CME ARTICLE

A JH
CME Information: Primary myelofibrosis: 2017 update on
diagnosis, risk-stratification and management

CME Editor: Ayalew Tefferi, M.D.

Author: Ayalew Tefferi, M.D.

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䊏 Educational Objectives
Upon completion of this educational activity, participants will be better able to:

 Highlight the 2016 revision on the classification and diagnosis of primary myelofibrosis, both overt and prefibrotic.
 Discuss contemporary risk stratification and the role of molecular prognostication.
 Provide an overview on risk-adapted treatment strategies.

䊏 Activity Disclosures
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American Journal of Hematology, Vol. 91, No. 12, December 2016 1261
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
AJH Educational Material A JH
Primary myelofibrosis: 2017 update on diagnosis,
risk-stratification, and management
Ayalew Tefferi*

Disease overview: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by

stem cell-derived clonal myeloproliferation that is often but not always accompanied by JAK2, CALR or MPL
mutation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary
hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression and shortened survival.
Diagnosis: Diagnosis is based on bone marrow morphology. The presence of JAK2, CALR or MPL mutation
is supportive but not essential for diagnosis; approximately 90% of patients carry one of these mutations
and 10% are “triple-negative.” None of these mutations are specific to PMF and are also seen in essential
thrombocythemia (ET). According to the revised 2016 World Health Organization (WHO) classification and
diagnostic criteria, “prefibrotic” PMF (pre-PMF) is distinguished from “overtly fibrotic” PMF; the former might
mimic ET in its presentation and it is prognostically relevant to distinguish the two.
Risk stratification: The Dynamic International Prognostic Scoring System-plus (DIPSS-plus) uses eight
predictors of inferior survival: age >65 years, hemoglobin <10 g/dL, leukocytes >25 3 109/L, circulating
blasts 1%, constitutional symptoms, red cell transfusion dependency, platelet count <100 3 109/L and
unfavorable karyotype (i.e., complex karyotype or sole or two abnormalities that include 18, 27/7q-, i(17q),
inv(3), 5/5q-, 12p-, or 11q23 rearrangement). The presence of 0, 1, “2 or 3” and 4 adverse factors defines
low, intermediate-1, intermediate-2 and high-risk disease with median survivals of approximately 15.4, 6.5, 2.9
and 1.3 years, respectively. Most recently, DIPSS-plus-independent adverse prognostic relevance has been
demonstrated for certain mutations including ASXL1 and SRSF2 whereas patients with type 1/like CALR
mutations, compared to their counterparts with other driver mutations, displayed significantly better survival.
Risk-adapted therapy: Observation alone is a reasonable treatment strategy for asymptomatic low or
intermediate-1 DIPSS-plus risk disease, especially in the absence of high-risk mutations. All other patients
with high or intermediate-2 risk disease, or those harboring high-risk mutations such as ASXL1 or SRSF2,
should be considered for stem cell transplant, which is currently the only treatment modality with the
potential to favorably modify the natural history of the disease. Non-transplant candidates should be
encouraged to participate in clinical trials, since the value of conventional drug therapy, including the use of
JAK2 inhibitors, is limited to symptoms palliation and reduction in spleen size. Specifically, JAK2 inhibitors
have not been shown to induce complete clinical or cytogenetic remissions or significantly affect JAK2/
CALR/MPL mutant allele burden. Splenectomy is considered for drug-refractory splenomegaly. Involved field
radiotherapy is most useful for post-splenectomy hepatomegaly, non-hepatosplenic EMH, PMF-associated
pulmonary hypertension and extremity bone pain.
Am. J. Hematol. 91:1262–1271, 2016. VC 2016 Wiley Periodicals, Inc.

䊏 Disease Overview
The World Health Organization (WHO) classification system for hematopoietic tumors was recently revised and the 2016 document recognizes
several major categories of myeloid malignancies including acute myeloid leukemia (AML) and related neoplasms, myelodysplastic syndromes
(MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap, mastocytosis, eosinophilia-associated myeloid/lymphoid neoplasms with specific
mutations (e.g., PDGFR) and myeloid neoplasms with germline predisposition (Fig. 1).[1]
“BCR-ABL1-negative MPN” is an operational sub-category of MPN that includes polycythemia vera (PV), essential thrombocythemia (ET) and
primary myelofibrosis (PMF).[2] The 2016 WHO classification system distinguishes prefibrotic (prePMF) from overtly fibrotic PMF (Figs. 1 and
2).[1,2] PMF, PV and ET are all characterized by stem cell-derived clonal myeloproliferation and presence of somatic mutations that are opera-
tionally classified into “driver” and “other” mutations; the former include JAK2, CALR and MPL and the latter LNK, CBL, TET2, ASXL1, IDH,
IKZF1, EZH2, DNMT3A, TP53, SF3B1, SRSF2, U2AF1 or other mutations (Table I) [3–5]. It is generally believed that driver mutations are essen-
tial for the MPN phenotype whereas the “other” mutations might contribute to disease progression and leukemic transformation.

Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota

*Correspondence to: Ayalew Tefferi, Division of Hematology, Department of Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. E-mail: tefferi.
ayalew@mayo.edu
Received for publication: 19 October 2016; Accepted: 20 October 2016
Am. J. Hematol. 91:1262–1271, 2016.
Published online: in Wiley Online Library (wileyonlinelibrary.com).
DOI: 10.1002/ajh.24592

C 2016 Wiley Periodicals, Inc.

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1262 American Journal of Hematology, Vol. 91, No. 12, December 2016 doi:10.1002/ajh.24592
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES: A CONTINUING MEDICAL EDUCATION SERIES Primary myelofibrosis
Figure 1. 2016 World Health Organization (WHO) classification of myeloid malignancies. [Color figure can be viewed at wileyonlinelibrary.com]
In PMF, clonal myeloproliferation is associated with reactive bone
marrow fibrosis, osteosclerosis, angiogenesis, extramedullary hemato-
poiesis (EMH) and abnormal cytokine expression. Clinical manifesta-
tions in PMF include severe anemia, marked hepatosplenomegaly,
constitutional symptoms (e.g., fatigue, night sweats, fever), cachexia,
bone pain, splenic infarct, pruritus, thrombosis and bleeding [6]. Inef-
fective erythropoiesis and EMH are the main causes of anemia and
organomegaly, respectively. Other disease complications include
symptomatic portal hypertension that might lead to variceal bleeding
or ascites and non-hepatosplenic EMH that might lead to cord com-
pression, ascites, pleural effusion, pulmonary hypertension or diffuse
extremity pain. It is currently assumed that aberrant cytokine produc-
tion by clonal cells and host immune reaction contribute to PMF-
associated bone marrow stromal changes, ineffective erythropoiesis,
EMH, cachexia and constitutional symptoms [7]. Causes of death
include leukemic progression that occurs in approximately 20% of
patients but many patients also die of comorbid conditions including
cardiovascular events and consequences of cytopenias including infec-
tion or bleeding [8].
䊏 Diagnosis
Current diagnosis of PMF is based on the 2016 WHO-criteria and
involves a composite assessment of clinical and laboratory features
(Fig. 2) [2]. The diagnosis of post-PV or post-ET MF should adhere
to criteria published by the International Working Group for MPN
Research and Treatment (IWG-MRT) (Table II) [9]. Peripheral blood
leukoerythroblastosis (i.e., presence of nucleated red cells, immature
granulocytes and dacryocytes) is a typical but not invariable feature
of PMF; prefibrotic PMF might not display overt leukoerythroblasto-
sis [10]. Bone marrow fibrosis in PMF is usually associated with
JAK2V617F or mutant CALR, or MPL, trisomy 9 or del(13q) [11,12].
doi:10.1002/ajh.24592
The presence of these genetic markers, therefore, strongly supports a
diagnosis of PMF, in the presence of a myeloid neoplasm associated
with bone marrow fibrosis.
PMF should be distinguished from other closely related myeloid
neoplasms including chronic myeloid leukemia (CML), PV, ET,
MDS, chronic myelomonocytic leukemia (CMML) and “acute
myelofibrosis.” The presence of dwarf megakaryocytes raises the pos-
sibility of CML and should be pursued with BCR-ABL1 cytogenetic
or molecular testing. Patients who otherwise fulfill the diagnostic cri-
teria for PV should be labeled as “PV” even if they display substantial
bone marrow fibrosis [13]. Prefibrotic PMF can mimic ET in its pre-
sentation and mutation profile (both can express JAK2, CALR or
MPL mutations) [14] careful morphologic examination is necessary
for distinguishing the two; megakaryocytes in ET are large and
mature-appearing whereas those in prefibrotic PMF display abnormal
maturation with hyperchromatic and irregularly folded nuclei [10];
the distinction between ET and pre-fibrotic PMF is prognostically rel-
evant [15]. MDS should be suspected in the presence of dyserythro-
poiesis or dysgranulopoiesis [16]. CMML is a possibility in the
presence of peripheral blood monocyte count of greater than 1 3
109/L [17]. Patients with acute myelofibrosis (either acute panmyelo-
sis with myelofibrosis or acute megakaryoblastic leukemia) usually
present with severe constitutional symptoms, pancytopenia, mild or
no splenomegaly, and increased circulating blasts [18].
䊏 Risk Stratification
Robust prognostic modeling in PMF started with the development
