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

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1 CME ARTICLE AJH CME Information: Primary myelofibrosis: 2017 update on diagnosis, risk-stratification and management CME Editor: Ayalew Tefferi, M.D. Author: Ayalew Tefferi, M.D. If you wish to receive credit for this activity, please refer to the website: Accreditation and Designation Statement: Blackwell Futura Media Services is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Blackwell Futura Media Services designates this journal-based CME for a maximum of 1 AMA PRA Category 1 Credit TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. 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. Activity Disclosures No commercial support has been accepted related to the development or publication of this activity. Author and CME Editor: Ayalew Tefferi, MD 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 Hematology. 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 Policy on Activity Disclosure and Conflict of Interest. The primary resolution method used was peer review and review by a non-conflicted expert. Instructions on Receiving Credit This activity is intended for physicians. For information on applicability and acceptance of continuing medical education credit for this activity, please consult your professional licensing board. This activity is designed to be completed within one hour; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity during the valid credit period, which is up to two years from initial publication. Additionally, up to 3 attempts and a score of 70% or better is needed to pass the post test. Follow these steps to earn credit: Log on to Read the target audience, educational objectives, and activity disclosures. Read the activity contents in print or online format. Reflect on the activity contents. Access the CME Exam, and choose the best answer to each question. Complete the required evaluation component of the activity. Claim your Certificate. This activity will be available for CME credit for twelve months following its launch date. At that time, it will be reviewed and potentially updated and extended for an additional twelve months. VC 2016 Wiley Periodicals, Inc. American Journal of Hematology, Vol. 91, No. 12, December

2 ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES AJH Educational Material Primary myelofibrosis: 2017 update on diagnosis, risk-stratification, and management AJH 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 > /L, circulating blasts 1%, constitutional symptoms, red cell transfusion dependency, platelet count < /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: , VC 2016 Wiley Periodicals, Inc. 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 operationally 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 essential 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 tefferi. ayalew@mayo.edu Received for publication: 19 October 2016; Accepted: 20 October 2016 Am. J. Hematol. 91: , Published online: in Wiley Online Library (wileyonlinelibrary.com). DOI: /ajh VC 2016 Wiley Periodicals, Inc American Journal of Hematology, Vol. 91, No. 12, December 2016 doi: /ajh.24592

3 ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES: A CONTINUING MEDICAL EDUCATION SERIES Primary myelofibrosis Figure 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 hematopoiesis (EMH) and abnormal cytokine expression. Clinical manifestations 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]. Ineffective 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 compression, ascites, pleural effusion, pulmonary hypertension or diffuse extremity pain. It is currently assumed that aberrant cytokine production by clonal cells and host immune reaction contribute to PMFassociated 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 infection or bleeding [8]. 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 leukoerythroblastosis [10]. Bone marrow fibrosis in PMF is usually associated with JAK2V617F or mutant CALR, or MPL, trisomy 9 or del(13q) [11,12]. 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 possibility of CML and should be pursued with BCR-ABL1 cytogenetic or molecular testing. Patients who otherwise fulfill the diagnostic criteria for PV should be labeled as PV even if they display substantial bone marrow fibrosis [13]. Prefibrotic PMF can mimic ET in its presentation 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 relevant [15]. MDS should be suspected in the presence of dyserythropoiesis or dysgranulopoiesis [16]. CMML is a possibility in the presence of peripheral blood monocyte count of greater than /L [17]. Patients with acute myelofibrosis (either acute panmyelosis with myelofibrosis or acute megakaryoblastic leukemia) usually present with severe constitutional symptoms, pancytopenia, mild or no splenomegaly, and increased circulating blasts [18]. 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 survival: age >65 years, hemoglobin <10 g/dl, leukocyte count >25 3 doi: /ajh American Journal of Hematology, Vol. 91, No. 12, December

4 Tefferi ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES: A CONTINUING MEDICAL EDUCATION SERIES Figure Revised WHO Diagnostic Criteria for Myeloproliferative Neoplasms (From After et al Blood 2016, 127, 2391). [Color figure can be viewed at wileyonlinelibrary.com] 10 9 /L, circulating blasts 1% and presence of constitutional symptoms [19]. The presence of 0, 1, 2 and 3 adverse factors defines low, intermediate-1, intermediate-2 and high-risk disease. The corresponding 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 < /L [25]. Accordingly, DIPSS was modified into DIPSS-plus by incorporating these three additional DIPSS-independent risk factors: platelet count < /L, red cell transfusion need and unfavorable karyotype [26]. The four DIPSS-plus risk categories based on the aforementioned 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, 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 /L or other unfavorable karyotype [27]. Similarly, inferior survival in PMF has been associated with nullizygosity 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 collaborative 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 ASXL1 1 patients (median 2.3 years). CALR 1 ASXL1 1 and CALR ASXL1 - patients had similar survival and were grouped together in an intermediate risk category (median survival 5.8 years). Guglielmelli et al subsequently demonstrated the additional value of the number of 1264 American Journal of Hematology, Vol. 91, No. 12, December 2016 doi: /ajh.24592

