell

46,49
transplant . The caveat with interpreting the above reports include the lack uniformity with

regard to the criteria used for response assessment in most series, and the relatively small

numbers of patients proceeding to transplantation. The same limitations preclude any

82
definitive conclusions regarding the optimal conditioning regimen in this context . Both
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17

reduced intensity and myeloablative regimens have been used and the choice of conditioning

regimen has not been predictive of TRM, relapse or survival in published retrospective series

46,47,49,83,84
. Donor source has not been an independent predictor of outcome in most reports,

although there has been a trend towards increased transplant related mortality in some series

in patients transplanted with a matched unrelated donor when compared with a matched

46,83
related donor . There is a paucity of data regarding alternative donor transplants, although

84
long term survivors post umbilical cord blood transplantation have been reported .

Patient 3 continued:

The patient proceeded to a matched unrelated allogeneic stem cell transplant with a

fludarabine/busulphan conditioning regimen. Her course was complicated by acute graft

versus host disease of the liver, which came under relatively quick control with corticosteroid

therapy. Serial bone marrow biopsies at Day 30 and day 100 post- transplant demonstrated

persistent myelofibrosis, but by day 180 the marrow fibrosis had improved (MF grade1+/3).

Serial chimerism analysis initially showed mixed donor chimerism. Following the development

of acute GVHD of the liver, chimerism improved to 100% donor in both unfractionated and T

cell compartments. Her bone marrow biopsy at 12 months morphologically revealed minimal

reticulin fibrosis 0-1, and trilineage hematopoiesis. She had continued improvement in her

splenomegaly, with the spleen being no longer palpable approximately 18 months post

allogeneic stem cell transplant.

Current status: She is six years out from transplant and is doing well.

Special considerations:
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18

Lymphoid blast transformation arising from the Ph-MPNs

Lymphoid blast transformation of the Ph-MPNs is a rare entity limited to case reports in the

literature. In a recent case report and review of the existing literature, 18 such cases were

85
summarized . The majority of these cases were B-acute lymphoblastic leukemia (ALL), with T

cell ALL occurring very rarely. In some of these cases the leukemia blasts harbored the JAK2

85-87
mutation , in keeping with earlier observations of the pluripotency of the JAK2V617F

88
stem/progenitor cell in Ph-MPN . In other cases however, a clonally distinct origin of the

89,90
lymphoblasts was demonstrated . Outcomes were uniformly fatal with only 2 patients

91,92
reported alive in the literature . In both of these cases, intensive induction with an ALL

chemotherapy regimen was employed, followed by transplantation in one case, once a

morphologic remission of the ALL was achieved. Rare case reports of BCR/ABL+ ALL arising in

90,93
patients with Ph-MPNs have also been reported . Complete characterization of the

leukemia blasts including exclusion of a BCR/ABL rearrangement is important in lymphoid blast

transformation of a Ph-MPN given the significant therapeutic implications. We can surmise

from the limited experience available however, that the majority of cases will be BCR/ABL

negative. An intensive induction approach followed by allogeneic stem cell transplant once a

response is achieved, is a reasonable approach in those patients who are fit enough to be able

to undergo such therapy.

Conclusion

My approach to treating MPN-BP is summarized in figure 3 and the accompanying Box 1. I

strongly favor prospective clinical investigation wherever possible in these diseases. There is a
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19

significant need to improve our ability to more accurately predict those individuals who are at

high risk for evolution to MPN-BP, and who could benefit from earlier intervention. Currently

28
such intervention is limited to allogeneic SCT, and the recently proposed MIPSS score if

validated, may be useful in refining transplant decisions in the chronic phase in PMF. The

molecular mechanisms underlying transformation to blast phase are increasingly being

understood, and will pave the way for more effective treatment approaches, but much remains

to be accomplished. We need improved preclinical models that accurately recapitulate the

human disease, including the clonal heterogeneity, and can be utilized for non-clinical drug

evaluation. This should be paired with rapid clinical translation of the most promising agents

and combinations. There is currently a paucity of trials in existence (Table 3) that include MPN-

AP/BP. Given the clinical and molecular heterogeneity of these diseases, subset specific therapy

is predicted to be necessary to improve outcomes. Advances in allogeneic SCT will continue to

be important in affording patients with MPN-BP a chance of cure, especially as this modality is

94
increasingly being extended to older adults . The potential utility of minimal residual disease

monitoring and post-transplant maintenance approaches require further investigation.

