Received: 30 April 2023 | Accepted: 21 July 2023

DOI: 10.1111/bjh.19010

REVIEW

Updates on accelerated and blast phase myeloproliferative

neoplasms: Are we making progress?

Dina Mahdi1 | Jessica Spiers1 | Alexandros Rampotas1 | Nicola Polverelli2 |

Donal P. McLornan1

1
Department of Haematology, University
College Hospital, London, UK
2
Unit of Blood Diseases and Stem Cell
Transplantation, University of Brescia,
Brescia, Italy
Correspondence
Donal P. McLornan, Department of
Haematology and Stem Cell Transplantation,
University College London Hospitals, 3rd
Floor West, 250 Euston Road, London NW1
2PG, UK.
Email: donal.mclornan@nhs.net
Summary
Management approaches for accelerated and blast phase myeloproliferative neo-
plasms remain challenging for clinicians and patients alike. Despite many thera-
peutic advances, outcomes for those patients who are not allogeneic haematopoietic
cell transplant eligible remain, in general, very poor. Estimated survival rates for
such blast phase patients is frequently reported as less than 6 months. No specific
immunological, genomic or clinicopathological signature currently exists that ac-
curately predicts the risk and timing of transformation, which frequently induces a
high degree of anxiety among patients and clinicians alike. Within this review arti-
cle, we provide an up-­to-­date summary of current understanding of the underlying
pathogenesis of accelerated and blast phase disease and discuss current therapeutic
approaches and realistic outcomes. Finally, we discuss how the horizon may look
with the introduction of more novel agents into the clinical arena.

K EY WOR DS
accelerated phase, AML, blast phase, essential thrombocythaemia, JAK2, MPN, polycythaemia vera

I N T RODUC T ION
The last two decades have observed major advances in di-
agnostic and prognostic algorithms and therapeutic ap-
proaches across the range of ‘Philadelphia chromosome
negative’ chronic phase myeloproliferative neoplasms
(MPNs). However, despite these advances, the management
of MPN in accelerated phase (AP) and blast phase (BP), par-
ticularly for those patients who are not considered transplant
eligible or lack a suitable donor, remains very challenging.
There remains a lack of clear progress despite many novel
agents entering the clinical arena. Overall survival (OS) rates
for those with BP disease remain sobering, with frequently
estimated survivals of less than 6 months for those treated
with non-­curative intent.1 Within this practical review, we
discuss the pathogenesis of disease progression to highlight
potential therapeutic opportunities, provide an overview
of contemporary management approaches for MPN AP/BP
disease and discuss how novel agents may change the future
therapeutic landscape.
DE F I N I T IONS
MPN AP is classically defined as a persistence of 10%–­19%
blasts in the peripheral blood (PB) or bone marrow (BM)
and MPN BP by ≥20% blasts.2 For transformed cases, most
commonly the disease progresses from chronic phase to
MPN BP via AP but direct blastic transformation can also
occur. Hence, MPN AP is part of a dynamic progressive dis-
ease spectrum leading towards BP disease at variable rates.
An outstanding question has been how increasing blasts
in the PB or BM, not yet reaching the assigned ‘cut off’ of
≥10% to define AP, can affect outcomes. Masarova and col-
leagues evaluated if there was a differential effect on sur-
vival outcomes determined by blast % in a cohort of 1314

Dina Mahdi and Jessica Spiers are joint first authors.

© 2023 British Society for Haematology and John Wiley & Sons Ltd.

