AJH

CME Information: : 2014 update on diagnosis, risk-stratification and management

Author: Ayalew Tefferi M.D. Editor: Carlo Brugnara M.D.

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᭿ Educational Objectives Upon completion of this educational activity, participants will be better able to identify appropriate management of primary myelofibrosis.

᭿ Activity Disclosures No commercial support has been accepted related to the development or publication of this activity. Author: Ayalew Tefferi, M.D. has no relevant financial relationships to disclose. Editor: Carlo Brugnara, M.D. has no relevant financial relationships to disclose. This activity underwent peer review in line with the standards of editorial integrity and publication ethics maintained by American Journal of . The peer reviewers have no conflicts of interest to disclose. The peer review process for American Journal of Hematology is single blinded. As such, the identities of the reviewers are not disclosed in line with the standard accepted practices of medical journal peer review. Conflicts of interest have been identified and resolved in accordance with Blackwell Futura Media Services’s Policy on Activity Disclosure and Conflict of Interest. The primary resolution method used was peer review and review by a non-conflicted expert.

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VC 2014 Wiley Periodicals, Inc. doi:10.1002/ajh.00038 American Journal of Hematology, Vol. 89, No. 9, September 2014 915 ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES AJH AJH Educational Material

Primary myelofibrosis: 2014 update on diagnosis, risk-stratification, and management

Ayalew Tefferi*

Disease overview: Primary myelofibrosis (PMF) is a myeloproliferative characterized by stem cell- derived clonal myeloproliferation, abnormal expression, , , , extramedullary hematopoiesis (EMH), constitutional symptoms, , leukemic progression, and shortened survival. Diagnosis: Diagnosis is based on bone marrow morphology. The presence of JAK2, CALR,orMPL is supportive but not essential for diagnosis; approximately 90% of patients carry one of these and 10% are “triple-negative.” None of these mutations are specific to PMF and are also seen in essential (ET). Prefibrotic PMF mimics ET in its presentation and the distinction, enabled by careful bone marrow morphological examination, is prognostically relevant. Differential diagnosis also includes chronic myeloid , myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute . 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, count <100 3 109/L, and unfavorable karyotype (i.e., complex karyotype or sole or two abnormalities that include 18, 27/7q2, i(17q), inv(3), 25/5q2, 12p2, 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. High risk disease is also defined by CALR2/ASXL11 mutational status. Risk-Adapted Therapy: Observation alone is adequate for asymptomatic low/intermediate-1 risk disease, especially with CALR1/ASXL12 mutational status. Stem cell transplant is considered for DIPSS-plus high risk disease or any risk disease with CALR2/ASXL11 mutational status. Investigational drug therapy is reasonable for symptomatic intermediate-1 or intermediate-2 risk disease. is considered for drug-refractory splenomegaly. Involved field radiotherapy is most useful for post-splenectomy , non- hepatosplenic EMH, PMF-associated , and extremity bone pain. Am. J. Hematol. 89:916–925, 2014. VC 2014 Wiley Periodicals, Inc.

᭿ Disease Overview The World Health Organization (WHO) classification system for hematopoietic tumors recognizes five categories of myeloid malignancies including (AML), myelodysplastic syndromes (MDS), myeloproliferative (MPN), MDS/MPN overlap, and PDGFR/ growth factor receptor 1 (FGFR1)-rearranged myeloid/lymphoid neoplasm with (Table I) [1]. “BCR-ABL1-negative MPN” is an operational sub-category of MPN that includes (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) [2]. These three disorders are characterized by stem cell-derived clonal myeloproliferation and presence of somatic mutations involving pri- marily JAK2 or CALR and to a smaller extent MPL, LNK, CBL, TET2, ASXL1, IDH, IKZF1, EZH2, DNMT3A, TP53, SF3B1, SRSF2,orU2AF1 mutations (Table II) [3–5]. The pathogenetic relevance of these mutations is currently under investigation (Table II) but none of them appear to garner the disease specificity or pathogenetic relevance otherwise displayed by BCR-ABL1. However, the phenotype of clonal erythrocytosis might require the presence of a mutation in JAK2 (JAK2V617F or JAK2 exon 12 mutation) [6]. Similarly, there appears to be a close association between SF3B1 mutations and presence of bone marrow ring sideroblasts in MPN [7]. In PMF, clonal myeloproliferation is associated with reactive bone marrow fibrosis, , angiogenesis, extramedullary hematopoiesis (EMH), and abnormal cytokine expression. Clinical manifestations in PMF include severe anemia, marked , constitutional symp- toms (e.g., fatigue, night sweats, and fever), cachexia, bone pain, splenic infarct, pruritus, thrombosis, and bleeding [8]. Ineffective erythropoiesis and EMH are the main causes of anemia and organomegaly, respectively. Other disease complications include symptomatic portal hypertension that might

Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota Conflict of interest: Nothing to report *Correspondence to: Ayalew Tefferi, Division of Hematology, Department of Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. E-mail: [email protected] Received for publication: 3 March 2014; Accepted: 3 March 2014 Am. J. Hematol. 89:916–925, 2014. Published online: in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.23703

VC 2014 Wiley Periodicals, Inc.