of the International Prognostic Scoring System (IPSS) in 2009 [19].
The IPSS for PMF is applicable to patients being evaluated at time of
initial diagnosis and uses five independent predictors of inferior sur-
vival: age >65 years, hemoglobin <10 g/dL, leukocyte count >25 3
American Journal of Hematology, Vol. 91, No. 12, December 2016 1263
Tefferi ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES: A CONTINUING MEDICAL EDUCATION SERIES
Figure 2. 2016 Revised WHO Diagnostic Criteria for Myeloproliferative Neoplasms (From After et al Blood 2016, 127, 2391). [Color figure can be viewed at
wileyonlinelibrary.com]
109/L, circulating blasts 1% and presence of constitutional symp-
toms [19]. The presence of 0, 1, 2 and 3 adverse factors defines
low, intermediate-1, intermediate-2 and high-risk disease. The corre-
sponding median survivals were 11.3, 7.9, 4 and 2.3 years [19].
The IWG-MRT subsequently developed a dynamic prognostic
model (DIPSS) that utilizes the same prognostic variables used in
IPSS but can be applied at any time during the disease course [20].
DIPSS assigns two, instead of one, adverse points for hemoglobin
<10 g/dL and risk categorization is accordingly modified: low (0
adverse points), intermediate-1 (1 or 2 points), intermediate-2 (3 or 4
points) and high (5 or 6 points). The corresponding median survivals
were not reached, 14.2, 4 and 1.5 years [20].
IPSS- and DIPSS-independent risk factors for survival in PMF
were subsequently identified and included unfavorable karyotype (i.e.,
complex karyotype or sole or two abnormalities that include 18, 27/
7q-, i(17q), inv(3), 25/5q-, 12p- or 11q23 rearrangement) [21,22],
red cell transfusion need [23,24] and platelet count <100 3 109/L
[25]. Accordingly, DIPSS was modified into DIPSS-plus by incorpo-
rating these three additional DIPSS-independent risk factors: platelet
count <100 3 109/L, red cell transfusion need and unfavorable kar-
yotype [26]. The four DIPSS-plus risk categories based on the afore-
mentioned eight risk factors are low (no risk factors), intermediate-1
(one risk factor), intermediate-2 (two or 3 risk factors) and high
(four or more risk factors) with respective median survivals of 15.4,
6.5, 2.9 and 1.3 years (Fig. 3) [26].
Since the publication of DIPSS-plus, several studies that suggest
additional prognostic information have been published. For example,
1264 American Journal of Hematology, Vol. 91, No. 12, December 2016
a >80% two-year mortality in PMF was predicted by monosomal
karyotype, inv(3)/i(17q) abnormalities, or any two of circulating blasts
>9%, leukocytes 40 3 109/L or other unfavorable karyotype [27].
Similarly, inferior survival in PMF has been associated with nulli-
zygosity for JAK2 46/1 haplotype [28], low JAK2V617F allele burden
[29,30], or presence of IDH [31], EZH2 [32], SRSF2 [33], or ASXL1
[34] mutations. Survival in PMF was also affected by increased serum
IL-8 and IL-2R levels as well as serum free light chain levels, both
independent of DIPSS-plus [35,36].
Most recently, the phenotypic and prognostic relevance of “driver”
and “other” mutations was carefully investigated in a series of collabo-
rative studies from the Mayo Clinic, USA and University of Florence,
Italy. In one of these studies involving 254 patients with PMF, reported
mutational frequencies were 58% for JAK2, 25% CALR, 8% MPL and
9% wild-type for all three mutations (i.e., triple-negative) [12]. CALR
mutational frequency in JAK2/MPL-unmutated cases was 74%. CALR
mutations were associated with younger age, higher platelet count and
lower DIPSS-plus score. CALR-mutated patients were also less likely to
be anemic, require transfusions or display leukocytosis. Spliceosome
mutations were infrequent in CALR-mutated patients.
In terms of prognostic relevance, in a subsequent study of 570
patients [37], the authors reported the longest survival in CALR 1
ASXL1- patients (median 10.4 years) and shortest in CALR–ASXL11
patients (median 2.3 years). CALR 1 ASXL11 and CALR–ASXL1-
patients had similar survival and were grouped together in an inter-
mediate risk category (median survival 5.8 years). Guglielmelli et al
subsequently demonstrated the additional value of the number of
doi:10.1002/ajh.24592
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES: A CONTINUING MEDICAL EDUCATION SERIES Primary myelofibrosis