Br J Haematol. 2023;00:1–13.  wileyonlinelibrary.com/journal/bjh | 1


2 |    UPDATES ON ACCELERATED AND BLAST PHASE MYELOPROLIFERATIVE NEOPLASMS
myelofibrosis (MF) patients.3 In particular, to understand
the impact of <10% PB blasts compared to MPN AP. Here,
patients with ≥5% PB or BM blasts actually had similar ad-
verse features to those patients with MPN AP, displayed a
twofold increase in leukaemic transformation compared
to those with lower blast %, and had comparable survival
to MPN AP. This highlights that therapeutic intervention
should be considered early for such patients. These findings,
confirmed also by other groups, have led to suggestions that
the blast % for defining MPN AP could be lowered to 5%
although this has not yet been widely accepted.3-­5
R ISK FAC TOR S A N D PAT HOGE N E SIS
OF AC CE L E R AT E D A N D BL A ST
PH A SE M PN
The risks of transformation differ across the MPN spectrum.
The cumulative hazard of MPN BP for polycythaemia vera
(PV) is estimated at 2.3% and 5.5% and for essential throm-
bocythaemia (ET) at 0.7% and 2.1% at 10 and 15 years re-
spectively.6,7 The risk of MPN BP is highest for primary MF
(PMF), in particular for those with so called ‘high molecular
risk’ (HMR) mutations, estimated between 10% and 20% at
10 years post-­diagnosis.8 Risk factors for transformation, in
general, are based on clinicopathological features and, more
recently, molecular profiling. For PV, older age, leucocytosis,
an abnormal karyotype, increasing reticulin fibrosis, his-
toric use of P32 and the presence of high-­risk mutations such
as TP53, RUNX1, ASXL1, EZH2 and SRSF2, among others,
are associated with a higher risk of transformation.1,7–­10 For
ET, again older age, leucocytosis, anaemia, extreme throm-
bocytosis (>1000 × 109/L), increasing reticulin deposition
and mutations in TP53, SRSF2, ASXL1, EZH2, U2AF1 and
IDH1/2 have been detailed across studies as increasing trans-
formation risk to varying degrees.1,6,8,11–­13
For PMF, risk factors include age, increasing throm-
bocytopenia, rising blasts in the PB, high-­risk cytogenetic
anomalies such as monosomy 7, chromosome 17p deletions;
isochrome (17q), inv (3)/3q21, 12p−/12p11.2, 11q−/11q23,
+8 and complex or monosomal karyotypes. HMR muta-
tions such as ASXL1, EZH2, SRSF2, IDH1/2 and U2AF1, or
being ‘triple-­negative’ for driver mutations, also increases
the risk in PMF.1,9,14-­17 Contemporary MF-­specific scores can
aid prediction of general risk. The Dynamic International
Prognostic Scoring System (DIPSS) was developed to predict
survival in PMF using five clinicopathological factors (age
≥65 years, haemoglobin <100 g/L, leucocytes ≥25 × 109/L,
circulating blasts ≥1% and constitutional symptoms), appli-
cable at any stage in the disease course. Patients within the
intermediate-­2 and high-­risk categories have an estimated
7.8-­and 24.9 fold increased risk of MPN BP, respectively,
compared to those in the low-­risk category.18 This model
was subsequently refined, as DIPSS-­plus, by addition of un-
favourable karyotype, thrombocytopenia and transfusion
dependency, all of which are independent risk factors for BP
in MF.19 The mutation-­enhanced international prognostic
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scoring system for transplant-­eligible patients (MIPSS70)
and MIPSS70-­version 2.0 scores were developed from a co-
hort of PMF patients, incorporating molecular information
to refine prognostication.15,16 For example, the category
identified as very high risk in MIPSS70-­plus has a 13.3-­fold
increased risk of BP, with an incidence of 23%, compared to
11% in the low-­risk category.
The prognostic scores described above include the poorly
standardised variable of PB blast count assessment by mor-
phology, which remains very operator dependent and indeed
the ‘cut off’ value as a significant variable in the model dif-
fers between the scoring systems. A recent study focussed
on the utility of multiparameter flow cytometric (MFC) as-
sessment of PB CD34+ count and degree of decreased side
scatter of neutrophils in 363 MF patients. The authors cate-
gorised the group into three arbitrarily defined groups based
on these two findings and relative thresholds; MFC ‘low’,
‘intermediate’ or ‘high’, which independently correlated
with survival. Next, they integrated these findings into the
IPSS and MIPSS70+ models in place of morphological as-
sessment of blast count. Patients were reclassified according
to these MFC-­enhanced models, highlighting significantly
better risk stratification performance. Of note, this was not
the case in the MYSEC-­PM model, perhaps in part due to
smaller sample size.20
A recent study evaluating risks of transformation in a co-
hort of 1306 patients with PMF, where 149 (11%) developed
MPN ­BP, suggested a three-­tier risk model.21 Time-­to-­event
Cox analysis demonstrated BP prediction risk factors within
5 years of diagnosis for: age >70 years (hazard ratio [HR] 2.1),
the presence of moderate/severe anaemia (HR 1.9), circulat-
ing blasts ≥3% (HR 3.3), and the presence of IDH1 mutations
(HR 4.3), SRSF2 mutations (HR 3.0) and ASXL1 mutations
(HR 2.0). The high-­risk category had a BP incidence of 57%,
compared with only 8% for the low-­risk category.
The exact genetic, epigenetic and immunological events
driving disease acceleration and transformation still re-
quires further elucidation (Figure 1). Numerous studies have
highlighted the differences in the mutational landscape of
MPN BP compared to de novo acute myeloid leukaemia
(AML). While the most common mutations seen in AML
(NPM1 and FLT3-­ITD) are rarely seen in MPN BP, there
is enrichment of mutations across a range of epigenetic
modifiers (TET2, DNMT3A, IDH1/2), transcription factors
(TP53, RUNX1, IKZF1) and splicing factors (SF3B1, U2AF1,
SRSF2).11–­13,22–­27 LNK, PTP1N1 and MYC anomalies also ap-
pear to be overrepresented in MPN BP.25,28 The increased
number of cumulative molecular mutations, as well as cyto-
genetic complexity, suggest that genomic instability plays an
important role in transformation.29
It is well documented that leukaemic clones with wild-­
type JAK2 can arise in patients whose chronic phase dis-
ease harbours the JAK2 V617F mutation. 25,28 Two possible
models of leukaemic transformation in these patients
have been hypothesised. 28,30,31 In the first, an antecedent
clone harbouring earlier genetic aberrations (e.g. in TET2
and DNMT3) promoting a growth advantage, genomic
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MAHDI et al.    | 3

F I G U R E 1 Models of myeloproliferative neoplasm (MPN) progression: MPN are frequently initiated by a driver mutation leading to the
development of the ‘MPN driver clone’. Additional phenomena driven by ‘chronic inflammation’ and the self-­reinforcing haematopoietic stem cell niche
paralleled with genomic instability can lead to the acquisition of further proleukaemic mutations. The increase in the mutational burden can lead to
the development of a ‘leukaemic stem cell’, which will drive the accelerated/blastic phase of the disease. This progression is depicted in a linear fashion,
but stepwise changes can accelerate the progression. Alternative pathways to MPN progression are also depicted. Pre-­existing clonal haematopoiesis
mutations can drive expansion of an aggressive clone if a secondary MPN mutation occurs, while ‘triple negative’ MPNs can also progress by acquisition
of further pro-­leukaemic mutations.