Ultimately, the hope is that a multipronged approach will bring us closer to improving

outcomes for high risk Ph-MPNs, including those evolving to MPN-BP.

Author Contribution Statement: Olatoyosi Odenike conceived and wrote this article.
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20

Acknowledgement: The author is indebted to Dr. Sandeep Gurbuxani in the Section of

Hematopathology for creating figure 2 (photomicrographs of the pathologic specimens of

cases of MPN-BP).

Conflict of interest disclosure: Olatoyosi Odenike has received research funding (paid to her

institution) from Agios, Astra Zeneca, ABBVIE, Celgene, CTI/Baxalta, Gilead, Incyte, Janssen, NS-

Pharma, Oncotherapy Sciences. She has served on advisory boards for Jazz Pharma, Pfizer,

DavaOncology, CTI BioPharma, Celgene, ABBVIE; has received honoraria from the American

Board of Internal Medicine (Medical Oncology Board Exam Committee), the American Society

of Hematology, American Society of Clinical Oncology (ASCO), NIH (MCH) Study Section,

American Society for Clinical Pathology. Membership on medical advisory board of the Aplastic

Anemia/MDS International foundation (no financial compensation involved).

Figure 1: An evolutionary pathway to MPN-BP: Following the acquisition of a JAK2V617F or

similar driver mutation by a hematopoietic stem cell (depicted in yellow), host genetic,

epigenetic and microenvironmental factors can facilitate the emergence of asymptomatic

clonal hematopoiesis ( depicted in black), subsequent clonal expansion and the emergence of

an MPN phenotype (depicted as doublet of black cells). The acquisition of additional mutations,

including high risk mutations (ASXL1, IDH1/2, SRSF2, EZH2, TP53) may lead to clonal evolution,

disease progression and may ultimately culminate in MPN-BP (depicted as an

outgrowth/cluster of red cells).

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21

Figure 2

Peripheral blood smears and bone marrow biopsies pre and post therapy of MPN-BP

Panel A: IDH2 mutated MPN-BP: Pre- therapy with enasidenib: Peripheral smear shows

pancytopenia with circulating blasts. Bone marrow is markedly hypercellular and composed

largely of blasts intermingled with increased atypical/dyspoietic megakaryocytes. Post- 6

months of therapy with enasidenib-peripheral smear showing normal neutrophils and decline

in circulating blasts. Bone marrow is hypercellular without significant increase in blasts, but

with increased granulopoiesis and atypical megakaryocytes consistent with the patient’s

underlying myeloproliferative neoplasm.

Panel B: TP53 mutated MPN-BP arising in patient with polycythemia vera: Pre- therapy with

decitabine: Peripheral smear shows mild thrombocytopenia. Bone marrow is markedly

hypercellular with panmyelosis and sheets of blasts. Post- 2 months of therapy with decitabine:

peripheral blood demonstrates leucopenia and anemia without circulating blasts. Bone marrow

is hypercellular without overt increase in blasts, but with marked proliferation of erythroid

precursors as well as megakaryocytes with clustering and atypia consistent with involvement

with the patient’s underlying myeloproliferative neoplasm.

Panel C: MPN-BP arising in patient with prior post-essential thrombocythemia myelofibrosis:

Pre-therapy with decitabine-The peripheral blood smear demonstrates circulating blasts (24%

on differential count), red blood cell anisopoikilocytosis, marked platelet anisocytosis and

hypogranular platelets. Bone marrow biopsy specimen shows mainly fibrosis with few

hematopoietic elements distorted by the markedly increased fibrosis. Few irregularly

distributed mononuclear cells (blasts) that are difficult to appreciate morphologically.

Post-allogeneic stem cell transplant day 180: peripheral smear demonstrates normocytic

anemia, mild thrombocytopenia, no circulating blasts. The marrow is hypercellular with

megakaryocytic and granulocytic proliferation and no increase in blasts. Fibrosis is mild at this

juncture.

Figure 3: How I treat Ph-MPN in the blast phase. My approach to the treatment of MPN-BP is

summarized in figure 3. The accompanying text in Box 1 outlines in greater detail, the

treatment algorithm illustrated in figure 3.