TABLE I. Somatic Mutations in Primary Myelofibrosis (PMF) and the Closely Related BCR-ABL1-Negative Myeloproliferative Neoplasms (MPN) Including Polycy-
themia Vera (PV) and Essential Thrombocythemia (ET)

Chromosome Mutational
Mutations location frequency Pathogenetic relevance

JAK2 (Janus kinase 2) 9p24 PV  96% Contributes to abnormal myeloproliferation and pro-
JAK2V617F exon 14 mutation ET 55% genitor cell growth factor hypersensitivity
PMF  65%
JAK2 exon 12 mutation 9p24 PV  3% Contributes to primarily erythroid myeloproliferation
CALR (Calreticulin) 19p13.2 PMF  25% Wild-type CALR is a multi-functional Ca21 binding
Exon 9 deletions and insertions ET  20% protein chaperone mostly localized in the endo-
PV 0% plasmic reticulum
MPL (Myeloproliferative leukemia virus oncogene) 1p34 ET 3% Contributes to primarily megakaryocytic
MPN-associated MPL mutations involve exon 10 PMF  10% myeloproliferation
LNK (as in Links) a.k.a. SH2B3 12q24.12 PV  rare Wild-type LNK is a negative regulator of JAK2
(a membrane-bound adaptor protein) ET rare signaling
MPN-associated mutations were PMF  rare
monoallelic and involved exon 2 BP-MPN  10%
TET2 (TET oncogene family member 2) 4q24 PV 16% TET proteins catalyze conversion of 5-
ET5% methylcytosine (5mC) to 5-hydroxymethylcytosine
PMF 17% (5hmC), which favors demethylated DNA. Both
Mutations involve several exons BP-MPN 17% TET1 and TET2 display this catalytic activity. IDH
and TET2 mutations might share a common path-
ogenetic effect.
ASXL1 (Additional Sex Combs-Like 1) 20q11.1 ET 3% Wild-type ASXL1 is needed for normal hematopoie-
PMF 13% sis and might be involved in co-activation of tran-
Exon 12 mutations BP-MPN 18% scription factors and transcriptional repression.
IDH1/IDH2 (Isocitrate dehydrogenase) 2q33.3/ PV 2% IDH mutations induce loss of activity for the conver-
Exon 4 mutations 15q26.1 ET1% sion of isocitrate to 2-ketoglutarate (2-KG) and
PMF 4% gain of function in the conversion of 2-KG to 2-
BP-MPN 20% hydroxyglutarate (2-HG). 2-HG might be the medi-
ator of impaired TET2 function in cells with
mutant IDH expression.
EZH2 (enhancer of zeste homolog 2) 7q36.1 PV 3% Wild-type EZH2 is part of a histone methyltransfer-
Mutations involve several exons PMF 7% ase (polycomb repressive complex 2 associated
MDS 6% with H3 Lys-27 trimethylation). MPN-associated
EZH2 mutations might have a tumor suppressor
activity, which contrasts with the gain-of-function
activity for lymphoma-associated EZH2 mutations.
DNMT3A (DNA cytosine methyltransferase 3a) 2p23 PV 7% DNA methyl transferases are essential In establish-
PMF 7% ing and maintaining DNA methylation patterns in
Most frequent mutations affect amino acid R882 BP-MPN 14% mammals
CBL (Casitas B-lineage lymphoma proto-oncogene) 11q23.3 PV rare CBL is an E3 ubiquitin ligase that marks mutant kin-
Exon 8/9 mutations ETrare ases for degradation. Transforming activity
MF 6% requires loss of this function.
IKZF1 (IKAROS family zinc finger 1) 7p12 CP-MPN rare IKZF1 is a transcription regulator and putative tumor
Mostly deletions including intragenic BP-MPN 19% suppressor
TP53 (tumor protein p53) Exons 4 through 9 17p13.1 PMF  4% A tumor suppressor protein that targets genes that
BP-MPN  27% regulate cell cycle arrest, apoptosis and DNA
repair.
SF3B1 (splicing factor 3B subunit 1) 2q33.1 PMF  7% SF3B1 is a component of the RNA spliceosome.
Exons 14 and 15, mostly SF3B1 mutations are closely associated with ring
sideroblasts.
SRSF2 (serine/arginine-rich splicing factor 2) Exon 2 17q25.1 PMF  17% SRSF2 is a component of the RNA spliceosome,
whose dysfunction promotes defects in alterna-
tive splicing.
U2AF1(U2 Small Nuclear RNA Auxiliary Factor 1) 21q22.3 PMF  16% U2AF1 is subunit of the U2 small nuclear ribonucleo-
protein auxiliary factor involved in pre-mRNA
processing

Mutational frequencies in blast phase (BP) disease are also provided.

Key: MPN, myeloproliferative neoplasms; ET, essential thrombocythemia; PV, polycythemia vera; PMF, primary myelofibrosis; MF includes both PMF and post-
ET/PV myelofibrosis; BP-MPN, blast phase MPN; CP-MPN, chronic phase MPN;.
See text for references.

prognostically-detrimental mutations [38]. Most recently, the favor-
able prognostic impact of CALR mutations in PMF was shown to be
restricted to its type 1 or type 1-like variants whereas there was no
prognostic difference between the other driver mutations [39,40]. Fur-
thermore, targeted next generation sequencing (NGS) studies have
identified ASXL1, SRSF2, CBL, KIT, RUNX1, SH2B3 and CEBPA
mutations as having an adverse effect on overall or leukemia-free sur-
vival [41].
Risk factors for leukemia-free survival in PMF include 3% circu-
lating blasts, platelet count <100 3 109/L and presence of unfavor-
able karyotype [42,43]. Although DIPSS has been shown to predict
leukemia-free survival [44], in the aforementioned DIPSS-plus study
of 793 patients with PMF [26], the only two risk factors for leukemic
transformation were unfavorable karyotype and platelet count <100
3 109/L; 10-year risk of leukemic transformation were 12% in the
absence of these two risk factors and 31% in the presence of one or

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Tefferi ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES: A CONTINUING MEDICAL EDUCATION SERIES

TABLE II. International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Recommended Criteria for Post-Polycythemia
Vera and Post-Essential Thrombocythemia Myelofibrosis [9]