4 |    UPDATES ON ACCELERATED AND BLAST PHASE MYELOPROLIFERATIVE NEOPLASMS
instability or both gives rise to two separate clones—­the
leukaemic clone and the underlying MPN clone. Genetic
mutations implicated in clonal haematopoiesis and fre-
quently present in MPN can precede JAK2 V617F and
associate with genomic instability, giving rise to a sub-
clone with multiple mutations which ultimately becomes
the dominant leukaemic clone. The question of whether
a JAK2 V617F-­positive clone may give rise to wild-­type
JAK2 AML, later losing this mutated allele or converting
to wild-­type JAK2 through mitotic recombination, gene
conversion or deletion, has been excluded in a number
of clonality studies using paired chronic and BP sam-
ples. 28,30,31 In the second model, the leukaemia arises
from a phylogenetically unrelated haematopoietic stem
cell from the MPN clone, perhaps reflecting DNA dam-
age from mutagenic treatments used in the chronic phase
of MPN, although this is unlikely to explain the majority
of cases, given that contemporary care generally involves
agents not known to associate with leukaemogeneis. 28
Leukaemic clones, which do harbour the driver mutation,
are also seen, and likely arise due to the acquisition of ad-
ditional genomic aberrations. 30
Luque Paz and colleagues described differential blastic
transformation events at a molecular level for 49 patients
with BP PV or ET utilising sequencing data.12 The most fre-
quent mutations were in TP53, TET2, RUNX1, ASXL1 and
EZH2, with no significant differences between PV and ET as
regards incidence. Hierarchical classification was used to de-
lineate three groups of patients with different times to trans-
formation. So-­called short-­term transformations (median
time to transformation 3-­years) occurred in patients with a
complex mutational landscape, with a median of seven mu-
tations, and were enriched for the presence of mutations in
RUNX1, IDH1/2, U2AF1 and TET2. Of note, there were no
TP53 mutations detected. In contrast, those demonstrat-
ing a longer time to transformation (median 21 years) were
enriched for TP53, NRAS and BCORL1 mutations in a less
complex mutational landscape. There was an equal distribu-
tion of ASXL1 mutations in both groups. Overall, the most
frequently mutated gene at the time of blast transformation
was TP53 (45%). It is important to note that previous work
has suggested that TP53 mutations at a low allelic burden
can be present for many years in chronic phase, while after
loss of the wild-­t ype TP53 allele, rapid clonal expansion and
leukaemic transformation frequently ensues.28,32 In this re-
gard, Li et al. recently evaluated a number of different TP53
allelic configurations in JAK2V617F/TP53 mutant MPN
murine models.33,34 Mice with biallelic inactivation of TP53
succumbed to rapid leukaemic transformation, of note de-
veloping a pure erythroid leukaemia which arose from the
megakaryocyte–­ erythroid progenitor (MEP) population.
This work additionally highlighted the importance of bone
morphogenetic protein 2 (BMP2)/SMAD pathway activation
in aberrant MEP self-­renewal and leukaemic initiation po-
tential, contributing to transformation, and also that target-
ing components of the DNA repair pathways (pCDC2 and
PARP) could be a rationale potential therapeutic strategy.
13652141, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.19010 by Christian Medical College, Wiley Online Library on [07/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Rodriguez-­Meira and colleagues have recently reported
on single-­cell multiomic analysis of haematopoietic stem/
progenitor cells (HSPC) in TP53-­mutated AML arising
from MPN.35 ‘TARGETseq’ analysis was performed on
Lin−CD34+ HSPCs from 14 TP53-­mutated AML patients
and 9 age-­matched controls. In all cases, the dominant clone
showed loss of wild-­type TP53 through varying patterns
of clonal evolution. Here, chronic inflammation supressed
TP53 wild-­t ype HSPC while, in parallel, the survival advan-
tage of TP53 mutant cells was augmented. Of interest, three
distinct clusters of HPSC in TP53-­sAML were described, one
of which was characterised by overexpression of erythroid
genes and another characterised by defective differentiation
and so-­called ‘quiescence signatures’.
The utilisation of patient-­derived xenograft (PDX) mu-
rine models that robustly engraft patient cells into immu-
nodeficient mice can increasingly inform on the complexity
of MPN transformation events. For example, the human-
ised murine model described by Celik and colleagues
reproduced patient genomic complexity and hierarchy,
pathological features such as reticulin deposition, and can
aid prediction/characterisation of clonal evolution events.36
Most importantly, these models are amenable to pharmaco-
logical and genomic manipulation to investigate therapeutic
vulnerability.
While there appears to be a significant association be-
tween inflammation and more advanced diseases phases,
the exact interaction between the MPN clone, the adap-
tive and innate immune system and the bone marrow
niche requires further clarification. A number of streams
of work have highlighted the link between disease-­
associated inflammation and risk of transformation. 37
Increased levels of a range of cytokines including IL-­2 ,
IL-­6 , sIL-­2RA and IL-­8 have been shown to significantly
associate with transformation to MPN BP. 37,38 Moreover,
generation of reactive oxygen species may contribute
to disease progression by both augmenting JAK/STAT
signalling and inducing genomic instability, laying the
foundation for acquisition of additional mutations. 24,37,39
‘Multiomic’ approaches are hence required to understand
the complex interaction between the bone marrow micro-
environment, ‘immunome’ and acquired genomic insta-
bility/mutational landscape.
OV E RV I E W OF T R E ATM E N T
A PPROACH E S BA SE D ON F I T N E S S
A N D T R A NSPL A N T E L IGI BI L I T Y
Current treatment options for MPN AP/BP still remain
unsatisfactory overall and allo-­HCT represents the only
curative strategy. Long-­term survival after allo-­HCT has
been reported to range between 30% and 70% in retro-
spective studies, dependent on patient-­ , disease-­and
transplant-­specific factors, and there is a trend towards
improvements in allo-­ HCT outcomes in more recent
years.40,41 However, considering the advanced age of