916 American Journal of Hematology, Vol. 89, No. 9, September 2014 doi:10.1002/ajh.23703 ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES

TABLE I. WHO Classification of Myeloid Malignancies ble feature of PMF; prefibrotic PMF might not display overt leukoery-

a throblastosis [13]. Bone marrow fibrosis in PMF is usually associated 1. Acute myeloid leukemia and related precursor neoplasms with JAK2V617F or mutant CALR,orMPL, trisomy 9, or del(13q) 2. MPN 2.1. Classic MPN [14, 15]. The presence of these genetic markers, therefore, strongly 2.1.1. Chronic myelogenous leukemia, BCR-ABL1 positive supports a diagnosis of PMF, in the presence of a myeloid neoplasm 2.1.2. Polycythemia vera (99% JAK2 mutated) associated with bone marrow fibrosis. 2.1.3. Primary myelofibrosis (90% JAK2, CALR,orMPL mutated) PMF should be distinguished from other closely related myeloid 2.1.4. Essential thrombocythemia (85% JAK2, CALR,orMPL mutated) 2.2. Non-classic MPN neoplasms including chronic myeloid leukemia (CML), PV, ET, 2.2.1. Chronic neutrophilic leukemia (90% CSF3R mutated) MDS, chronic myelomonocytic leukemia (CMML), and “acute 2.2.2. Chronic eosinophilic leukemia, not otherwise specified myelofibrosis.” The presence of dwarf raises the pos- 2.2.3. (90% KIT mutated) sibility of CML and should be pursued with BCR-ABL1 cytogenetic 2.2.4. Myeloproliferative neoplasm, unclassifiable or molecular testing. Patients who otherwise fulfill the diagnostic cri- 3. MDS 3.1. Refractory cytopeniab with unilineage (RCUD) teria for PV should be labeled as “PV” even if they display substantial 3.1.1. Refractory anemia (ring sideroblasts < 15% of erythroid bone marrow fibrosis [11]. Prefibrotic PMF can mimic ET in its pre- precursors) sentation and mutation profile (both can express JAK2, CALR,or 3.1.2. Refractory neutropenia MPL mutations) [18] careful morphologic examination is necessary 3.1.3. Refractory 3.2. Refractory anemia with ring sideroblasts (RARS; dysplasia for distinguishing the two; megakaryocytes in ET are large and limited to erythroid lineage and ring sideroblasts  15% of bone mature-appearing whereas those in prefibrotic PMF display abnormal marrow erythroid precursors) maturation with hyperchromatic and irregularly folded nuclei [13]; 3.3. Refractory cytopenia with multi-lineage dysplasia (RCMD; the distinction between ET and pre-fibrotic PMF is prognostically rel- ring sideroblast count does not matter) evant [19]. MDS should be suspected in the presence of dyserythro- 3.4. Refractory anemia with excess blasts (RAEB) 3.4.1. RAEB-1 (2–4% circulating or 5–9% marrow blasts) poiesis or dysgranulopoiesis [20]. CMML is a possibility in the 3.4.2. RAEB-2 (5–19% circulating or 10–19% marrow blasts or presence of peripheral blood count of greater than 1 3 Auer rods present) 109/L [21]. Patients with acute myelofibrosis (either acute panmyelo- 3.5. MDS associated with isolated del(5q) sis with myelofibrosis or acute megakaryoblastic leukemia) usually 3.6. MDS, unclassifiable 4. MDS/MPN present with severe constitutional symptoms, , mild or 4.1. CMML no splenomegaly, and increased circulating blasts [22]. 4.2. Atypical chronic myeloid leukemia, BCR-ABL1 negative 4.3. Juvenile myelomonocytic leukemia 4.4. MDS/MPN, unclassifiable ᭿ Risk Stratification 3.4.1. Provisional entity: Refractory anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T) Robust prognostic modeling in PMF started with the development 5. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of the International Prognostic Scoring System (IPSS) in 2009 [23]. of PDGFRA,c PDGFRB,c or FGFR1c The IPSS for PMF is applicable to patients being evaluated at time of 5.1. Myeloid and lymphoid neoplasms with PDGFRA rearrangement initial diagnosis and uses five independent predictors of inferior sur- 5.2. Myeloid neoplasms with PDGFRB rearrangement 5.3. Myeloid and lymphoid neoplasms with FGFR1 abnormalities vival: age >65 years, hemoglobin <10 g/dL, leukocyte count >25 3 109/L, circulating blasts 1%, and presence of constitutional symp- a Acute myeloid leukemia-related precursor neoplasms include “therapy- toms [23]. The presence of 0, 1, 2, and 3 adverse factors defines related ” and “.” b low, intermediate-1, intermediate-2, and high risk disease. The corre- Either mono- or bi-cytopenia: hemoglobin level < 10 g/dL, absolute neu- sponding median survivals were 11.3, 7.9, 4, and 2.3 years [23]. trophil count <1.8 3 109/L, or platelet count <100 3 109/L. However, higher blood counts do not exclude the diagnosis in the presence of unequivocal The IWG-MRT subsequently developed a dynamic prognostic histological/cytogenetic evidence for myelodysplastic syndrome. model (dynamic international prognostic scoring system [DIPSS]) c Genetic rearrangements involving platelet-derived growth factor receptor that uses the same prognostic variables used in IPSS but can be a/b (PDGFRA/PDGFRB)orFGFR1. applied at any time during the disease course [24]. DIPSS assigns two, instead of one, adverse points for hemoglobin <10 g/dL and risk lead to variceal bleeding or ascites and non-hepatosplenic EMH that categorization is accordingly modified: low (0 adverse points), might lead to cord compression, ascites, pleural effusion, pulmonary intermediate-1 (1 or 2 points), intermediate-2 (3 or 4 points), and hypertension, or diffuse extremity pain. It is currently assumed that high (5 or 6 points). The corresponding median survivals were not aberrant cytokine production by clonal cells and host immune reaction reached, 14.2, 4, and 1.5 years [24]. contribute to PMF-associated bone marrow stromal changes, ineffective IPSS- and DIPSS-independent risk factors for survival in PMF erythropoiesis, EMH, cachexia, and constitutional symptoms [9]. were subsequently identified and included unfavorable karyotype (i.e., Causes of death include leukemic progression that occurs in approxi- complex karyotype or sole or two abnormalities that include 18, 27/ mately 20% of patients but many patients also die of comorbid condi- 7q2, i(17q), inv(3), 25/5q2, 12p2, or 11q23 rearrangement) [25, tions including cardiovascular events and consequences of cytopenias 26], red cell transfusion need [27, 28], and platelet count <100 3 including infection or bleeding [10]. 109/L [29]. Accordingly, DIPSS was modified into DIPSS-plus by incorporating these three additional DIPSS-independent risk factors: ᭿ platelet count <100 3 109/L, red cell transfusion need, and unfavora- Diagnosis ble karyotype [30]. The four DIPSS-plus risk categories based on the Current diagnosis of PMF is based on WHO-criteria and involves aforementioned eight risk factors (Fig. 1) are low (no risk factors), a composite assessment of clinical and laboratory features (Table III) intermediate-1 (one risk factor), intermediate-2 (two or three risk fac- [11]. The diagnosis of post-PV or post-ET MF should adhere to crite- tors), and high (four or more risk factors) with respective median ria recently published by the International Working Group for MPN survivals of 15.4, 6.5, 2.9, and 1.3 years [30]. Research and Treatment (IWG-MRT) (Table IV) [12]. Peripheral Since the publication of DIPSS-plus, several studies that suggest blood leukoerythroblastosis (i.e., presence of nucleated red cells, additional prognostic information have been published. For example, immature , and dacryocytes) is a typical but not invaria- a >80% 2-year mortality in PMF was predicted by monosomal

