Primary myelofibrosis: 2023 update on diagnosis, risk-stratification, and management

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Disease Overview: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell-derived clonal myeloproliferation that is often but not always accompanied by JAK2, CALR, or MPL mutations; additional features include bone marrow reticulin/collagen fibrosis, aberrant inflammatory cytokine expression, anemia, hepatosplenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, risk of leukemic progression, and shortened survival. Diagnosis: Bone marrow examination with cytogenetic and mutation studies provides integrated diagnostic information; presence of JAK2, CALR or MPL mutation is expected but not required. New Classification System: The International Consensus Classification distinguishes “prefibrotic” from “overtly fibrotic” PMF; the former might mimic essential thrombocythemia (ET) in its presentation. Approximately 15% of patients with ET or polycythemia vera (PV) might progress into post-ET/PV MF. Mutations: SRSF2, ASXL1, and U2AF1-Q157 mutations predict inferior survival in PMF; RAS/CBL mutations predict resistance to ruxolitinib therapy. Type 1/like CALR mutation is associated with superior survival. Karyotype: Very high-risk abnormalities include −7, inv (3), i(17q), +21, +19, 12p- and 11q-. Favorable risk abnormalities include normal karyotype or isolated +9, 13q-, 20q-, 1q abnormalities and loss of Y chromosome. Risk Stratification: Contemporary prognostic systems include GIPSS (genetically-inspired prognostic scoring system) and MIPSS70+ version 2.0 (MIPSSv2; mutation-and karyotype-enhanced international prognostic scoring system). GIPSS is based exclusively on mutations and karyotype; MIPSSv2 includes, in addition, clinical risk factors. Risk-Adapted Therapy: Observation alone is advised for MIPSSv2 “low” and “very low” risk disease (estimated 10-year survival 56%–92%); allogeneic hematopoietic stem cell transplant (AHSCT) is the preferred treatment of choice for “very high” and “high” risk disease (estimated 10-year survival 0–13%), as well as in carefully selected patients with intermediate-risk disease (estimated 10-year survival 30%). Drug therapy in MF is currently palliative and targets anemia, splenomegaly, and constitutional symptoms. JAK2 Inhibitors: Ruxolitinib, fedratinib, and pacritinib are FDA approved and respectfully utilized in patients failing treatment with hydroxyurea, ruxolitinib, or with platelet count <50 × 10 (9)/L. Momelotinib is another JAK2 inhibitor that is poised for approval sometime in 2023 and has shown erythropoietic benefits, in addition to affecting spleen and symptom responses. Other Treatment Modalities: Splenectomy is considered for drug-refractory splenomegaly and involved field radiotherapy for non-hepatosplenic EMH and extremity bone pain. New Directions: New agents, alone or in combination with ruxolitinib, are currently under clinical trial investigation ( and preliminary results were presented at the 2022 ASH annual meeting and highlighted in the current review.

Original languageEnglish (US)
Pages (from-to)801-821
Number of pages21
JournalAmerican journal of hematology
Issue number5
StatePublished - May 2023

ASJC Scopus subject areas

  • Hematology


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