Criteria for post-polycythemia vera myelofibrosis

Required criteria:
1 Documentation of a previous diagnosis of polycythemia vera as defined by the WHO criteria (see Table II)
2 Bone marrow fibrosis grade 2–3 (on 0–3 scale) or grade 3–4 (on 0–4 scale) (see footnote for details)
Additional criteria (two are required):
1 Anemia or sustained loss of requirement for phlebotomy in the absence of cytoreductive therapy
2 A leukoerythroblastic peripheral blood picture
3 Increasing splenomegaly defined as either an increase in palpable splenomegaly of  5 cm (distance of the tip of the spleen from the
left costal margin) or the appearance of a newly palpable splenomegaly
4 Development of  1 of three constitutional symptoms: >10% weight loss in 6 months, night sweats, unexplained fever (>37.58C)
Criteria for post-essential thrombocythemia myelofibrosis
Required criteria:
1 Documentation of a previous diagnosis of essential thrombocythemia as defined by the WHO criteria (see Table II)
2 Bone marrow fibrosis grade 2–3 (on 0–3 scale) or grade 3–4 (on 0–4 scale) (see footnote for details)
Additional criteria (two are required):
1 Anemia and a  2 g/dL decrease from baseline hemoglobin level
2 A leukoerythroblastic peripheral blood picture
3 Increasing splenomegaly defined as either an increase in palpable splenomegaly of  5 cm (distance of the tip of the spleen from the left
costal margin) or the appearance of a newly palpable splenomegaly
4 Increased lactate dehydrogenase
5 Development of  1 of three constitutional symptoms: >10% weight loss in 6 months, night sweats, unexplained fever (>37.58C)

Grade 2–3 according to the European classification: [94] diffuse, often coarse fiber network with no evidence of collagenization (negative trichrome stain) or
diffuse, coarse fiber network with areas of collagenization (positive trichrome stain). Grade 3–4 according to the standard classification: [95] diffuse and
dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis or diffuse and dense
increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis.

Figure 3. Survival data of 793 patients with primary myelofibrosis evaluated at time of their first Mayo Clinic referral and stratified by their Dynamic Interna-
tional Prognostic Scoring System (DIPSS-plus) that employs eight variables: Age>65 yrs; Hgb <10 g/dL;R8C transfusion-dependent; platelets<1003 10(9)/L;
WBC > 25 3 10(9)/L;>1% circulating blasts; constitutional symptoms; karyotype. [Color figure can be viewed at wileyonlinelibrary.com]

both risk factors. As is becoming evident for overall survival,
leukemia-free survival is also significantly compromised in patients
carrying certain mutations including IDH and SRSF2 [31,33]. CALR/
ASXL1 mutational status and the number of prognostically-
detrimental mutations, as outlined above, were also predictive of leu-
kemic transformation [37,38]. In the most recent NGS study of PMF
patients mentioned above, leukemia-free survival was adversely affect-
ed by SRSF2, RUNX1, CEBPA and SH2B3 mutations [41].
䊏 Risk-Adapted Therapy
The only treatment modality that is currently capable of prolong-
ing survival or potential cure in PMF is allogeneic stem cell trans-
plant (ASCT). Unfortunately, ASCT in PMF is currently associated
with at least 50% rate of transplant-related deaths or severe morbidi-
ty, regardless of the intensity of conditioning regimens used [45].
Therefore, for the individual patient, the risk of ASCT must be justi-
fied, in the context of disease prognosis. On the other hand, current