MAHDI et al.
many MPN AP/BP patients, allo-­HCT can be offered to
only a minority. At present, in some centres, the use of
chronological age alone is largely outdated, and biologi-
cal fitness is of key importance. In addition, the role of
comorbidities, as evaluated by the Haematopoietic Stem
Cell Transplantation Comorbidity Index (HCT-­CI), ap-
pears to be of less importance among elderly subjects
compared to younger, particularly in transplant cohorts
from the most recent era.42 Novel multidimensional and
comprehensive geriatric assessment tools are becoming a
mainstay for the evaluation of eligibility for allo-­HCT in
the more elderly population.43,44 A modern approach to
patients with MPN AP/BP should hence include a com-
prehensive evaluation of all patients up to 70–­75 years of
age; disease-­and patient-­specific characteristics should
be considered along with patients' preferences and an
overview of social and family support. Early referral is
necessary with identification of donors. Achievement
of disease control, that is achieving complete remission
(CR) prior to transplant, and tailoring of the transplant
platform can maximise allo-­HCT outcomes. Clinically
challenging cases remain where the decision-­ making
process is less than straightforward, including potential
allo-­HCT eligible patients where one or more comorbidi-
ties exist that will predict higher non-­relapse mortality
(NRM), patients towards the upper end of ‘acceptable’
chronological age, the presence of a complex/monosomal
karyotype, particularly accompanied by the presence of
a TP53 mutation, as the relapse risk may be unacceptable
and the presence of difficult social or financial circum-
stances. Clearly, MDT discussions are paramount in such
cases to individualise such recommendations.
T H E R A PY
Hypomethylating agents alone
The hypomethylating agents (HMAs), azacytidine and
decitabine, are frequently considered as monotherapy
for MPN AP/BP patients unsuitable for intensive chem-
otherapy and allo-­HCT. Utilisation in this setting has
originated from results generated in the myelodysplastic
neoplasm-­A ML arena. Practically, HMA can be favour-
able treatment options in MPN AP/BP due to good tol-
erability, including for older patients or those with poor
performance status, paralleled with their potential abil-
ity to induce transient disease control in some. From a
biological perspective, hypermethylation of p15 and p16
genes has been shown in MPN BP, but not chronic phase,
with resultant myeloid differentiation block, suggesting
that agents targeting dysregulated methylation status may
be useful, in addition to demonstration of in vitro sensi-
tivity of MPN-­derived cells with aberrant DNA methyla-
tion to HMAs.45,46
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   | 5
Unfortunately, HMA therapy has not been prospec-
tively evaluated to examine survival benefit in MPN AP/
BP or in direct comparison with intensive chemotherapy;
current evidence base is drawn from small, frequently het-
erogeneous cohorts. In 2010, the Groupe Francophone Des
Myelodysplasies reported on 26 MPN ­BP patients who had
received azacytidine monotherapy.47 The overall response
rate (ORR) was 38%, with a median OS of 8 months, and
combined CR/CR with incomplete haematological recovery
(CR/CRi) was achieved in 12%. Other studies of either single
agent azacytidine or decitabine suggested OS estimates be-
tween approximately 7 and 10 months, with CR/CRi rates of
less than 25%.48,49 In a recent meta-­analysis, monotherapy
with azacytidine or decitabine was found to have an ORR of
38%, with significant heterogeneity amongst the studies.50
Pooled ORR analysis did not show a statistically significant
difference between azacytidine (42%) and decitabine (27%)
responses, suggesting no clear ‘winner’. Treating clinicians
should be aware that response are often short lived, ongoing
transfusion dependency is frequent and HMA frequently do
not address MPN AP/BP-­related symptom burdens.
Hypomethylating agents in combination with
JAK inhibitors
Small case series initially reported the potential efficacy of
ruxolitinib in combination with either HMA or low-­dose
cytarabine.51 A phase 2 trial of ruxolitinib and decitabine
enrolled 25 patients with MPN A ­ P/BP with an ORR of 44%;
median OS for all patients on study was 9.5 months and
hence not significantly longer than monotherapy studies.52
Another phase 1/2 study of the same combination enrolled
12 and 15 patients in phases 1 and 2, respectively. A total
of 18 patients were treated at the recommended phase 2
dose (RP2D; 50 milligrams (mg) twice daily of ruxolitinib,
along with 20 mg/m2/day of decitabine, given for 5 days per
cycle) with an ORR of 61% in these 18 patients, and a median
survival of 8.4 months. Of note, four patients were bridged
to allo-­HCT.53 Regarding azacytidine, the UK generated
phase 1b PHAZAR study evaluated the combination of
azacytidine and ruxolitinib in advanced MPN with an aim
to establish the maximum tolerated dose, safety and clinical
activity of this combination.54 A total of 34 patients were
recruited (15 MPN BP and 19 MPN AP) and a modified
two-­stage continual reassessment model was implemented
as regards dose escalation. Median number of azacytidine
and ruxolitinib cycles received were 4 and 3 respectively;
overall, 20/34 patients were evaluable for disease response
assessment. Toxicity was acceptable and as expected. A total
of 10/20 patients achieved either a PR or CR. Meaningful
red cell transfusion reduction was also seen in 3/14 patients.
Median duration responses were relatively short: MPN AP
322 days and MPN BP 199 days. Longer term outcomes are
awaited but the approach is promising, with some long-­term