 From www.bloodjournal.org by guest on May 20, 2019. For personal use only.

22

Box 1: My approach to treating MPN-BP is summarized in figure 3.

• I favor offering the option for therapy to as many patients as possible, survival is very short

when a supportive care only approach is adopted.

• Since allogeneic stem cell transplant is the only approach that has been shown to have the

potential to provide durable remissions, I prospectively HLA type my patients and start looking

into donor options as soon as the diagnosis is made.

• I perform Next Generation Sequencing (NGS) analysis on the leukemia blasts at diagnosis to

evaluate for potentially actionable mutations. In many patients particularly those who develop

MPN-BP from a background of myelofibrosis (which is the majority), a peripheral blood sample

is generally adequate for performing such an analysis since the marrow is frequently

inaspirable.

• I strongly favor enrollment on a clinical trial whenever possible, especially clinical trials

designed with a particular focus on this patient population.

• I tailor therapy wherever possible if there is an actionable mutation for which there is a

targeted therapeutic approach available. For IDH1/2 mutant disease, I favor a clinical trial that

would allow access to IDH1 or IDH2 inhibitor either as single agents or in combination with a

hypomethylating agent and for fit patients, in combination with chemotherapy.

• For TP53 mutant disease, I strongly favor clinical trial enrollment. In the absence of a trial I am

inclined to favor hypomethylating agent therapy over a 7+3 approach from a risk/benefit

standpoint especially in older adults who are less fit.

• For those patients (with other mutations) who are fit for transplant and in whom a donor will

be readily available, I favor intensive chemotherapy. It is important to stress that remissions are

not durable with intensive chemotherapy alone. Therefore, one needs to be prepared to move

forward with an allogeneic stem cell transplant as soon as a remission or significant

cytoreduction is achieved. There are no standard guidelines regarding how deep the remission

needs to be, prior to stem cell transplantation.

• Many patients will not have a donor immediately available or be transplant eligible, and some

who do, may not wish to undergo intensive chemotherapy given the uncertainty that this will

lead to a long term leukemia free survival. For those patients, I favor HMA based therapy, on a

clinical trial if there is one available. In the absence of a clinical trial, I favor the use of

decitabine or azacitidine given the emerging experience in MPN-BP. Even though these agents

are designed for outpatient use, it is essential to stress that they are particularly

myelosuppressive in the MPNs with underlying fibrosis, especially when administered on a 10

day schedule.

• I advocate meticulous attention to supportive care including blood product support and the use

of prophylactic antimicrobials in the setting of neutropenia. I utilize growth factor support

according to established guidelines in the presence of febrile neutropenia.

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Table 1: Risk factors for evolution to MPN-BP

Risk Factor Comments Reference
Clinico-pathologic
33
MPN subtype Cumulative incidence over
16
PMF 20 years for MPN-BP=3.8%,
12
Post-ET MF 6.8% and 14.2% in ET, PV
15
Post-PV MF and PMF respectively in
19
contemporary series from
95
the Mayo clinic.
96
Evolution to overt MF
phenotype often precedes
MPN-BF in PV
In post PV MF, high
circulating CD34 counts;
platelet count<100X109/L
implicated in MPN-BP
Age>61y/o-PV
Age >60y/o-ET
Age>65y/o -MF
15,20,24
Cytoreductive agents Controversy re:
19,21-23
32P leukemogenic potential of
Chlorambucil hydroxyurea in the MPNs is
Piprobroman not supported by evidence
Busulphan from large retrospective
series.
13
Laboratory parameters Blasts ≥3%
Circulating blasts +platelets<100X109/L high
Anemia risk for MPN-BP
18
Leucocytosis Blasts≥10%
Thrombocytopenia +platelets<50X109/L
denotes accelerated
disease/v. high risk for
17
MPN-BP
Transfusion dependency
WBC>30X109/L 14

WBC>15X109/L+
19
age>61y/o+ abnormal
karyotype (in PV)
27
Molecular-genetic Unfavorable karyotype in
Unfavorable karyotype (PMF) DIPSS plus=+8, -7/7q,
18
17p deletion i(17q), -5/5q-, 12p-,inv(3)
Mutations and 11q23
32
*HMR=*ASXL1,* IDH1/2, Chromosome 5, 7 or 17p
26
*EZH2, *SRSF2 abnormalities =>6X risk of
TET2, TP53 MPN-BP
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24