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TABLE II. Somatic Mutations in PMF and the Closely Related BCR-ABL1-Negative MPN Including PV and ET

Chromosome Mutational Mutations location frequency Pathogenetic relevance

JAK2 ( 2) 9p24 PV  96% Contributes to abnormal myeloproliferation and progenitor cell JAK2V617F exon 14 mutation ET  55% growth factor hypersensitivity PMF  65%

JAK2 exon 12 mutation 9p24 PV  3% Contributes to primarily erythroid myeloproliferation CALR () 19p13.2 PMF  25% Wild-type CALR is a multi-functional Ca21 binding protein chaperone Exon 9 deletions and insertions ET  20% mostly localized in the endoplasmic reticulum PV  0% MPL (Myeloproliferative leukemia virus 1p34 ET  3% Contributes to primarily megakaryocytic myeloproliferation oncogene) MPN-associated MPL mutations involve PMF  10% exon 10

LNK (as in Links) a.k.a. SH2B3 12q24.12 PV  rare Wild-type LNK is a negative regulator of JAK2 signaling (a membrane-bound adaptor protein) ET  rare 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-methylcytosine (5mC) to Mutations involve several exons ET  5% 5-hydroxymethylcytosine (5hmC), which favors demethylated DNA. PMF  17% Both TET1 and TET2 display this catalytic activity. IDH BP-MPN  17% and TET2 mutations might share a common pathogenetic effect

ASXL1 (Additional Sex Combs-Like 1) 20q11.1 ET  3% Wild-type ASXL1 is needed for normal hematopoiesis and might be Exon 12 mutations PMF  13% involved in co-activation of transcription factors and transcriptional BP-MPN  18% repression

IDH1/IDH2 (Isocitrate dehydrogenase) 2q33.3/15q26.1 PV  2% IDH mutations induce loss of activity for the conversion of isocitrate Exon 4 mutations ET  1% to 2-ketoglutarate (2-KG) and gain of function in the PMF  4% conversion of 2-KG to 2-hydroxyglutarate (2-HG). 2-HG might BP-MPN  20% be the mediator 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 methyltransferase (polycomb Mutations involve several exons PMF  7% repressive complex 2 associated with H3 Lys-27 trimethylation). MDS  6% 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 2p23 PV  7% DNA methyl transferases are essential In establishing and methyltransferase 3a) PMF  7% maintaining DNA methylation patterns in mammals Most frequent mutations affect BP-MPN  14% amino acid R882