6 |    UPDATES ON ACCELERATED AND BLAST PHASE MYELOPROLIFERATIVE NEOPLASMS
responses identified for MPN AP. The meta-­ analysis by
Chen et al., additionally compared single agent HMA versus
HMA with ruxolitinib.50 Here, responses with HMA and
ruxolitinib showed higher ORR than monotherapy (45% vs.
30%, p = 0.04) but no difference in rates of CR/CRi.
Intensive chemotherapy
Historically, intensive chemotherapy (IC) regimens for
MPN ­BP generally mimicked those used for de novo AML.
Standard of care, in general, remains induction chemother-
apy over HMA with a view to allo-­HCT in those deemed fit
enough to tolerate potential treatment-­related toxicity. Few
prospective studies have directly addressed comparison of
regimens. While one small retrospective study evaluating
a heterogeneous range of induction and consolidation ap-
proaches suggested a trend towards improved responses
following combinatorial therapy with mitoxantrone, etopo-
side and high-­dose cytarabine (NOVE-­HIDAC), this has
not been supported in other studies.55 In this retrospective
study, 38/75 patients underwent IC with a view to allo-­HCT.
Of these, 76% of patients responded (18 with CR/CRi and
11 reverted to chronic phase); 17 patients subsequently un-
derwent allo-­HCT. OS was significantly better in those re-
sponding patients undergoing allo-­HCT compared to those
not-­transplanted (47% compared to 15% (p = 0.03). No sig-
nificant survival difference was evident between those re-
sponding to IC alone who did not undergo transplant and
those treated non-­intensively (median survival of 9.4 and
6.6 months, respectively; p = 0.18). Globally, multiple de novo
AML style induction strategies are used for these patients
despite lack of evidence or consensus recommendations.
Combinatorial approaches of intensive chemotherapy and
venetoclax are also being evaluated.
A large study of two separate cohorts (Mayo-­AGIMM)
totalling 410 patients with MPN BP evaluating outcomes
over time found no significant improvement had been made
in the 15 years covered in this study period.1 In the first co-
hort, 66/125 patients received IC, with 59% achieving CR
or CRi compared to <5% with other agents such as HMAs.
In the second, 48/162 patients received IC with a combined
CRCRi rate of 35.4%. Of note, while the OS benefit of allo-­
HCT over no transplant was confirmed, this study failed
to demonstrate a significant difference in survival between
those achieving CR or CRi and those undergoing allo-­SCT
(irrespective of achievement of CR or CRi prior to trans-
plant), with HR 0.6 (95% CI 0.3–­1.1) for allo-­HCT versus
CR/CRi without allo-­ HCT. Other retrospective studies
have confirmed no OS benefit between IC treated versus
non-­intensive treated cohorts without early allo-­HCT.56,57
Optimal induction regimen and required depth of response
require further evaluation but is limited by a lack of co-­
operative group trials. It is clear that novel approaches are
needed to get this challenging group of patients in remis-
sion safely followed by allo-­HCT, as this currently offers the
best chance of long-­term cure.
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Allo-­HCT for MPN AP/BP: Where are we now?
Multiple studies have evaluated the efficacy and safety of allo-­
SCT in the context of MPN AP/BP. The MD Anderson group
reported, for the first time, the superiority of a transplant
approach over IC without allo-­SCT consolidation in MPN
BP.57 Long-­term disease control was only achievable with
allo-­SCT, with an impressive 73% OS rate after a median fol-
low-­up of 31 months. In contrast, patients who achieved CR
after chemotherapy but did not undergo transplant had an
OS of 0%. These findings primarily supported the potency
of the so-­called graft-­versus-­leukaemia (GVL) effect, in this
high-­risk setting. Baron et al. confirmed this observation
by leading an extensive analysis of the connection between
graft-­versus-­host disease (GVHD) and GVL effects on a co-
hort of 2414 cases of secondary leukaemia, including cases
arisen from antecedent MPNs, who underwent allo-­HCT in
first or second CR.58 Limited and extensive chronic GVHD
(cGVHD) associated with a lower relapse incidence; how-
ever, due to a higher risk of NRM among patients with ex-
tensive cGHVD, only limited cGVHD translated into better
OS. The effect of GVL is also supported by studies highlight-
ing objective response rates following donor lymphocyte in-
fusions (DLIs) for relapse post allo-­HCT.59,60
One recent study focused on RIC allo-­HCT outcomes
for MPN AP, reporting on the outcomes of 35 patients com-
pared with those in chronic phase (n = 314). The estimated 5-­
year OS for the AP group was 65% versus 64% for the chronic
phase cohort; however, the AP cohort had a higher 5-­year
relapse incidence at 30%.
Many centres and working groups have reported out-
comes of MPN BP allo-­HCT in Europe, Japan and North
America (summarised in Table 1). With the limits of marked
heterogeneity in terms of induction treatments and trans-
plant characteristics across studies, OS did not exceed
20–­30% in the longer term. In particular, a retrospective
analysis by the Center for International Blood and Marrow
Transplant Research (CIBMTR) of 6030 AML transplanted
patients, including 177 with MPN BP, highlighted a worse
OS and higher relapse risk for MPN BP compared to patients
in remission from de novo AML or post-­myelodysplastic
neoplasm AML undergoing allo-­HCT.61 Longer duration
of the underlying disease, older age and higher genomic
complexity leading to lower rates of CR may all contribute,
highlighting the need for improved allo-­HCT strategies.
Very recently, the Chronic Malignancies Working Party of
the EBMT published the largest transplant cohort of MPN
BP patients available to date.41 This study confirmed that
approximately 1/3 of patients could be cured with transplant
(32% OS at 5-­years) and revealed a gradual improvement in
outcomes over the years. Compared to previous experiences,
the prognostic role of donor match was less evident, with no
differences in OS according to donor type, although NRM
was increased in mismatched related and unrelated donor
allo-­HCT. Patients with a good performance status who
achieved pretransplant CR had an expected survival of 60%
at 3-­years, highlighting the potential benefits of utilising
 TA BL E 1 List of the available studies on the role of allo-­SCT in blast phase MPN.

Transplant Median age

Author Year Pts period at allo-­SCT Pretreatment Conditioning Donor CIR NRM OS Favourable factors
MAHDI et al.

41
Orti 2023 663 2005–­2019 60 Chemo (49%) MAC (35%) MRD (28%) 51% at 5 years 24% at 5 years 32% at 5 years • KPS ≥90
HMA (6%) UD (63%) • CR at allo
Ruxolitinib (3%) MMRD (9%) • Earlier transplant period
Other (33%)
Shah87 2021 43 2001–­2016 59 Chemo (83%) MAC (67%) MSD (40%) 43% at 4 years 24% at 4 years 38% at 4 years • Earlier transplant period
HMA (23%) MUD (60%)
JAKi (21%)
None (16%)
Gupta61 2020 177 2001–­2015 59 Chemo (66%) MAC (53%) MRD (31%) 63% at 5 years (CR) 21% at 5 years (CR) 22% at 5 years (CR) • Younger age
HMA (4%) UD (62%) 71% (no CR) 23% (no CR) 11% (no CR) • Female gender
MMRD (7%) • KPS ≥90
• MRD
• Earlier transplant period
• Absence of TP53 mutation
• Absence of adverse
cytogenetics
Kröger88 2019 422 2000–­2014 59 NA MAC (34%) MRD (36%) 50% at 3 years 25% at 3 years 33% at 3 years • MRD
UD (64%) • BM as a source
• CR at allo
• Younger age
• KPS ≥90
• CMV seronegative
• Normal karyotype
• Absence of ex vivo TCD
Takagi89 2016 39 2000–­2013 57 Chemo (69%) MAC (38%) MRD (21%) 34.4% at 2 years 34.2% at 2 years 29.2% at 2 years • None identified
Untreated (31%) UD (38%)
UCB (41%)
Cahu90 2014 60a 2000–­2010 57 NA MAC (23%) MRD (38%) 68% at 3 years 22% at 3 yeares 18% at 3 years • CR at allo
UD (62%)
Alchalby40 2014 46 NA 55 Chemo (91%) MAC 43% MRD (37%) 47% at 3 years 28% at 1 year 33% at 3 years • CR at allo (on LFS)
UD (61%)
MMRD (2%)
Kennedy55 2013 17 1998–­2011 NA Chemo (100%) MAC (47%) MRD (70%) 24% 47% 47% at 2 years NA
UD (30%)
Ciurea91 2010 14 1994–­2008 59 Chemo (93%) MAC (21%) MRD (57%) 23% at 2 years 29% at 2 years 49% at 2 years None identified
MUD (29%)
MMRD (14%)
Tam57 2008 8 1994–­2007 57 Chemo (75%) NA MRD (63%) 13% 25% 73% at 5 years NA
UD (37%)