1266 American Journal of Hematology, Vol. 91, No. 12, December 2016 doi:10.1002/ajh.24592
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES: A CONTINUING MEDICAL EDUCATION SERIES Primary myelofibrosis
Figure 4. Clinical and molecular risk stratification and risk-adapted therapy in primary myelofibrosis. [Color figure can be viewed at wileyonlinelibrary.com]
drug therapy for PMF is mostly palliative in scope and has not been
shown to favorably modify disease natural history or prolong survival;
specifically, JAK inhibitor treatment in PMF has not been shown to
reverse bone marrow fibrosis or induce complete or partial remis-
sions; instead, its value is limited to symptoms relief and reduction in
spleen size [46–49].
Management of DIPSS-plus low or intermediate-1 risk
patients
There is no evidence to support the value of specific therapy in
asymptomatic patients with DIPSS-plus low or intermediate-1 risk
disease. However, some of these patients might require palliative ther-
apy for anemia, splenomegaly, non-hepatosplenic EMH, bone pain,
EMH-associated pulmonary hypertension or constitutional symptoms.
In addition, cytoreductive therapy might be needed in the presence of
extreme leukocytosis or thrombocytosis.
Treatment of MF-associated anemia includes androgens (e.g., tes-
tosterone enanthate 400-600 mg IM weekly, oral fluoxymesterone
10 mg TID) [50], prednisone (0.5 mg/kg/day) [50], danazol (600 mg/
day) [51], thalidomide (50 mg/day) 6 prednisone [52–54] or lenalido-
mide (10 mg/day) 6 prednisone [55,56] (10 mg/day). I do not use
erythropoiesis stimulating agents (ESAs) because they are ineffective
in transfusion-dependent patients and could exacerbate splenomegaly
[57]. Response rates to each one of the aforementioned drugs are in
the vicinity of 15 to 25% and response durations average about one
to two years. Lenalidomide works best in the presence of del(5q31)
[58]. Drug side effects include hepatotoxicity and virilizing effects for
androgens, peripheral neuropathy for thalidomide and myelosuppres-
sion for lenalidomide. Pomalidomide is another thalidomide analog
doi:10.1002/ajh.24592
that might alleviate anemia in a subset of JAK2-mutated patients
without marked splenomegaly or excess circulating blasts [59].
Among currently investigational drugs (not FDA approved as yet),
those that have shown promise for the treatment of anemia include
the JAK2 inhibitor momelotinib [60] and the telomerase inhibitor
imetelstat [61].
First-line therapy for MF-associated splenomegaly is hydroxyurea,
which is effective in reducing spleen size by half in approximately
40% of patients [62]. Spleen response to hydroxyurea lasts for an
average of one year and treatment side effects include myelosuppres-
sion and mucocutaneous ulcers. Both thalidomide and lenalidomide
might improve splenomegaly and thrombocytopenia in some patients
[52–54,56] The related agent pomalidomide might also alleviate
thrombocytopenia in MF but is ineffective for the treatment of
splenomegaly [59]. Interferon (IFN)-a is of limited value in the treat-
ment of MF-associated splenomegaly [63]. The degree of splenomega-
ly in low or intermediate-1 risk patients is often not severe enough to
require either splenectomy or radiotherapy. Similarly, I do not con-
sider the use of ruxolutinib (JAK1/2 inhibitor) in low or
intermediate-1 risk patients, considering the acute (e.g., anemia,
thrombocytopenia) and long-term toxicity, known (e.g., immunosup-
pression) and unknown, of the particular agent [64–67]. The same is
true for other investigational drugs that are currently not approved
by the FDA [60,61].
Recommendations: Low or intermediate-1 risk asymptomatic
patients with PMF can be observed without any therapeutic interven-
tion, unless they harbor high-risk mutations (e.g., ASXL1, SRSF2). Spe-
cific therapy is considered only in the presence of symptoms. First-line
drugs of choice for symptomatic anemia include
American Journal of Hematology, Vol. 91, No. 12, December 2016 1267
Tefferi ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES: A CONTINUING MEDICAL EDUCATION SERIES
thalidomide 1 prednisone, an androgen preparation or danazol. Pros-
tate cancer screening in men and monitoring of liver function tests are
necessary when considering treatment with androgen preparations. I
use lenalidomide in the presence of del(5q) or in case of treatment fail-
ure with thalidomide, danazol or androgens. First-line drug of choice
for symptomatic splenomegaly is hydroxyurea (starting dose 500 mg
TID). Of special challenge is the DIPSS-plus low or intermediate-1 risk
patient with a high-risk mutation; at present I prefer close monitoring
of such patients although I would not object to proceeding with ASCT
sooner than later. In general, I do not consider the use of JAK inhibi-
tors in low or intermediate-1 risk patients; I am concerned about more
harm than good because of immunosuppression associated with chronic
use and exacerbation of anemia associated with some of these agents.
Management of intermediate-2 or high-risk disease
PMF patients with DIPSS-plus high or intermediate-2 risk disease,
or those with high-risk mutations such as ASXL1 and SRSF2, should
be considered for ASCT or investigational drug therapy, sooner than
later. In considering ASCT as a treatment modality, one should be
acutely aware of the risks involved. In one of the largest studies of
ASCT in PMF [45], 5-year disease-free survival (DFS) and treatment-
related mortality (TRM) were 33% and 35% for matched related and
27% and 50% for unrelated transplants, respectively. Of note, out-
come did not appear to be favorably affected by reduced intensity
conditioning (RIC). In another RIC transplant study, 5-year DFS was
estimated at 51%; chronic graft-versus-host disease (cGVHD)
occurred in 49% of the patients and relapse (29%) was predicted by
high-risk disease and prior splenectomy [68]. In the earlier study
[45], the respective cGVHD and relapse rates for matched related
transplants were 40% and 32% and history of splenectomy did not
affect outcome. More recent outcome reports on ASCT in MF were
more encouraging: 100-day mortality 13%, a relapse rate of 11%, and
a 7-year survival of 61% [69]. There is currently much interest in