29
Absence of CALR (in PMF) ***associated with a
30
≥2 mutations familial MPN phenotype
***Germline duplication of with high risk of MF and
ATG2B/GSKIP MPN-BP evolution
31

25
Prognostic Scoring Systems In DIPSS-HR for evolution
(PMF) to MPN-BP=7.8 for
Higher risk DIPSS intermediate-2 risk disease
****DIPSS plus and 24.9 for high risk
High risk MIPSS70 disease when compared to
Very high risk MIPSS70 plus low risk
In DIPSS plus-Unfavorable
karyotype +platelet
count<100K/uK were high
risk for MPN-BP
MIPSS-70 very high risk
28
category-23% developed
MPN BP (HR=13.3) when
compared to low risk
*HMR, high molecular risk mutation; DIPSS, dynamic international prognostic scoring system; MIPSS70,
mutation –enhanced international prognostic scoring system for transplant age patients with primary
myelofibrosis; Unfavorable karyotype in MIPSS 70 plus=any abnormal karyotype other than normal
karyotype or sole abnormalities of 20q-, 13q-, +9, chromosome 1 translocation /duplication, or sex
chromosome abnormality other than-Y
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Table 2. Treatment series focused on MPN-accelerated or blast phase disease

Treatment Patient Comments Survival Reference
approach Population
8
*Intensive MPN-BP 24 (26%) received IC. OS=2.6 mos; 3.9
chemotherapy (n=91) 41% of IC group had months in IC group.
(IC) return to cMPN. 1 patient received
+/-allo-HCT allo-HCT
9
MPN 41(55%) received IC. OS=5months; OS=6
BP(n=74) CR/CRi=46% months and PFS=5
months with IC.
Eight patients
received early SCT;
73% of these were
alive at median of
31mos
50
MPN 39 (51%) treated with OS=6.6 mos; median
BP(n=75) curative intent and OS of curative intent
received IC and/or group=9.4 months .
allo-HCT. 17 (23%) received
allo-HCT; median
OS=47 months for
allo-HCT
10
MPN-BP 66 of 122 patients OS=3mos; 1 year
(n=248) assessable for survival before yr
response received IC, 2000=5%, and was
26 received HMA 20% in 2010 and
beyond. CR=35%
with IC; CR<5% with
HMA
67
Hypomethylating MPN BP ORR=52% (CR 24%) OS=11 months
agents (HMA) (n=26);MPN- with azacitidine
AP (n=28) therapy; median
response duration=9
months; recurrence of
cMPN in 39%
responders
64
MPN BP=19 ORR=47% (CR-26%) OS=9.9 months
with azacitidine
therapy
65
MPN BP ORR in MPN BP=29% OS=6.9 mos in MPN-
(n=21) MPN with decitabine BP; OS=9.7 mos in
AP (n=13), therapy, median MPN-AP
PMF chronic response duration=7
phase(n=11) months
66
MPN BP=11 6 patients received 67% in decitabine
decitabine, 5 patients group alive at 9
received allo-HCT months; 53% in
transplant group
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26

alive at 20 months
77
JAK inhibition R/R AML 3 of 18 patients with NR
(n=38), MPN-BP treated with
including ruxolitinib at dose of
MPN 25mg bid achieved
BP(n=18 ) CR/CRi
78
R/R acute 1 patient with NR
leukemia AML(prior MDS)
(n=28), achieved CRp. No
including 7 objective response in
with MPN-BP cohort.
antecedent Ruxolitinib dosed
Ph-MPN between 50mg and
200mg bid
80
JAK inhibition MPN- Ph1 study of OS=10.4 mos
plus HMA AP/BP=21 ruxolitinib+decitabine
7/21 responded
79
MPN-BP=10 Ph I/II Study of NR
ruxolitinib+decitabine
47
Allo-HCT MPN- 60 received allo-HCT, OS=18% at 3 years;
BP(n=43); 3 yr TRM was 22%, 3 3 yr LFS was 18% for
MDS/MPN yr CIR=68% allo-HCT in CR and
BP (n=17) 3% for allo-HCT in
advanced disease
48
MPN-BP=13 8 received allo-HCT; 5 At median f/up of
of 8 were in CR or 20 mos, 6 patients
cMPN at time of allo- were alive in CR
HCT post allo-HCT
49
MF-chronic Of the 14 MF-BP who OS=49% at 2 years
phase=41, received allo-HCT, 7 in MF-BP cohort.
MF-BP=14 survived; median 3 of 6 patients in
f/up=31 mos remission and 4 of 8
patients with
relapsed disease at
allo-HCT were long
term survivors
46
MF-BP=46 1 yr TRM=28%, CIR at 3yr PFS=26%,
3 yrs=47%; OS=33%; CR pre-
Only 8 of 46 were in alloHCT, was
CR pre allo-HCT significantly
predictive of OS and
PFS
IC-intensive chemotherapy, cMPN- reversion to chronic phase MPNOS, overall survival; ORR,