CBL (Casitas B-lineage lymphoma 11q23.3 PV  rare CBL is an E3 ubiquitin ligase that marks mutant kinases for proto-oncogene) ET  rare degradation. Transforming activity requires loss of this function Exon 8/9 mutations MF  6%

IKZF1 (IKAROS family zinc finger 1) 7p12 CP-MPN  rare IKZF1 is a transcription regulator and putative tumor suppressor Mostly deletions including intragenic BP-MPN  19%

TP53 (tumor protein p53) 17p13.1 PMF  4% A tumor suppressor protein that targets genes that regulate cell Exons 4 through 9 BP-MPN  27% cycle arrest, apoptosis and DNA repair SF3B1 (splicing factor 3B subunit 1) 2q33.1 PMF  7% SF3B1 is a component of the RNA spliceosome. SF3B1 mutations are Exons 14 and 15, mostly closely associated with ring sideroblasts

SRSF2 (serine/arginine-rich splicing 17q25.1 PMF  17% SRSF2 is a component of the RNA spliceosome, whose dysfunction factor 2) promotes defects in alternative splicing Exon 2

U2AF1(U2 Small Nuclear RNA Auxiliary 21q22.3 PMF  16% U2AF1 is subunit of the U2 small nuclear ribonucleoprotein auxiliary Factor 1) factor involved in pre-mRNA processing

Mutational frequencies in blast phase (BP) disease are also provided. 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. karyotype, inv(3)/i(17q) abnormalities, or any two of circulating blasts [38] mutations. In contrast, the presence or absence of JAK2V617F >9%, leukocytes 40 3 109/L or other unfavorable karyotype [31]. [33, 34], MPL [39], or TET2 [40] mutations did not appear to affect Similarly, inferior survival in PMF has been associated with nulli- survival. Survival in PMF was also affected by increased serum IL-8 zygosity for JAK2 46/1 haplotype [32], low JAK2V617F allele burden and IL-2R levels as well as serum free light chain levels, both inde- [33, 34], or presence of IDH [35], EZH2 [36], SRSF2 [37], or ASXL1 pendent of DIPSS-plus [41, 42].

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TABLE III. WHO Diagnostic Criteria for Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis

2008 WHO diagnostic criteria

Polycythemia veraa Essential thrombocythemia a Primary myelofibrosis a

1 Hgb > 18.5 g/dL (men) 1 Platelet count  450 3 109/L 1 proliferation and atypiac accompanied by either reticulin and/or fibrosis, ord > 16.5 g/dL (women) orb 2 Presence of JAK2V617F or 2 Megakaryocyte proliferation with large 2 Not meeting WHO criteria for CML, PV, JAK2 exon 12 mutation and mature morphology MDS, or other myeloid neoplasm 3 Not meeting WHO criteria for CML, 3 Demonstration of JAK2V617F or other PV, PMF, MDS, or other clonal marker or no evidence of reactive myeloid neoplasm marrow fibrosis 4 Demonstration of JAK2V617F or other clonal marker or no evidence of reactive thrombocytosis Minor criteria 1 BM trilineage 1 Leukoerythroblastosis myeloproliferation 2 Subnormal serum 2 Increased serum LDH level Epo level 3 EEC growth 3 Anemia 4 Palpable splenomegaly a PV diagnosis requires meeting either both major criteria and one minor criterion or the first major criterion and two minor criteria. ET diagnosis requires meeting all four major criteria. PMF diagnosis requires meeting all three major criteria and two minor criteria. b or Hgb or Hct > 99th percentile of reference range for age, sex, or altitude of residence or red cell mass > 25% above mean normal predicted or Hgb > 17 g/dL (men)/ > 15 g/dL (women) if associated with a sustained increase of 2 g/dL from baseline that can not be attributed to correction of iron deficiency. c Small to large megakaryocytes with aberrant nuclear/cytoplasmic ratio and hyperchromatic and irregularly folded nuclei and dense clustering. d or in the absence of reticulin fibrosis, the megakaryocyte changes must be accompanied by increased marrow cellularity, granulocytic proliferation, and often decreased erythropoiesis (i.e., pre-fibrotic PMF). BM, bone marrow; Hgb, hemoglobin; Hct, hematocrit; Epo, ; EEC, endogenous erythroid colony; WHO, World Health Organization; CML, chronic myelogenous leukemia; PV, polycythemia vera; PMF, primary myelofibrosis; MDS, myelodysplastic syndromes; LDH, lactate dehydrogenase.

TABLE IV. IWG-MRT Recommended Criteria for Post-Polycythemia Vera and Post-Essential Thrombocythemia Myelofibrosis [12]

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 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 (>37.5C) 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 (>37.5C)

Grade 2–3 according to the European classification [16]: 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 [17]: 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.