evaluating the use of JAK inhibitors before transplant with favorable
or unfavorable experiences reported by different investigators. I do
not currently advise the use of JAK inhibitors in the context of trans-
plant until more information on its value becomes available.
In my opinion, all non-transplant candidates with high or
intermediate-2 risk disease should first be offered participation in
investigational drug therapy before treatment with conventional drugs
including JAK inhibitors. This is because the latter agents are unlikely
to significantly modify the natural history of the disease and would
not prevent progression into acute leukemia. JAK inhibitors are rea-
sonable palliative agents in patients who are both non-transplant can-
didates and are unable to participate in clinical trials. JAK inhibitor
ATP mimetics that have undergone clinical trials in MPN include
ruxolitinib (INCB018424), fedratinib (SAR302503), momelotinib
(CYT387) and pacritinib (SB1518). Results of these studies so far sug-
gest substantial differences among these drugs in their toxicity and
efficacy profiles, some of which might be linked to their variable in
vitro activity against other JAK and non-JAK kinase targets. Among
the aforementioned agents, ruxolitinib is now FDA approved, fedrati-
nib was withdrawn from the market because of side effects (encepha-
lopathy), pacritinib is currently on FDA-imposed full clinical hold
because of side effects (deaths from intracranial hemorrhage, cardiac
arrest and heart failure) and momelotinib is undergoing phase-3
study./////
Two randomized studies comparing ruxolitinib with either placebo
or best supportive care have now been published [70,71]. In the
COMFORT-1 trial that compared the drug with placebo (n 5 309)
[70], the spleen response rate was approximately 42% for ruxolitinib
versus <1% for placebo. In addition, about 46% of patients experi-
enced substantial improvement in their constitutional symptoms.
1268 American Journal of Hematology, Vol. 91, No. 12, December 2016
However, the benefit of the drug was antagonized by ruxolitinib-
associated anemia (31% vs. 13.9%) and thrombocytopenia (34.2% vs.
9.3%). In the COMFORT-2 trial that compared the drug with “best
available therapy” (n 5 219) [71], the spleen response was 28.5% with
ruxolitinib vs. 0% otherwise but the drug was detrimental in terms of
thrombocytopenia (44.5% vs. 9.6%), anemia (40.4% vs. 12.3%) and
diarrhea (24.0% vs. 11.0%). The long-term outcome of ruxolitinib
therapy in MF was recently reported and disclosed a very high treat-
ment discontinuation rate (92% after a median time of 9.2 months)
and the occurrence of severe withdrawal symptoms during ruxolitinib
treatment discontinuation (“ruxolitinib withdrawal syndrome”) char-
acterized by acute relapse of disease symptoms, accelerated spleno-
megaly, worsening of cytopenias and occasional hemodynamic
decompensation, including a septic shock-like syndrome [48]. The 3-
year follow-up information on COMFORT-2 suggested a 55% drug
discontinuation rate and a slight but significant improvement in sur-
vival, which is however confounded by the cross-over design of the
study and lack of substantial drug effect on JAK2V617F allele burden
or bone marrow fibrosis [46]. Furthermore, several reports have now
associated the drug with serious opportunistic infections [72].
Fedratinib, a selective JAK2 inhibitor, was initially evaluated in 59
patients with PMF or post-PV/ET MF, in a phase-1/2 study [73]. The
dose limiting toxicity (DLT) was a reversible and asymptomatic
increase in serum amylase/lipase and the maximum tolerated dose
(MTD) was 680 mg/day. Grade 3 or 4 adverse events were all revers-
ible and dose-dependent and included nausea (3%), vomiting (3%),
diarrhea (10%), asymptomatic mild increases in serum lipase (27%),
transaminases (27%) or creatinine (24%), thrombocytopenia (24%)
and anemia (35%). By 6 or 12 months of treatment, 39% and 47% of
patients, respectively, experienced a 50% decrease in palpable spleen
size. In addition, the majority of patients with early satiety, fatigue,
night sweats, cough or pruritus reported a durable resolution of their
symptoms. Almost all patients with thrombocytosis and the majority
with leukocytosis had normalization of their counts. Among 23
patients with a baseline JAK2V617F allele burden of >20%, 9 (39%)
had 50% decrease in allele burden. Effect on bone marrow patholo-
gy was limited. In general, response was not affected by the presence
of JAK2V617F. Most recently, the results of a phase-3 study
(n 5 289) comparing fedratinib at two different doses (500 or
400 mg/day) with placebo were disclosed and confirmed the efficacy
of the drug in inducing spleen (49%, 47% and 1%, respectively) and
symptom response. However, reports of encephalopathy associated
with the use of the drug resulted in the withdrawal of the drug from
further development. Other side effects included anemia (grade 3 or
4 in 43% to 60%), thrombocytopenia (grade 3 or 4 in 17% to 27%)
and diarrhea (56% to 66%) [74].
Momelotinib (MMB, GS-0387, CYT387) is a JAK1 and JAK2
inhibitor. Among the first 60 patients patients treated in a phase-1/2
study [75], MTD was 300 mg/day and DLT included grade 3 head-
ache and hyperlipasemia. Anemia and spleen responses were 59%
and 48%, respectively. Among 33 patients who were red cell-
transfused in the month prior to study entry, 70% achieved a mini-
mum 12-week period without transfusions (range 4.7->18.3 months).
Most patients experienced constitutional symptoms improvement.
Grade 3/4 adverse reactions included thrombocytopenia (32%),
hyperlipasemia (5%), elevated liver transaminases (3%) and headache
(3%). New-onset treatment-related peripheral neuropathy was
observed in 22% of patients (sensory symptoms, grade 1) and the
particular side effect was further elaborated in a subsequent follow-up
study [76]. The study was subsequently expanded to include 166
patients treated at either 150 mg or 300 mg once-daily, or 150 mg
twice-daily for 9 months, with similar results [77]. The drug is cur-
rently undergoing phase-3 study.
doi:10.1002/ajh.24592
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES: A CONTINUING MEDICAL EDUCATION SERIES Primary myelofibrosis