Abbreviations: BM, bone marrow; chemo, chemotherapy; CIR, cumulative incidence of relapse; CR, complete remission; HMA, hypomethylating agents; JAKi, JAK-­i nhibitors; KPS, Karnofsky Performance Score; LFS, leukaemia-­f ree
survival; MAC, myeloablative conditioning regimen; MMRD, mismatched related donor; MPN, myeloproliferative neoplasm; MRD, matched related donor; NA, not available; NRM, non-­relapse mortality; OS, overall survival; Pts,
  

patients; RIC, reduced intensity conditioning; TCD, T-­cell depletion; UCB, unit of cord blood; UD, unrelated donor.
|

a
7

13 Patients with MDS/MPN were included.

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8 |    UPDATES ON ACCELERATED AND BLAST PHASE MYELOPROLIFERATIVE NEOPLASMS
effective pretransplantation therapies that preserve recipient
fitness. In this regard, there is a general agreement among
the studies regarding the importance of pretransplant CR.
However, MPN BP patients demonstrate lower CR rates
compared to de novo AML, in part related to the presence of
high-­risk cytogenetic or molecular features (e.g. TP53 mu-
tations), the prevalence of which are more frequent in this
patient group as described above.25,62 The presence of such
alterations predicts a lower propensity to reach deep and du-
rable responses, even in the context of novel approaches.56,63
To date, several questions remain unresolved. Which
pretransplant therapy is preferable for MPN BP remains an
ongoing matter of debate, as no prospective and randomised
clinical trials have been designed with an intention to get to
allo-­HCT. Also, the extent and depth of response required
before transplant remains unknown. From the transplant
perspective, the role of conditioning intensity and stem cell
source, the use of alternative donors, post-­transplant strate-
gies for preventing relapse (adoptive immunotherapy with
pre-­emptive DLI, role of maintenance, etc.) are issues that
both the MPN and transplant community needs to address
through co-­operative trials.
NOV E L T H E R A PI E S : W H AT DO W E
H AV E NOW A N D W H AT M AY BE ON
T H E HOR I Z ON ?
Below, we discuss some of the currently available agents and
also discuss potential future strategies. How best to navi-
gate the correct sequencing and combination approaches
with these agents remains an unknown; however, we have
attempted to highlight those of particular interest and where
combination approaches may be more rational.
BCL-­2 inhibition in MPN AP and BP
Venetoclax, a selective BCL-­2 inhibitor, has been trialled
in combination with both HMA and IC regimens. The
combination of venetoclax and HMA was retrospectively
evaluated in 35 patients from a single centre with high-­risk
myeloid disease: either MDS/MPN in accelerated or blastic
phase, MPN AP/BP or AML with extramedullary disease.
For the entire cohort, the composite CR rate was 42.9% with
a median OS of 9.7 months. There was a suggestion that
those with advanced MDS/MPN had higher CR rates and
an improved OS compared to those with advanced MPN but
the numbers were too small for robust conclusions.64 In the
meta-­analysis by Chen and colleagues, HMA and venetoclax
yielded higher CR rates than HMA +/− ruxolitinib with a
trend to improved survival. Further data on this combina-
tion are required to guide future combination approaches.
Of interest, venetoclax has been trialled in combination with
low-­dose navitoclax, a BCL-­X L and BCL-­2 inhibitor. Most
data have emerged in the heavily treated, refractory acute
lymphoblastic leukaemia setting, with 60% of patients in one
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phase I trial gaining a response following therapy with this
combination alongside chemotherapy, with some patients
being successfully bridged to allo-­HCT or chimeric antigen
receptor T-­cell (CAR-­T) therapy.65 Given such potential syn-
ergy, data is urgently required in the MPN AP/BP setting. In
this regard, a phase I study (NCT05455294) has been opened
investigating the triplet combination of navitoclax, veneto-
clax and decitabine across high-­risk myeloid neoplasms, in-
cluding MPN AP/BP.
Liposomal daunorubicin and cytarabine
Liposomal cytarabine–­ daunorubicin is a combination of
daunorubicin and cytarabine in a 1:5 molar ratio. Ilyas and
colleagues evaluated efficacy of this agent in a small cohort
of MPN BP patients (n = 12), with a median age of 63 years.66
Response rates were disappointing overall, with only 3/12
(25%) achieving a CR and 1/12 (8%) a partial response (PR),
in comparison to the previously demonstrated efficacy
in AML with myelodysplasia-­related changes (MRC) and
therapy-­related AML where CR rates approached 48%.67 A
total of seven patients proceeded with second-­line therapy
following treatment failure; three out of five patients treated
with HMA–­venetoclax or cytarabine–­venetoclax achieved a
CR and one proceeded to allo-­HCT as did another patient
post-­FLAG-­Ida. Further work is needed to understand if this
agent—­either alone or in combination with agents such as
venetoclax—­has a role in the management of MPN AP/BP,
as current data remains disappointing.
IDH1/IDH2 inhibitors
Compared to chronic phase MPN, the incidence of IDH1/
IDH2 mutations is much higher in MPN AP/BP; one study
highlighted that the incidence is up to 22% in those with
BP MPN.68 Ivosidenib is a potent and selective inhibitor of
mutated IDH1 whereas enasidinib is a selective inhibitor of
IDH2; both have shown activity in relapsed/refractory AML
but initial trials contained only a few MPN BP patients.
Chifotides and colleagues published a study on the efficacy
of ivosidenib and enasidenib in 12 MPN BP patients either
as monotherapy or in combination with HMA, venetoclax,
ruxolitinib or IC.69 This was a heterogeneous cohort with a
median age of 67 where seven patients harboured an IDH1
mutation (R132C [n = 6] and R132H [n = 1]) and five patients
the IDH2 R140Q mutation; a majority (10/12) had JAK2
V617F. Three patients achieved CR (enasidinib/ruxolitinib/
azacytidine [n = 1]; ivosidenib + venetoclax as a bridge to
allo-­HCT [n = 1] and a transient CR on ivosideninib and IC
for 7 months [n = 1]) with a median OS of 19 months. Several
other patients achieved significant reductions in blasts al-
beit did not achieve a CR. In addition, Patel et al. reported
on eight patients with IDH2-­mutated MPN BP treated with
enasidenib—­six were initial treatments and for two it was
for management in the relapsed/refractory setting.70 ORR