Most recently, Tefferi et al. studied 254 patients with PMF and also less likely to be anemic, require transfusions, or display leukocy- reported mutational frequencies of 58% for JAK2, 25% CALR,8% tosis. Spliceosome mutations were infrequent in CALR-mutated MPL, and 9% wild-type for all three mutations (i.e., triple-negative) patients. In a subsequent international study of 570 patients [43], the [15]. CALR mutational frequency in JAK2/MPL-unmutated cases was authors reported the longest survival in CALR1ASXL12 patients 74%. CALR mutations were associated with younger age, higher plate- (median 10.4 years) and shortest in CALR2ASXL11 patients (median let count, and lower DIPSS-plus score. CALR-mutated patients were 2.3 years). CALR1ASXL11 and CALR2ASXL12 patients had similar

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Figure 1. DIPSS-plus (dynamic international prognostic scoring system 1 karyotype 1 platelet count 1 transfusion status) risk stratification in 793 patients with primary myelofibrosis seen at Mayo Clinic Rochester (with permission from Gangat et al.) [30] [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]. survival and were grouped together in an intermediate risk category files (e.g., CALR1/ASXL12) can be observed without any therapeutic (median survival 5.8 years). Guglielmelli et al. subsequently demon- intervention and some can be effectively managed by conventional strated the additional value of the number of prognostically detrimen- drug therapy (Fig. 2). tal mutations [44]. Risk factors for leukemia-free survival include 3% circulating Management of low or intermediate-1 risk patients < 3 9 blasts, platelet count 100 10 /L and presence of unfavorable karyo- There is no evidence to support the value of specific therapy in type [45, 46]. Although DIPSS has been shown to predict leukemia-free asymptomatic patients with low or intermediate-1 risk disease. It is survival [47], in the aforementioned DIPSS-plus study of 793 patients conceivable that some low or intermediate-1 risk patients might with PMF [30], the only two risk factors for leukemic transformation require therapy for symptomatic anemia, splenomegaly, non- < 3 9 were unfavorable karyotype and platelet count 100 10 /L; 10-year hepatosplenic EMH, bone pain, EMH-associated pulmonary hyper- risk of leukemic transformation were 12% in the absence of these two tension, or constitutional symptoms (e.g., fatigue, night sweats, and risk factors and 31% in the presence of one or both risk factors. As is pruritus). In addition, cytoreductive therapy is reasonable but not becoming evident for overall survival, leukemia-free survival is also sig- mandated in the presence of extreme leukocytosis or thrombocytosis. nificantly compromised in patients carrying certain mutations includ- MF-associated anemia is usually treated with androgens (e.g., tes- ing IDH and SRSF2 [35, 37]. CALR/ASXL1 mutational status and the tosterone enanthate 400–600 mg IM weekly, oral fluoxymesterone 10 number of prognostically detrimental mutations, as outlined above, mg TID) [53], prednisone (0.5 mg/kg/day) [53], danazol (600 mg/ were also predictive of leukemic transformation [43, 44]. day) [54], (50 mg/day) 6 prednisone [55–57], or lenali- domide (10 mg/day) 6 prednisone [58, 59] (10 mg/day). I do not use ᭿ erythropoiesis stimulating agents because they are ineffective in Risk-Adapted Therapy transfusion-dependent patients and could exacerbate splenomegaly Current drug therapy for PMF is not curative and has not been [60]. Response rates to each one of the aforementioned drugs are in shown to prolong survival; although there is controversy regarding the vicinity of 15–25% and response durations average about 1–2 the value of JAK inhibitors, in this regard, these drugs have not been years. works best in the presence of del(5q31) [61]. shown to display disease-modifying activity, including reversal of Drug side effects include hepatotoxicity and virilizing effects for bone marrow fibrosis or induction of complete or partial remissions androgens, for thalidomide, and myelosuppres- [48–51]. ASCT for PMF is potentially curative but dangerous; sion for lenalidomide. transplant-related death or severe morbidity occurs in about half of First-line therapy for MF-associated splenomegaly is hydroxyurea, transplanted patients, regardless of the intensity of conditioning regi- which is effective in reducing spleen size by half in approximately mens used [52]. As a result, more and more patients with PMF (or 40% of patients [62]. Spleen response to hydroxyurea lasts for an post-PV/ET MF) are seeking treatment with novel drugs. However, it average of 1 year and treatment side effects include myelosuppression should be noted that many patients especially those with low or and mucocutaneous ulcers. Both thalidomide and lenalidomide might intermediate-1 risk disease per DIPSS-plus or low risk molecular pro- improve splenomegaly and thrombocytopenia in some patients [55–

920 American Journal of Hematology, Vol. 89, No. 9, September 2014 doi:10.1002/ajh.23703 ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES

Figure 2. Contemporary treatment algorithm for primary myelofibrosis. High, intermediate-2, intermediate-1, and low risk categories are according to the DIPSS-plus (see Fig. 1) [30]. Molecular risk stratification is according to CALR/ASXL1 mutational status [43] [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.].