overall response rate; R/R AML, relapsed or refractory acute myeloid leukemia, allo-HCT,

allogeneic hematopoietic cell transplantation; PFS, progression free survival

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Table 3: Selected trials that include subjects with Ph-MPN-AP or MPN-BP

Agent(s) Mechanism of Phase of Disease Clinicaltrials.gov

action trial NCT ID
Ruxolitinib JAK inhibition Phase I/II MPN-AP/BP NCT02076191
+ decitabine +HMA
Ruxolitinib+ JAK inhibition+ Phase I/II MPN AP/BP NCT02257138
decitabine HMA
SGI-110 HMA Phase II Ph-MPN including NCT03075826
MF-AP
Various Various Phase I/II AML-TN in older NCT03013998
molecularly adults; includes MPN-
targeted BP
Enasidenib or IDH2 or IDH1 Phase I/II AML-TN; includes NCT02677922
ivosidenib + inhibition MPN-BP
azacitdine + HMA
Azacitidine +/- HMA +/- Phase III AML-TN includes NCT03173248
ivosidenib IDH1 inhibition MPN-BP, not
candidate for IC
Ivosidenib or IDH1 or IDH2 Phase 1 AML-TN, includes NCT02632708
Enasidenib + Inhibition+ MPN-BP
Cytarabine/ IC
daunorubicin
Venetoclax+ BCL2 Phase 1 Advanced heme NCT03471260
ivosidenib inhibition+IDH1 malignancies
inhibition including MPN-AP/BP
Decitabine HMA Phase II TP53 mutant R/R NCT03063203
AML
Decitabine+ HMA+ NAE Phase 1 AML –R/R including NCT03009240
pevonedistat inhibition secondary AML, AML-
TN >60y/o
Not candidate for IC

Azacitidine+ HMA+MEK Phase 1 Advanced myeloid NCT03326310

selumetinib inhibition neoplasms including
MPN-AP
XmAb14045 CD123 Phase 1 Advanced CD123+ NCT0273012
BiTE antibody heme malignancies
including R/R AML
HMA-hypomethylating agent; NAE-Nedd8 activating enzyme inhibitor, BiTE-bispecific T cell engaging;
MPN-AP/BP-myeloproliferative neoplasm accelerated or blast phase, MF-AP-myelofibrosis accelerated
phase; AML-TN-acute myeloid leukemia treatement naïve; R/R- relapsed/refractory
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28

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 From www.bloodjournal.org by guest on May 20, 2019. For personal use only.

Figure 3: How I treat Ph -MPN in the Blast Phase

MPN Blast Phase Diagnosis

NGS Analysis to include IDH 1 /2; TP53

Clinical Trial Participation is strongly encouraged

IDH1 / 2 TP53 Other

Mutation Mutation Mutations

**IDH 1 / 2 ~HMA-Based Intensive HMA-Based

Inhibitor therapy Therapy or ICT Chemotherapy Therapy

Allogeneic stem cell transplant if response is achieved and the patient is transplant
eligible. Clinical trial participation is strongly encouraged if lack of a response.

** The potential promise of IDH1/2 inhibitor based therapy is not yet validated in MPN-
BP and is recommended in the context of clinical trial participation; ~HMA based
therapy has not been validated as superior to intensive chemotherapy (ICT) in TP53
mutated cases and the choice of one over the other must be individualized.
 From www.bloodjournal.org by guest on May 20, 2019. For personal use only.

Prepublished online October 17, 2018;

doi:10.1182/blood-2018-03-785907

How I treat blast phase of Philadelphia-negative myeloproliferative

neoplasms
Olatoyosi Odenike

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