MAHDI et al.
was 75% when MPN B ­ P criteria were used for response
and median OS was not reached with a median follow-­up
of 272 days. A phase II trial of 50–­100 mg of enasidenib and
ruxolitinib is currently open recruiting IDH2-­mutated MPN
AP/BP patients (NCT04281498). Further data on the opti-
mal sequencing and combination approaches with IDH1/
IDH2-­targeted therapies are needed.
Murine double minute 2 (MDM2) inhibitors
Wang and colleagues initially demonstrated that MPN BP
CD34+ cells contain higher levels of MDM2 than their nor-
mal counterparts; MDM2 is a negative regulator of TP53 and
hence MDM2 inhibitors, such as navtemadlin (KRT-­232),
can restore normal p53 functionality and induce apoptosis in
TP53 wild-­t ype (TP53WT) cells.71 The efficacy of navtemad-
lin has been shown in PDX MPN ­BP murine models.71 Here,
monotherapy with navtemadlin depleted MPN BP blast cells
and additionally prolonged survival in these PDX mice.
Next, MPN ­BP PDX mice were treated with multiple cycles of
either low-­dose or high-­dose navtemadlin, at 3-­weekly inter-
vals. MPN BP stem cells and leukaemic blasts were reduced
in the spleen and PB but not the marrow, and there was an as-
sociated survival improvement. Additional evaluation in this
PDX model suggested better efficacy of navtemadlin than
decitabine. A phase 1b/2 trial (NCT04113616) is currently
evaluating the safety and efficacy of navtemadlin in TP53WT
relapsed/ refractory MPN BP.72
Telomerase inhibitors
Imetelstat is a 13-­mer oligonucleotide, which displays in-
hibitory activity against telomerase. Clinically beneficial
responses have been highlighted to date in lower risk MDS
and predominantly chronic phase MF.73,74 Interestingly, Ma
et al. have suggested that targeting telomerase activity with
imetelstat can in fact prevent survival and self-­renewal of
both preleukaemic stem cell (LSC) and LSC in MPN models,
where both adenosine deaminase acting on RNA (ADAR1)
and hTERT activation appear pivotal.75 A novel Phase II trial
(NCT05583552) investigating the efficacy and safety of im-
etelstat in patients with high risk MDS or AML who have
failed HMA therapy is ongoing. Given the findings to date,
future trials focused on activity of this agent in MPN-­BP
would be of interest.
BET inhibitors
The BRD subfamily of bromodomain and extra-­terminal
(BET) proteins bind to acetylated chromatin and are in-
volved in gene transcription regulation.76 BET inhibitors
(BETi) have entered the clinical arena across a number of
haematological malignancies including AML, MPN and
lymphoma.77 In MF, strong clinical responses have emerged
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   | 9
from the phase II MANIFEST study, evaluating the efficacy
of the BETi pelabresib for chronic phase MF patients. The
combination of ruxolitinib and pelabresib was well tolerated
in JAK inhibitor naive patients and demonstrated improve-
ments in symptom and spleen burden, alongside potential
anaemia benefits.78 No currently recruiting trials are using
pelabresib in combination with either JAKi or HMA or
other agents in MPN AP/BP and, in our opinion, such com-
bination trials would be of high interest and should be pri-
oritised. Of interest, Saenz and colleagues showed that the
BETi JQ1 inhibited growth and induced apoptosis in MPN
derived blast cells. Moreover, synergistic activity was shown
with both ruxolitinib and heat shock protein 90 inhibitors,
highlighting potential future strategies for MPN AP/BP.79
I M M U NOT H E R A PY A N D CE L LU L A R
T H E R A PY A PPROACH E S
Vaccination strategies in chronic phase MPN and MPN AP/
BP remain in their relative infancy but with growing inter-
est among the community. Initial strategies in the chronic
phase setting included a phase I clinical trial of the safety
and efficacy of a ‘CALRLong36 peptide vaccine’, which in-
cluded 10 CALR mutated (CALR MUT) chronic phase MPN
patients, receiving a total of 15 vaccines over a 12-­month
period.80 The majority demonstrated evidence of a vaccine
induced response, which increased in ET patients over the
study period but, in contrast, not after the third vaccine dose
in MF. However, despite such responses, no molecular or
clinical responses were identified demonstrating the signifi-
cant challenges of such approaches.
Gigoux and colleagues next evaluated the potential of
heteroclitic peptide-­based vaccines for CALR MUT MPN.81
T cells recognise non-­self-­antigens via interaction between
the T-­cell receptor (TCR) and the peptide–­MHC-­I com-
plex (pMHC). Heteroclitic peptide modifications aim to
increase immunogenicity. This group had recognised that
in CALR MUT MPN there was an underrepresentation of
MHC-­I alleles that present CALR MUT neoepitopes with high
affinity and hence appraised that heteroclitic CALR MUT
peptides specifically designed for the MHC-­ I alleles of
CALR-­mutated MPN patients could elicit a CALR MUT cross-­
reactive CD8+ T-­cell response. Their initial data emphasised
the potential therapeutic benefit of this approach but more
work is required to see if it is applicable to the MPN AP/BP
setting for transformed CALR MPN.
Arginase-­1 (ARG1)-­and programmed cell death ligand 1
(PD-­L1)-­derived peptide vaccines have demonstrated safety
in a first in man phase I–­II study performed in nine JAK2-­
mutated chronic phase MPN patients but were insufficient
by themselves to generate clinical response.82 Both ARG1
and PD-­L1 can inhibit T-­cell activation and proliferation in
MPN. Handlos Grausland and colleagues hypothesized that
by augmenting ARG1-­and PD-­L1-­specific T-­cell responses
via peptide vaccines this in turn would lead to a reduction
in immunosuppressive cells in MPN and hence result in