57, 59]. In contrast, -a is of limited value in the treatment and 27% and 50% for unrelated transplants, respectively. Of note, of MF-associated splenomegaly [63]. The degree of splenomegaly in outcome did not appear to be favorably affected by reduced intensity low or intermediate-1 risk patients is often not severe enough to conditioning (RIC). In another RIC transplant study, 5-year DFS was require either splenectomy or radiotherapy. estimated at 51%; chronic graft-versus-host disease (cGVHD) Recommendations: Low or intermediate-1 risk asymptomatic occurred in 49% of the patients and relapse (29%) was predicted by patients with PMF can be observed without any therapeutic interven- high-risk disease and prior splenectomy [64]. In the earlier study tion, unless they harbor high risk molecular profile (e.g., CALR2/ [52], the respective cGVHD and relapse rates for matched related ASXL11 mutational status). Specific therapy is considered only in the transplants were 40% and 32% and history of splenectomy did not presence of symptoms. First-line drugs of choice for anemia include affect outcome. More recent outcome reports on ASCT in MF were thalidomide 1 prednisone, an androgen preparation, or danazol. Pros- more encouraging: 100-day mortality 13%, a relapse rate of 11%, and tate cancer screening in men and monitoring of function tests are a 7-year survival of 61% [65]. There is currently much interest in necessary when considering treatment with androgen preparations. I evaluating the use of JAK inhibitors before transplant with favorable use lenalidomide in the presence of del(5q) or in case of treatment fail- or unfavorable experiences reported by different investigators. I do ure with thalidomide, danazol, or androgens. First-line drug of choice not currently advise the use of JAK inhibitors in the context of trans- for symptomatic splenomegaly is hydroxyurea (starting dose 500 mg plant until more information on its value becomes available. TID). Investigational drug therapy. Several experimental drugs have Management of intermediate-2 or high risk disease been and are currently being evaluated in PMF, post-PV/ET MF, and other related MPN [66]. These include , JAK inhibiting PMF patients with high or intermediate-2 risk disease should be ATP mimetics, and mTOR inhibitors. Although not further elabo- considered for investigational drug therapy or ASCT. Based on the rated in the current review, it is important to note that JAK-STAT associated extremely poor prognosis (i.e., >80% 2-year mortality), the can be inhibited by many other classes of drugs, which have been presence of monosomal karyotype, inv(3)/i(17q) abnormalities, or any evaluated for the treatment of MF and related MPN; these include 9 two of circulating blasts >9%, leukocytes 40 3 10 /L, or other histone deacetylase inhibitors, such as panobinostat (LBH589) and unfavorable karyotype warrant immediate consideration of (ASCT) givinostat (ITF2357) [67, 68]. (Fig. 2). ASCT is also indicated in the presence of high risk molecular profile (i.e., CALR2/ASXL11 mutational status). Pomalidomide. Pomalidomide is a second generation immunomodu- Transplant. In considering ASCT as a treatment modality, one latory drug and in a phase-2 randomized study, 25% of patients with should be acutely aware of the risks involved. In one of the largest anemia responded to the drug used alone (2 mg/day) or in combina- studies of ASCT in PMF [52], 5-year disease-free survival (DFS) and tion with prednisone (0.5 or 2 mg/day) [69]. In a subsequent phase-2 treatment-related mortality were 33% and 35% for matched related study of single agent pomalidomide (0.5 mg/day) [70], anemia

