A JH CME Information: Primary myelofibrosis: 2014 update on diagnosis, risk-stratification and management Author: Ayalew Tefferi M.D. Editor: Carlo Brugnara M.D.
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䊏 Educational Objectives Upon completion of this educational activity, participants will be better able to identify appropriate management of primary myelofibrosis.
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American Journal of Hematology, Vol. 89, No. 9, September 2014
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AJH Educational Material
Primary myelofibrosis: 2014 update on diagnosis, risk-stratification, and management
Ayalew Tefferi* Disease overview: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by stem cellderived clonal myeloproliferation, 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). 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 leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. Risk Stratification: The Dynamic International Prognostic Scoring System-plus (DIPSS-plus) uses eight predictors of inferior survival: age >65 years, hemoglobin 25 3 109/L, circulating blasts 1%, constitutional symptoms, red cell transfusion dependency, platelet count 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, erythropoietin; 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  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 (>37.5 C) 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 (>37.5 C) Grade 2–3 according to the European classification : 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 : 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 reported mutational frequencies of 58% for JAK2, 25% CALR, 8% MPL, and 9% wild-type for all three mutations (i.e., triple-negative) . 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 doi:10.1002/ajh.23703
also less likely to be anemic, require transfusions, or display leukocytosis. Spliceosome mutations were infrequent in CALR-mutated patients. In a subsequent international study of 570 patients , the authors reported the longest survival in CALR1ASXL12 patients (median 10.4 years) and shortest in CALR2ASXL11 patients (median 2.3 years). CALR1ASXL11 and CALR2ASXL12 patients had similar American Journal of Hematology, Vol. 89, No. 9, September 2014
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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.)  [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 (median survival 5.8 years). Guglielmelli et al. subsequently demonstrated the additional value of the number of prognostically detrimental mutations . Risk factors for leukemia-free survival include 3% circulating blasts, platelet count 9%, leukocytes 40 3 109/L, or other unfavorable karyotype warrant immediate consideration of (ASCT) (Fig. 2). ASCT is also indicated in the presence of high risk molecular profile (i.e., CALR2/ASXL11 mutational status). Transplant. 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 , 5-year disease-free survival (DFS) and treatment-related mortality were 33% and 35% for matched related doi:10.1002/ajh.23703
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 . In the earlier study , 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% . 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. Investigational drug therapy. Several experimental drugs have been and are currently being evaluated in PMF, post-PV/ET MF, and other related MPN . These include pomalidomide, JAK inhibiting ATP mimetics, and mTOR inhibitors. Although not further elaborated in the current review, it is important to note that JAK-STAT can be inhibited by many other classes of drugs, which have been evaluated for the treatment of MF and related MPN; these include histone deacetylase inhibitors, such as panobinostat (LBH589) and givinostat (ITF2357) [67, 68]. Pomalidomide. Pomalidomide is a second generation immunomodulatory drug and in a phase-2 randomized study, 25% of patients with anemia responded to the drug used alone (2 mg/day) or in combination with prednisone (0.5 or 2 mg/day) . In a subsequent phase-2 study of single agent pomalidomide (0.5 mg/day) , anemia American Journal of Hematology, Vol. 89, No. 9, September 2014
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response was documented only in the presence of JAK2V617F (24% vs. 0%) and predicted by the presence of pomalidomide-induced basophilia (38% vs. 6%) or absence of marked splenomegaly (38% vs. 11%). Platelet response was seen in 58% of patients but the drug had limited activity in reducing spleen size. Drug-associated neuropathy or myelosuppression was infrequent but possible. A phase-1 study did not uncover better activity at higher doses (>2 mg/day), which were instead associated with increased myelosuppression . Most recently, the results of a phase-3 study comparing pomalidomide with placebo did not show significant difference in anemia response, which was approximately 16% for each arm, whereas platelet response was significantly better with pomalidomide . JAK inhibitor ATP mimetics. JAK inhibitor ATP mimetics that have undergone clinical trials in MPN include ruxolitinib (INCB018424), fedratinib (SAR302503), momelotinib (CYT387), lestaurtinib (CEP701), pacritinib (SB1518), AZD1480, BMS911543, LY2784544, and XL019 (clinicalTrials.gov). 