Primary myelofibrosis: 2017 update on diagnosis, risk‐stratification, and management
Authors: Tefferi Ayalew 
Published: November 2016

Disease overview:Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell‐derived clonal myeloproliferation that is often but not always accompanied byJAK2,CALRorMPLmutation, 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 ofJAK2,CALRorMPLmutation is supportive but not essential for diagnosis; approximately 90% of patients carry one of these mutations and 10% are “triple‐negative.” None of these mutations are specific to PMF and are also seen in essential thrombocythemia (ET). According to the revised 2016 World Health Organization (WHO) classification and diagnostic criteria, “prefibrotic” PMF (pre‐PMF) is distinguished from “overtly fibrotic” PMF; the former might mimic ET in its presentation and it is prognostically relevant to distinguish the two.

Risk stratification:The Dynamic International Prognostic Scoring System‐plus (DIPSS‐plus)uses eight predictors of inferior survival: age >65 years, hemoglobin <10 g/dL, leukocytes >25 × 109/L, circulating blasts ≥1%, constitutional symptoms, red cell transfusion dependency, platelet count <100 × 109/L and unfavorable karyotype (i.e., complex karyotype or sole or two abnormalities that include +8, −7/7q‐, 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 includingASXL1andSRSF2whereas patients with type 1/likeCALRmutations, compared to their counterparts with other driver mutations, displayed significantly better survival.

Risk‐adapted therapy:Observation alone is a reasonable treatment strategy for asymptomaticloworintermediate‐1DIPSS‐plus risk disease, especially in the absence of high‐risk mutations. All other patients withhighorintermediate‐2 riskdisease, or those harboring high‐risk mutations such asASXL1orSRSF2, 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 affectJAK2/CALR/MPLmutant allele burden. Splenectomy is considered for drug‐refractory splenomegaly. Involved field radiotherapy is most useful for post‐splenectomy hepatomegaly, non‐hepatosplenic EMH, PMF‐associated pulmonary hypertension and extremity bone pain. Am. J. Hematol. 91:1262–1271, 2016. © 2016 Wiley Periodicals, Inc.