5 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 Polycythemia Vera (PV) and Essential Thrombocythemia (ET) Mutations Chromosome location Mutational frequency Pathogenetic relevance JAK2 (Janus kinase 2) 9p24 PV 96% Contributes to abnormal myeloproliferation and progenitor JAK2V617F exon 14 mutation ET 55% PMF 65% cell growth factor hypersensitivity 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 Ca 21 binding Exon 9 deletions and insertions ET 20% PV 0% protein chaperone mostly localized in the endoplasmic 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 monoallelic and involved exon 2 PMF rare BP-MPN 10% TET2 (TET oncogene family member 2) 4q24 PV 16% TET proteins catalyze conversion of 5- Mutations involve several exons ET5% PMF 17% BP-MPN 17% methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which favors demethylated DNA. Both TET1 and TET2 display this catalytic activity. IDH 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 Exon 12 mutations PMF 13% BP-MPN 18% and might be involved in co-activation of tran- scription factors and transcriptional repression. IDH1/IDH2 (Isocitrate dehydrogenase) 2q33.3/ PV 2% IDH mutations induce loss of activity for the conversion Exon 4 mutations 15q26.1 ET1% PMF 4% BP-MPN 20% of isocitrate to 2-ketoglutarate (2-KG) and gain of function in the conversion of 2-KG to 2- hydroxyglutarate (2-HG). 2-HG might 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 Mutations involve several exons PMF 7% (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 establishing Most frequent mutations affect amino acid R882 PMF 7% BP-MPN 14% and maintaining DNA methylation patterns in mammals CBL (Casitas B-lineage lymphoma proto-oncogene) 11q23.3 PV rare CBL is an E3 ubiquitin ligase that marks mutant kinases Exon 8/9 mutations ETrare MF 6% for degradation. Transforming activity 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) Exons 14 and 15, mostly 2q33.1 PMF 7% SF3B1 is a component of the RNA spliceosome. 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 alternative splicing. U2AF1(U2 Small Nuclear RNA Auxiliary Factor 1) 21q22.3 PMF 16% U2AF1 is subunit of the U2 small nuclear ribonucleoprotein 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 favorable 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]. Furthermore, 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 survival [41]. Risk factors for leukemia-free survival in PMF include 3% circulating blasts, platelet count < /L and presence of unfavorable 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 < /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 doi: /ajh American Journal of Hematology, Vol. 91, No. 12, December

6 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 International Prognostic Scoring System (DIPSS-plus) that employs eight variables: Age>65 yrs; Hgb <10 g/dl;r8c transfusion-dependent; platelets< (9)/L; WBC > (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 prognosticallydetrimental mutations, as outlined above, were also predictive of leukemic transformation [37,38]. In the most recent NGS study of PMF patients mentioned above, leukemia-free survival was adversely affected by SRSF2, RUNX1, CEBPA and SH2B3 mutations [41]. Risk-Adapted Therapy The only treatment modality that is currently capable of prolonging survival or potential cure in PMF is allogeneic stem cell transplant (ASCT). Unfortunately, ASCT in PMF is currently associated with at least 50% rate of transplant-related deaths or severe morbidity, regardless of the intensity of conditioning regimens used [45]. Therefore, for the individual patient, the risk of ASCT must be justified, in the context of disease prognosis. On the other hand, current 1266 American Journal of Hematology, Vol. 91, No. 12, December 2016 doi: /ajh.24592

7 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 remissions; 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 therapy 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., testosterone enanthate 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 lenalidomide (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 myelosuppression for lenalidomide. Pomalidomide is another thalidomide analog 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 myelosuppression 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 treatment of MF-associated splenomegaly [63]. The degree of splenomegaly in low or intermediate-1 risk patients is often not severe enough to require either splenectomy or radiotherapy. Similarly, I do not consider 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., immunosuppression) 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 intervention, unless they harbor high-risk mutations (e.g., ASXL1, SRSF2). Specific therapy is considered only in the presence of symptoms. First-line drugs of choice for symptomatic anemia include doi: /ajh American Journal of Hematology, Vol. 91, No. 12, December

8 Tefferi ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES: A CONTINUING MEDICAL EDUCATION SERIES thalidomide 1 prednisone, an androgen preparation or danazol. Prostate 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 failure 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 inhibitors 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 treatmentrelated mortality (TRM) were 33% and 35% for matched related and 27% and 50% for unrelated transplants, respectively. Of note, outcome 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 transplant 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 reasonable palliative agents in patients who are both non-transplant candidates 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 suggest 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, fedratinib was withdrawn from the market because of side effects (encephalopathy), 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 experienced substantial improvement in their constitutional symptoms. However, the benefit of the drug was antagonized by ruxolitinibassociated 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 treatment 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 ) characterized by acute relapse of disease symptoms, accelerated splenomegaly, 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 survival, 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 reversible 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 pathology 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 headache and hyperlipasemia. Anemia and spleen responses were 59% and 48%, respectively. Among 33 patients who were red celltransfused in the month prior to study entry, 70% achieved a minimum 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 currently undergoing phase-3 study American Journal of Hematology, Vol. 91, No. 12, December 2016 doi: /ajh.24592

9 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 recommended dose for phase-2 study, which included 34 patients [78]. The most common treatment-related adverse events were gastrointestinal, 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 related 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 oligonucleotide that targets the RNA template of human telomerase reverse transcriptase. In the particular study, imetelstat was administered 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%), alkaline phosphatase (in 21%), and aspartate aminotransferase (in 27%); these observations have led to additional clinical trials in other myeloid 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 splenectomy [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 benefit lasted for a median of one year; specific benefits included becoming 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 pancytopenia [85]. Non-hepatosplenic EMH might involve the vertebral column, lymph nodes, pleura and peritoneum (ascites) and is effectively treated with low-dose radiotherapy ( cgy in 5 to 10 fractions) [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 advances 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 management of drug-refractory splenomegaly is participation in experimental drug therapy. Both splenectomy and low-dose radiotherapy are reasonable alternative treatment options. Prophylactic therapy with hydroxyurea is advised to prevent post-splenectomy thrombocytosis [[82]]. Post-splenectomy thrombosis might be prevented by instituting short term systemic anticoagulation. 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Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: A prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Blood 2009;114: American Journal of Hematology, Vol. 91, No. 12, December 2016 doi: /ajh.24592