doi:10.1002/ajh.23703 American Journal of Hematology, Vol. 89, No. 9, September 2014 921 Tefferi ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES response was documented only in the presence of JAK2V617F (24% ated splenomegaly, worsening of cytopenias, and occasional vs. 0%) and predicted by the presence of pomalidomide-induced hemodynamic decompensation, including a septic shock-like syn- basophilia (38% vs. 6%) or absence of marked splenomegaly (38% vs. drome [50]. The 3-year follow-up information on COMFORT-2 sug- 11%). Platelet response was seen in 58% of patients but the drug had gested a 55% drug discontinuation rate and a slight but significant limited activity in reducing spleen size. Drug-associated neuropathy improvement in survival, which is however confounded by the cross- or myelosuppression was infrequent but possible. A phase-1 study over design of the study and lack of substantial drug effect on did not uncover better activity at higher doses (>2 mg/day), which JAK2V617F allele burden or bone marrow fibrosis [48]. Furthermore, were instead associated with increased myelosuppression [71]. Most several reports have now associated the drug with serious opportunis- recently, the results of a phase-3 study comparing pomalidomide with tic infections [77]. placebo did not show significant difference in anemia response, which , a selective JAK2 inhibitor, was initially evaluated in 59 was approximately 16% for each arm, whereas platelet response was patients with PMF or post-PV/ET MF, in a phase-1/2 study [78]. The significantly better with pomalidomide [72]. dose limiting toxicity (DLT) was a reversible and asymptomatic increase in serum amylase/lipase and the maximum tolerated dose JAK inhibitor ATP mimetics. JAK inhibitor ATP mimetics that have (MTD) was 680 mg/day. Grade 3 or 4 adverse events were all reversi- undergone clinical trials in MPN include (INCB018424), ble and dose-dependent and included nausea (3%), vomiting (3%), fedratinib (SAR302503), (CYT387), (CEP- diarrhea (10%), asymptomatic mild increases in serum lipase (27%), 701), (SB1518), AZD1480, BMS911543, LY2784544, and transaminases (27%) or creatinine (24%), thrombocytopenia (24%), XL019 (clinicalTrials.gov). Results of these studies so far suggest sub- and anemia (35%). By 6 or 12 months of treatment, 39% and 47% of stantial differences among these drugs in their toxicity and efficacy patients, respectively, experienced a 50% decrease in palpable spleen profiles, some of which might be linked to their variable in vitro size. In addition, the majority of patients with early satiety, fatigue, activity against other JAK and non-JAK kinase targets. For the pur- night sweats, cough, or pruritus reported a durable resolution of their poses of this review, I will focus on ruxolitinib (now FDA approved symptoms. Almost all patients with thrombocytosis and the majority for use in MF), fedratinib (phase-3 study completed but drug with- with leukocytosis had normalization of their counts. Among 23 drawn because of side effects), and momelotinib and pacritinib patients with a baseline JAK2V617F allele burden of >20%, 9 (39%) (phase-3 study ongoing vs. ruxolitinib or best available therapy, had 50% decrease in allele burden. Effect on bone marrow pathol- respectively). ogy was limited. In general, response was not affected by the presence Ruxolitinib is a JAK1/JAK2 inhibitor. The drug was initially eval- of JAK2V617F. Most recently, the results of a phase-3 study uated in 153 patients with PMF or post-PV/ET MF, in a phase-1/2 (n 5 289) comparing fedratinib at two different doses (500 or 400 study [73]. DLT was thrombocytopenia and the MTD was either 25 mg/day) with placebo were disclosed and confirmed the efficacy of mg twice-daily or 100 mg once-daily. Adverse events included throm- the drug in inducing spleen (49%, 47%, and 1%, respectively) and bocytopenia, anemia, and a “cytokine rebound reaction” upon drug symptom response. However, reports of encephalopathy associated discontinuation, characterized by acute relapse of symptoms and with the use of the drug resulted in the withdrawal of the drug from splenomegaly [51, 74]. Non-hematologic adverse events were infre- further development. Other side effects included anemia (grade 3 or 4 quent. Grade 3/4 thrombocytopenia or anemia (in transfusion- in 43–60%), thrombocytopenia (grade 3 or 4 in 17–27%), and diar- independent patients at baseline), respectively, occurred in 39% and rhea (56–66%) [79]. 43% of patients receiving the drug at 25 or 10 mg twice daily. Among Momelotinib (MMB, GS-0387, CYT387) is a JAK1 and JAK2 all evaluable patients, 44% experienced 50% decrease in palpable inhibitor. Among the first 60 patients treated in a phase-1/2 study spleen size. Improvement in constitutional symptoms (fatigue, pruri- [80], MTD was 300 mg/day and DLT included grade 3 headache and tus, abdominal discomfort, early satiety, night sweats, and exercise hyperlipasemia. Anemia and spleen responses were 59% and 48%, tolerance) and weight gain were seen in the majority of patients. Four respectively. Among 33 patients who were red cell-transfused in the (14%) of twenty-eight transfusion-dependent patients became month prior to study entry, 70% achieved a minimum 12-week transfusion-independent. The drug’s effect on JAK2V617F allele bur- period without transfusions (range 4.7 to >18.3 months). Most den or bone marrow pathology was negligible but a major reduction patients experienced constitutional symptoms improvement. Grade 3/ in proinflammatory (e.g., IL-1RA, IL-6, TNF-a, and MIP- 4 adverse reactions included thrombocytopenia (32%), hyperlipasemia 1b) was documented and coincided with improvement in constitu- (5%), elevated liver transaminases (3%), and headache (3%). New- tional symptoms. onset treatment-related peripheral neuropathy was observed in 22% Two randomized studies comparing ruxolitinib with either placebo of patients (sensory symptoms, grade 1). The study was subsequently or best supportive care have now been published [75, 76]. In the expanded to include 166 patients treated at either 150 mg or 300 mg COMFORT-1 trial that compared the drug with placebo (n 5 309) once-daily, or 150 mg twice-daily for 9 months, with similar results [75], the spleen response rate was approximately 42% for ruxolitinib [81]. The drug is currently undergoing phase-3 study compared to versus <1% for placebo. In addition, about 46% of patients experi- ruxolitinib. enced substantial improvement in their constitutional symptoms. Pacritinib (SB1518) is a JAK2/FLT3 inhibitor. In phase-1 studies, However, the benefit of the drug was antagonized by ruxolitinib- myelosuppression was minimal and 400 mg/day was chosen as the associated anemia (31% vs. 13.9%) and thrombocytopenia (34.2% vs. recommended dose for phase-2 study, which included 34 patients 9.3%). In the COMFORT-2 trial that compared the drug with “best [82]. The most common treatment-related adverse events were gas- available therapy” (n 5 219) [76], the spleen response was 28.5% with trointestinal, especially diarrhea. Spleen response rate was 44% (32% ruxolitinib versus 0% otherwise but the drug was detrimental in by MRI) and accompanied by symptoms response. Anemia response terms of thrombocytopenia (44.5% vs. 9.6%), anemia (40.4% vs. was reported in 2 (6%) patients. The drug is currently undergoing 12.3%), and diarrhea (24.0% vs. 11.0%). The long-term outcome of phase-3 study compared to best available therapy. ruxolitinib therapy in MF was recently reported and disclosed a very The above observations demonstrate major differences in toxicity high treatment discontinuation rate (92% after a median time of 9.2 and activity profile among several JAK inhibitor small molecules and months) and the occurrence of severe withdrawal symptoms during underscore the need to evaluate more such drugs before making any ruxolitinib treatment discontinuation (“ruxolitinib withdrawal syn- conclusions regarding the value of anti-JAK2 therapy in MF or drome”) characterized by acute relapse of disease symptoms, acceler- related MPN. It is also becoming evident that some of the salutary