Pacritinib (SB1518) is a JAK2/FLT3 inhibitor. In phase-1 studies,
myelosuppression was minimal and 400 mg/d was chosen as the rec-
ommended dose for phase-2 study, which included 34 patients [78].
The most common treatment-related adverse events were gastrointes-
tinal, especially diarrhea. Spleen response rate was 44% (32% by
MRI) and accompanied by symptoms response. Anemia response was
reported in 2 (6%) patients. The drug was undergoing phase-3 study,
compared to best available therapy, when increased deaths from
intracranial hemorrhage, cardiac arrest and heart failure were
observed and resulted in FDA-imposed full clinical hold.
The above observations demonstrate major differences in toxicity
and activity profile among several JAK inhibitor small molecules and
underscore the need to evaluate more such drugs before making any
conclusions regarding the value of anti-JAK2 therapy in MF or relat-
ed MPN. It is also becoming evident that some of the salutary effects
of these drugs might be the result of a potent anti-cytokine activity.
JAK-STAT activation leads to Akt/mTOR activation as well and it
is therefore reasonable to evaluate the therapeutic activity of Akt and
mTOR inhibitors. In a phase 1/2 study involving the mTOR inhibitor
everolimus including 39 MF patients, the commonest toxicity was
grade 1-2 stomatitis. A >50% reduction in splenomegaly occurred in
20% of the patients evaluated and the constitutional symptoms
response was 69%; 80% experienced complete resolution of pruritus
[79]. Drug effect on cytosis or anemia was modest and on
JAK2V617F burden negligible. Overall IWG-MRT response rate was
23%.
Currently, many other drugs are being tested for their therapeutic
value in MF and the most intriguing results were recently reported
with the use of imetelestat, which is a 13-mer lipid-conjugated oligo-
nucleotide that targets the RNA template of human telomerase
reverse transcriptase. In the particular study, imetelstat was adminis-
tered as a 2-hour intravenous infusion (9.4 mg per kilogram of body
weight) every 1 to 3 weeks. A complete or partial remission occurred
in 7 of 33 patients (21%), with a median duration of response of 18
months for complete responses. Bone marrow fibrosis was reversed in
all 4 patients who had a complete response, and a molecular response
occurred in three of the four patients. Response rates were 32%
among patients without an ASXL1 mutation versus 0% among those
with an ASXL1 mutation. The rate of complete response was 38%
among patients with a mutation in SF3B1 or U2AF1 versus 4%
among patients without a mutation in these genes. Treatment-related
adverse events included grade 4 thrombocytopenia (in 18% of
patients), grade 4 neutropenia (in 12%), grade 3 anemia (in 30%),
and grade 1 or 2 elevation in levels of total bilirubin (in 12%), alka-
line phosphatase (in 21%), and aspartate aminotransferase (in 27%);
these observations have led to additional clinical trials in other mye-
loid malignancies [61,80,81].
Recommendations: Considering the lack of effective drug therapy in
PMF, the risk of transplant-related complications might be justified in
those patients in whom median survival is expected to be <5 years
and leukemic transformation risk >20%. These include DIPSS-plus
high or intermediate-2 risk patients as well as those with high-risk
mutations. Non-transplant candidates are best managed with
experimental drug therapy. I have yet to be satisfied by the value of
any currently available JAK inhibitor and strongly advise patients to
continue participating in clinical trials.
Management of refractory disease and specific disease
complications
Hydroxyurea-refractory splenomegaly is often managed by splenec-
tomy [82]. Other indications for splenectomy include symptomatic
portal hypertension, thrombocytopenia and frequent red blood cell
transfusions. In a recent report of 314 splenectomized patients with
MF [83], more than 75% benefited from the procedure and the bene-
fit lasted for a median of one year; specific benefits included becom-
ing transfusion-independent and resolution of severe
thrombocytopenia. Perioperative complications occurred in 28% of
the patients and included infections, abdominal vein thrombosis and
bleeding. Overall perioperative mortality rate was 9%. Approximately
10% of patients experienced progressive hepatomegaly and 29%
thrombocytosis after splenectomy. Median survival after splenectomy
was 19 months. Leukemic transformation was documented in 14% of
patients whose survival was not different than that of patients without
“leukemic transformation,” although others had suggested otherwise
[84].
Splenic irradiation (100 cGy in 5–10 fractions) induces transient
reduction in spleen size but can be associated with severe pancytope-
nia [85]. Non-hepatosplenic EMH might involve the vertebral col-
umn, lymph nodes, pleura and peritoneum (ascites) and is effectively
treated with low-dose radiotherapy (100–1000 cGy in 5 to 10 frac-
tions) [86]. Diagnosis of MF-associated pulmonary hypertension is
confirmed by a technetium 99m sulphur colloid scintigraphy and
treatment with single-fraction (100 cGy) whole-lung irradiation has
been shown to be effective [87]. Single fraction of 100 to 400 cGy
involved field radiotherapy has also been shown to benefit patients
with MF-associated extremity pain [88].
Transjugular intrahepatic portosystemic shunt might be considered
to alleviate symptoms of portal hypertension. Recent technical advan-
ces in the procedure and the introduction of specially coated stents
have greatly improved shunt patency and clinical efficacy of TIPS in
general. Current TIPS indications include recurrent variceal bleeding
and refractory ascites, both of which could accompany advanced MF.
The therapeutic value of TIPS has not been systematically studied in
MF but relevant information is available from several case reports
that confirm feasibility and efficacy [89].
Recommendations: At present, my first-line choice for the manage-
ment of drug-refractory splenomegaly is participation in experimental
drug therapy. Both splenectomy and low-dose radiotherapy are reason-
able alternative treatment options. Prophylactic therapy with hydroxy-
urea is advised to prevent post-splenectomy thrombocytosis [[82]].
Post-splenectomy thrombosis might be prevented by instituting short
term systemic anticoagulation. Laparoscopic splenectomy is not advised
in the setting of MF [[90]] and data on the value of splenic artery
embolization are limited [[91–93]]. I do not believe that splenectomy
increases the risk of leukemic transformation [[84]].

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