Primary myelofibrosis: 2013 update on diagnosis, risk-stratification, and management.
BACKGROUND
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.


METHODS
Diagnosis is based on bone marrow morphology. The presence of fibrosis, JAK2/MPL mutation, or +9/13q- cytogenetic abnormality is supportive but not essential for diagnosis. Prefibrotic PMF mimics essential thrombocythemia in its presentation and the distinction is prognostically relevant. Differential diagnosis of myelofibrosis should include chronic myeloid leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia.


METHODS
The Dynamic International Prognostic Scoring System-plus (DIPSS-plus) prognostic model for PMF can be applied at any point during the disease course and uses eight independent 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. A >80% two-year mortality is predicted by monosomal karyotype, inv(3)/i(17q) abnormalities, or any two of circulating blasts >9%, leukocytes ≥ 40 × 10⁹/L or other unfavorable karyotype. Most recently, mutations involving ASXL1, SRSF2, EZH2, and IDH1/2 or increased plasma IL-2R, IL-8, or serum-free light chain levels have been shown to adversely affect survival.


METHODS
Observation alone is adequate for asymptomatic low/intermediate-1 risk disease. Allogeneic stem cell transplantation (ASCT) is often considered for high risk disease. Conventional or experimental drug therapy is reasonable for symptomatic intermediate-1 or intermediate-2 risk disease; however, ASCT is an acceptable treatment option for such patients in the presence of ASXL1 or other prognostically adverse mutations. Splenectomy and low-dose radiotherapy are used for drug-refractory splenomegaly. Radiotherapy is also used for the treatment of non-hepatosplenic EMH, PMF-associated pulmonary hypertension, and extremity bone pain.
Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA. tefferi.ayalew@mayo.edu
Ayalew
A
Tefferi
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001853:Bone Marrow / Q000473:pathology; D003663:Decision Trees; D003937:Diagnosis, Differential; D019008:Drug Resistance, Neoplasm; D015507:Drugs, Investigational / Q000627:therapeutic use; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D055728:Primary Myelofibrosis / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D011379:Prognosis; D011878:Radiotherapy; D053628:Receptors, Thrombopoietin / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013156:Splenectomy; D033581:Stem Cell Transplantation
C473949:ASXL1 protein, human; D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D053628:Receptors, Thrombopoietin; D012097:Repressor Proteins; C082218:MPL protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2