10 |    UPDATES ON ACCELERATED AND BLAST PHASE MYELOPROLIFERATIVE NEOPLASMS
more MPN directed T-­cell responses. Future strategies may
include combination of such peptide vaccines with the PD-­1
checkpoint inhibitor, pembrolizumab. Although a previous
study with this agent alone in chronic phase MPN failed to
generate clinical benefit, improved T-­cell responses directed
at the MPN clone were observed.83 Novel studies are open-
ing with vaccines targeting both JAK2 and CALR and results
are eagerly awaited alongside translational studies to under-
stand how clinical efficacy may be enhanced. As these de-
velop in the chronic phase MPN setting, we aspire for rapid
transition to the MPN AP/BP cohorts.
Effective and non-­ toxic chimeric antigen receptor T
(CART) or bispecific T-­ cell engagers (BiTE) remain the
holy grail in the management of MPN AP/BP but develop-
ment is challenged by the lack of specific, truly universally
expressed MPN blast cell antigens. CALR MUT, as discussed
above, is an appealing immunotherapeutic target, resulting
from a frameshift mutation that leads to a novel C Terminus
which is absent in other cells. Additionally, CALR MUT is ex-
pressed on the cell surface by binding to the thrombopoietin
(TPO) receptor.84 Antibody strategies have been developed
and showed very promising results in preclinical studies.84
A ‘silent-­Fc’ antibody to block the CALR-­MPL interaction
has also been developed and will enter a phase I clinical trial,
initially in chronic phase disease. CART cell therapy or BiTE
approaches are also feasible and under evaluation in the pre-
clinical setting.
Targeting of CD33 or CD34 alone would likely lead to
multiple ‘off target’ effects on normal haematopoietic pro-
genitors. Many approaches are being taken in the AML field
to address these challenges and a host of early phase CART
trials are open globally, predominantly focused on differing
targets in relapsed/refractory AML. These include CD33,
CD123, CLL-­ 1, CD70, TIM-­ 3 and CD93.85 Interestingly,
Ramos et al. have recently reported the use of mass spec-
trometry to evaluate surface protein expression—­t he ‘surfa-
ceome’—­in MPN BP cell lines compared to other AML cell
lines.86 They reported over 70 membrane proteins enriched
in MPN BP-­derived cell lines and identified specific poten-
tial targets such as the G protein receptor C3AR1, which is
enriched in MPN BP and not expressed in the endothelium,
granulocytic or monocytic cells or donor-­derived normal
CD34+ cells, and CALR. Preclinical studies using immuno-
therapeutic strategies to target these antigens, and others,
are ongoing and ideally will lead to rapid adoption in the
clinical trial arena.
C ONC LUSIONS
MPN AP and BP still remain challenging diseases, particu-
larly when allo-­HCT is not an option. HMA and venetoclax
+/− JAK inhibitors can be effective for a period of time yet
require more clarity on dosing and optimal scheduling.
Prospective platform style trials based on comprehensive
drug synergy studies are required to evaluate approaches in
MPN AP/BP paralleled with dynamic translational studies
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to help us personalise and optimise sequencing and com-
binatorial therapy. We additionally predict that, given the
aggressiveness of these disease states, MPN AP and BP re-
main a prime group to explore novel immunotherapeutic
approaches including peptide vaccination and ultimately
BiTEs and CART cells. Within the transplant-­eligible popu-
lation, we still need to optimise conditioning approaches and
prospectively evaluate optimisation of pretransplant ther-
apy, depth of response and maintenance approaches in the
post allo-­HCT setting to decrease the risk of relapse. Lastly,
there remains an urgent unmet need of dynamic predictive
tools for transformation events, particularly in ET and PV.
We look forward to further international collaboration to
answer such questions and ultimately improve patient prog-
nostication and outcomes.
AU T HOR C ON T R I BU T ION S
All authors contributed equally to this work and reviewed
the final version.
AC K N O​W L E​D G E​M E N T S
All authors contributed equally to this paper, critically re-
viewed and revised the paper and approved the final paper
prior to submission.
F U N DI N G I N F OR M AT ION
There is no funding associated with this work.
C ON F L IC T OF I N T E R E S T S TAT E M E N T
None of the authors have a conflict of interest to declare.
ORC I D
Nicola Polverelli https://orcid.org/0000-0001-6297-9697
Donal P. McLornan https://orcid.
org/0000-0003-1224-091X
TWITTER
Donal P. McLornan @DrLornan
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How to cite this article: Mahdi D, Spiers J, Rampotas
A, Polverelli N, McLornan DP. Updates on accelerated
and blast phase myeloproliferative neoplasms: Are we
making progress? Br J Haematol. 2023;00:1–13.
https://doi.org/10.1111/bjh.19010