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. For the purposes of this review, I will focus on ruxolitinib (now FDA approved for use in MF), fedratinib (phase-3 study completed but drug withdrawn because of side effects), and momelotinib and pacritinib (phase-3 study ongoing vs. ruxolitinib or best available therapy, respectively). Ruxolitinib is a JAK1/JAK2 inhibitor. The drug was initially evaluated in 153 patients with PMF or post-PV/ET MF, in a phase-1/2 study . DLT was thrombocytopenia and the MTD was either 25 mg twice-daily or 100 mg once-daily. Adverse events included thrombocytopenia, anemia, and a “cytokine rebound reaction” upon drug discontinuation, characterized by acute relapse of symptoms and splenomegaly [51, 74]. Non-hematologic adverse events were infrequent. Grade 3/4 thrombocytopenia or anemia (in transfusionindependent patients at baseline), respectively, occurred in 39% and 43% of patients receiving the drug at 25 or 10 mg twice daily. Among all evaluable patients, 44% experienced 50% decrease in palpable spleen size. Improvement in constitutional symptoms (fatigue, pruritus, abdominal discomfort, early satiety, night sweats, and exercise tolerance) and weight gain were seen in the majority of patients. Four (14%) of twenty-eight transfusion-dependent patients became transfusion-independent. The drug’s effect on JAK2V617F allele burden or bone marrow pathology was negligible but a major reduction in proinflammatory cytokines (e.g., IL-1RA, IL-6, TNF-a, and MIP1b) was documented and coincided with improvement in constitutional symptoms. Two randomized studies comparing ruxolitinib with either placebo or best supportive care have now been published [75, 76]. In the COMFORT-1 trial that compared the drug with placebo (n 5 309) , the spleen response rate was approximately 42% for ruxolitinib versus 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 43–60%), thrombocytopenia (grade 3 or 4 in 17–27%), and diarrhea (56–66%) . Momelotinib (MMB, GS-0387, CYT387) is a JAK1 and JAK2 inhibitor. Among the first 60 patients treated in a phase-1/2 study , 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 cell-transfused in the month prior to study entry, 70% achieved a minimum 12-week period without transfusions (range 4.7 to >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%). Newonset treatment-related peripheral neuropathy was observed in 22% of patients (sensory symptoms, grade 1). 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 . The drug is currently undergoing phase-3 study compared to ruxolitinib. Pacritinib (SB1518) is a JAK2/FLT3 inhibitor. In phase-1 studies, myelosuppression was minimal and 400 mg/day was chosen as the recommended dose for phase-2 study, which included 34 patients . 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 is currently undergoing phase-3 study compared to best available therapy. 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 doi:10.1002/ajh.23703
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES effects of these drugs might be the result of a potent anti-cytokine activity. mTOR inhibitors. 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 . Drug effect on cytosis or anemia was modest and on JAK2V617F burden negligible. Overall IWG-MRT response rate was 23%. 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 20%. These include DIPSS-plus high or intermediate-2 risk patients as well as those with ASXL11/ CALR2 mutational status. 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 . 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 , more than 75% benefited from the procedure and the benefit lasted for a median of 1 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
䊏 References 1. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes. Blood 2009;114:937–951. Prepublished on 2009/04/10 as DOI 10.1182/blood-2009-03209262. 2. Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008;22:14–22. 3. Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia 2010;24:1128–1138. 4. Tefferi A, Thiele J, Vannucchi AM, Barbui T. An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms. Leukemia 2014. Prepublished on 2014/01/21 as DOI 10.1038/leu.2014.35. 5. Tefferi A, Finke CM, Lasho TL, et al. U2AF1 mutations in primary myelofibrosis are strongly associated with anemia and thrombocytopenia despite clustering with JAK2V617F and normal karyotype. Leukemia 2014;28:431–433. Prepublished on 2013/10/08 as DOI 10.1038/ leu.2013.286. 6. Pardanani A, Lasho TL, Finke C, et al. Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617F-negative polycythemia vera. Leukemia 2007;21:1960– 1963. 7. Lasho TL, Finke CM, Hanson CA, et al. SF3B1 mutations in primary myelofibrosis: Clinical,
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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 . Splenic irradiation (100 cGy in 5–10 fractions) induces transient reduction in spleen size but can be associated with severe pancytopenia . Non-hepatosplenic EMH might involve the vertebral column, lymph nodes, pleura, and peritoneum (ascites) and is effectively treated with low-dose radiotherapy (100–1,000 cGy in 5–10 fractions) . Diagnosis of MF-associated pulmonary hypertension is confirmed by a technetium 99m sulfur colloid scintigraphy and treatment with single-fraction (100 cGy) whole-lung irradiation has been shown to be effective . Single fraction of 100–400 cGy involved field radiotherapy has also been shown to benefit patients with MFassociated extremity pain . 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 . 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 . Postsplenectomy thrombosis might be prevented by instituting short term systemic anticoagulation. Laparoscopic splenectomy is not advised in the setting of MF  and data on the value of splenic artery embolization are limited [93–95]. I do not believe that splenectomy increases the risk of leukemic transformation .
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