Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by clonal proliferation of bone marrow stem cells with abnormal megakaryocyte morphology and proliferation, leading to release of cytokines (PDGF, TGF-beta, FGF) that stimulate fibroblasts and produce reticulin and collagen fibrosis. The disease progresses from prefibrotic/early stage (hypercellular marrow with megakaryocytic abnormalities, minimal fibrosis) to overt fibrotic stage (extensive marrow fibrosis with osteosclerosis, leukoerythroblastic peripheral blood, extramedullary hematopoiesis with hepatosplenomegaly). Annual incidence is 0.5-1.5 per 100,000 with median age 65 years.
WHO 2022 classification distinguishes prefibrotic/early PMF and overt fibrotic PMF, both requiring driver mutation (JAK2 V617F in 60%, CALR exon 9 in 25%, MPL W515 in 8%, or triple-negative in 10%) plus characteristic bone marrow morphology and exclusion of other myeloid neoplasms. High molecular risk mutations include ASXL1 (most common, ~30%), EZH2, IDH1/2, SRSF2, U2AF1 Q157 - presence of any associated with shorter survival and increased blast transformation risk. Risk stratification: DIPSS-Plus integrates age >65, hemoglobin <10, leukocytes >25,000, peripheral blasts >=1%, constitutional symptoms, transfusion need, platelets <100,000, unfavorable karyotype. MIPSS70 and MIPSS70+v2.0 add high molecular risk mutations and additional cytogenetic categories for younger patients (<70 years) eligible for allogeneic stem cell transplantation.
JAK inhibitors are mainstay of treatment for symptomatic patients: ruxolitinib (JAK1/2 inhibitor) is first-line, providing >35% spleen volume reduction at 24 weeks in COMFORT-I/II trials and significant symptom improvement, with prolonged overall survival; main toxicities are anemia and thrombocytopenia. Fedratinib (JAK2 selective) approved for ruxolitinib-resistant or intolerant patients; FDA black box warning for Wernicke encephalopathy requires thiamine supplementation. Momelotinib (JAK1/JAK2/ACVR1 inhibitor) approved 2023 for myelofibrosis with anemia, additionally improving anemia by inhibiting hepcidin via ACVR1 inhibition. Pacritinib (JAK2/IRAK1 inhibitor) approved for severe thrombocytopenia (<50,000/microL). Allogeneic stem cell transplantation is the only curative therapy, indicated for intermediate-2 or high-risk disease in patients <70 years with adequate performance status; reduced-intensity conditioning preferred. Supportive care includes red blood cell transfusions for anemia, danazol or luspatercept for transfusion-dependent anemia, hydroxyurea for symptomatic leukocytosis or thrombocytosis, and splenectomy in select cases (high morbidity, last resort).