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

DISEASE OVERVIEW: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by stem cell-derived 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 <10 g/dL, leukocytes >25 × 10(9) /L, circulating blasts ≥1%, constitutional symptoms, red cell transfusion dependency, platelet count <100 × 10(9) /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. High risk disease is also defined by CALR(-) /ASXL1(+) mutational status. RISK-ADAPTED THERAPY: Observation alone is adequate for asymptomatic low/intermediate-1 risk disease, especially with CALR(+) /ASXL1(-) mutational status. Stem cell transplant is considered for DIPSS-plus high risk disease or any risk disease with CALR(-) /ASXL1(+) mutational status. Investigational drug therapy is reasonable for symptomatic intermediate-1 or intermediate-2 risk disease. 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.