Myelofibrosis (MF)

Primary and secondary myelofibrosis — DIPSS Plus risk scoring, JAK inhibitor therapy with ruxolitinib, fedratinib, pacritinib, and momelotinib, and allogeneic stem cell transplantation

Key Points

• Myelofibrosis — primary (PMF) or secondary to PV/ET — is a clonal myeloproliferative neoplasm driven by JAK2 V617F (~60%), CALR exon 9 (~25%), or MPL mutations (~5%); bone marrow fibrosis, extramedullary hematopoiesis, and a leukoerythroblastic blood picture are the hallmarks.
• Prognosis is determined by the Dynamic IPSS Plus (DIPSS Plus) score incorporating age, constitutional symptoms, hemoglobin, WBC, blasts, platelet count, transfusion need, and unfavorable cytogenetics — median survival ranges from >10 years (low risk) to <2 years (high risk).
• High-risk somatic co-mutations — the "HMR" (high molecular risk) mutations ASXL1, EZH2, SRSF2, and IDH1/2 — independently worsen prognosis and lower the threshold for allogeneic SCT referral regardless of DIPSS score.
• Ruxolitinib (Jakafi, 2011) — the first FDA-approved JAK1/2 inhibitor for MF — reduces spleen volume and constitutional symptoms in the majority of patients but does not achieve molecular remission or cure; fedratinib (Inrebic), pacritinib (Vonjo, for platelets <50K), and momelotinib (Ojjaara, for anemic MF) are approved alternatives.
• Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only potentially curative therapy and should be considered for all DIPSS Plus intermediate-2 and high-risk patients aged ≤70 with an adequate performance status and available donor.
• Anemia is the dominant symptom in many MF patients — momelotinib (ACVR1/JAK1/2 inhibitor, targeting the ACVR1/SMAD pathway to increase hepcidin) is the only JAK inhibitor with a demonstrated transfusion independence signal in anemic MF.

Pathogenesis, Bone Marrow Histology, and WHO Diagnosis

**Pathogenesis:** Myelofibrosis results from clonal expansion of a transformed hematopoietic stem cell harboring a driver mutation (JAK2, CALR, or MPL) that constitutively activates JAK-STAT signaling. The aberrant clone releases inflammatory cytokines (TGF-β, PDGF, FGF) that stimulate non-clonal marrow fibroblasts to deposit collagen and reticulin, generating progressive bone marrow fibrosis. As fibrosis replaces the marrow, hematopoiesis shifts to extramedullary sites — primarily the spleen and liver — causing massive organomegaly and associated symptoms (early satiety, left upper quadrant…

Prognosis — DIPSS Plus and Molecular Scoring

**Dynamic International Prognostic Scoring System Plus (DIPSS Plus):** The standard clinical prognostic tool for MF. Based on 8 parameters assessable at any point in the disease course: | Variable | Points | |---|---| | Age >65 years | 1 | | Constitutional symptoms (weight loss, night sweats, fever) | 1 | | Hemoglobin 25 × 10⁹/L | 1 | | Circulating blasts ≥1% | 1 | | Transfusion dependency | 1 | | Platelet count 10 years - **Intermediate-1 (1–2 points):** ~5–6 years - **Intermediate-2 (3–4 points):** ~2.5–3 years - **High (≥5 points):** ~1.5–2 years **MIPSS70+ and MYSEC-PM** incorporate…

JAK Inhibitor Therapy

Four JAK inhibitors are FDA-approved for MF, each with a distinct niche: **Ruxolitinib (Jakafi) — FDA-approved November 2011:** First approved JAK1/2 inhibitor; the most extensively used. COMFORT-I (vs. placebo, US) and COMFORT-II (vs. best available therapy, Europe) trials: ≥35% spleen volume reduction in 41–42% of ruxolitinib patients vs. 0–1% controls; significant improvement in constitutional symptoms, quality of life, and — in COMFORT-I — a survival benefit emerged over long-term follow-up. Dose: 15–20 mg twice daily for platelets 100,000–200,000/μL; 5 mg twice daily for platelets…

Allogeneic SCT and Special Management

**Allogeneic HSCT — the only curative therapy:** Recommended for DIPSS Plus intermediate-2 and high-risk patients aged ≤70 with acceptable performance status and available donor. Consider for intermediate-1 patients with unfavorable molecular features (HMR mutations, triple-negative driver, complex karyotype). *Pretransplant JAK inhibitor use:* Ruxolitinib before SCT reduces spleen size, improves performance status, and reduces transplant-related mortality — most experts recommend pretransplant ruxolitinib for 3–6 months in patients with symptomatic splenomegaly. Taper (not abrupt…