922 American Journal of Hematology, Vol. 89, No. 9, September 2014 doi:10.1002/ajh.23703 ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES effects of these drugs might be the result of a potent anti-cytokine experienced progressive hepatomegaly and 29% thrombocytosis after activity. splenectomy. Median survival after splenectomy was 19 months. Leu- kemic transformation was documented in 14% of patients whose sur- mTOR inhibitors. JAK-STAT activation leads to Akt/mTOR activa- vival was not different than that of patients without “leukemic tion as well and it is therefore reasonable to evaluate the therapeutic transformation,” although others had suggested otherwise [86]. activity of Akt and mTOR inhibitors. In a phase 1/2 study involving Splenic irradiation (100 cGy in 5–10 fractions) induces transient the mTOR inhibitor everolimus including 39 MF patients, the com- reduction in spleen size but can be associated with severe pancytope- monest toxicity was grade 1–2 stomatitis. A >50% reduction in nia [87]. Non-hepatosplenic EMH might involve the vertebral col- splenomegaly occurred in 20% of the patients evaluated and the con- umn, lymph nodes, pleura, and peritoneum (ascites) and is effectively stitutional symptoms response was 69%; 80% experienced complete treated with low-dose radiotherapy (100–1,000 cGy in 5–10 fractions) resolution of pruritus [83]. Drug effect on cytosis or anemia was [88]. Diagnosis of MF-associated pulmonary hypertension is con- modest and on JAK2V617F burden negligible. Overall IWG-MRT firmed by a technetium 99m sulfur colloid scintigraphy and treatment response rate was 23%. with single-fraction (100 cGy) whole- irradiation has been shown Recommendations: Considering the lack of effective drug therapy in to be effective [89]. Single fraction of 100–400 cGy involved field PMF, the risk of transplant-related complications might be justified in radiotherapy has also been shown to benefit patients with MF- those patients in whom median survival is expected to be <5 years associated extremity pain [90]. and leukemic transformation risk >20%. These include DIPSS-plus Transjugular intrahepatic portosystemic shunt might be considered 1 high or intermediate-2 risk patients as well as those with ASXL1 / to alleviate symptoms of portal hypertension. Recent technical advan- 2 CALR mutational status. Non-transplant candidates are best man- ces in the procedure and the introduction of specially coated stents aged with experimental drug therapy. I have yet to be satisfied by the have greatly improved shunt patency and clinical efficacy of TIPS in value of any currently available JAK inhibitor and strongly advise general. Current TIPS indications include recurrent variceal bleeding patients to continue participating in clinical trials. and refractory ascites, both of which could accompany advanced MF. Management of refractory disease and specific disease The therapeutic value of TIPS has not been systematically studied in MF but relevant information is available from several case reports complications that confirm feasibility and efficacy [91]. Hydroxyurea-refractory splenomegaly is often managed by splenec- Recommendations: At present, my first-line choice for the manage- tomy [84]. Other indications for splenectomy include symptomatic ment of drug-refractory splenomegaly is participation in experimental portal hypertension, thrombocytopenia, and frequent red drug therapy. Both splenectomy and low-dose radiotherapy are reason- transfusions. In a recent report of 314 splenectomized patients with able alternative treatment options. Prophylactic therapy with hydrox- MF [85], more than 75% benefited from the procedure and the bene- yurea is advised to prevent post-splenectomy thrombocytosis [84]. Post- fit lasted for a median of 1 year; specific benefits included becoming splenectomy thrombosis might be prevented by instituting short term transfusion-independent and resolution of severe thrombocytopenia. systemic anticoagulation. Laparoscopic splenectomy is not advised in Perioperative complications occurred in 28% of the patients and the setting of MF [92] and data on the value of splenic artery emboli- included infections, abdominal vein thrombosis, and bleeding. Overall zation are limited [93–95]. I do not believe that splenectomy increases perioperative mortality rate was 9%. Approximately 10% of patients the risk of leukemic transformation [86].

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