Primary myelofibrosis (PMF)

Overview

• Clonal myeloproliferation with bone marrow fibrosis and extramedullary hematopoiesis, predominantly in the spleen, leading to marked splenomegaly.
• May occur secondary to PV/ET or as a primary illness (PMF).
• Pathophysiology: clonal hematopoiesis (~50% abnormal karyotype); aberrantly secreted cytokines from megakaryocytes; fibroblast activation with reticulin deposition; increased circulating CD34+ cells.
• Natural history: variable (hence prognostic indices), median overall survival approx. 3 to 5 years; ~20% progress to AML.

Diagnosis

• Major: (1) megakaryocyte proliferation and atypia with fibrosis (grade 2 to 3, overt PMF; grade 0 to 1 with clinical features, pre-fibrotic PMF); (2) not meeting WHO criteria for another myeloid neoplasm (PV, CML, MDS); (3) JAK2/CALR/MPL, or another clonal marker, or absence of reactive fibrosis.
• Minor (≥1 required): anemia not attributed to a comorbid condition, leukocytosis ≥11k, palpable splenomegaly, ↑ LDH above upper normal limit, leukoerythroblastosis (immature myeloid plus nucleated RBCs in peripheral blood).
• Smear classics: leukoerythroblastic picture, teardrop RBCs (dacrocytes), nucleated RBCs.

Symptoms & Signs

• Symptoms: constitutional (fever, sweats, weight loss), fatigue, abdominal pain, early satiety, splenic infarct, GI bleeding, bruising.
• Signs: splenomegaly (85 to 100%), hepatomegaly, extramedullary hematopoiesis, cachexia, gout, portal hypertension/ascites.

Prognostic Scoring

• IPSS, DIPSS, DIPSS-Plus: older systems based on clinical/lab variables.
• MIPSS70: HMR mutations (ASXL1, EZH2, SRSF2, IDH1/2) plus clinical variables (no karyotype). MIPSS70-plus v2.0: adds cytogenetic/karyotype risk and U2AF1 Q157.
• GIPSS: purely genetic (cytogenetics plus driver plus HMR).
• HMR mutations: worse prognosis. ≥2 HMR = "very high molecular risk."
• Triple-negative MF: absence of JAK2/CALR/MPL, poor prognosis (inferior leukemia-free survival vs JAK2- and/or CALR-mutated PMF).
• CALR type 1 (52-bp deletion): best prognosis among PMF; lower thrombosis risk.

IPSS for Myelofibrosis

Risk factors (1 point each): age >65 years, constitutional symptoms, Hb <10 g/dL, leukocyte count >25,000/mcL, circulating blasts ≥1%.

DIPSS-plus Risk Stratification

Adverse factors: anemia (Hb <10 g/dL), RBC transfusion dependence, leukocytosis (>25K), thrombocytopenia (<100K), circulating blasts (>=1%), unfavorable karyotype, constitutional symptoms, age >65 years.

JAK Inhibitors

• Ruxolitinib (Jakafi), Nov 16, 2011: intermediate or high-risk MF (PMF, post-PV/post-ET MF), including int-1 per label; COMFORT trials enrolled int-2/high. JAK1/2 inhibitor, first ever FDA-approved drug for MF; approved regardless of JAK2 mutational status. COMFORT-I (Verstovsek NEJM 2012), SVR35 42% vs 1% placebo; COMFORT-II (Harrison NEJM 2012), vs best available therapy, both showed improved splenomegaly and constitutional symptoms in int-2/high-risk MF. OS benefit on long-term follow-up (Verstovsek Leukemia 2017). Platelet-dependent dosing: 20 mg BID if platelets >200,000/uL, 15 mg BID if platelets 100,000 to 200,000/uL (range 5 to 25 mg BID); 5 mg BID if platelets 50,000 to <100,000; can be given if platelets >=50,000. Also approved for PV (2014), steroid-refractory acute GVHD (2019), chronic GVHD (2021).
• Fedratinib (Inrebic), Aug 16, 2019: int-2/high-risk PMF, post-PV/ET MF, naive or post-ruxolitinib. JAK2-selective (IC50 ~3 nmol/L) with modest activity against JAK1, JAK3, TYK2. Recommended dose 400 mg once daily for platelets ≥50 × 10⁹/L; reduce to 200 mg daily with strong CYP3A4 inhibitors or CrCl <30 mL/min. JAKARTA (Pardanani JAMA Oncol 2015), of 96 patients on 400 mg, 37% achieved ≥35% spleen volume reduction at end of cycle 6 vs 1 of 96 on placebo (P<0.0001), median spleen response duration 18.2 months, and 40% had ≥50% symptom reduction vs 9% placebo; JAKARTA-2 (Harrison Lancet Haematol 2017), post-rux. NCCN lists fedratinib as a category 1 option (with ruxolitinib) for higher-risk MF with platelets >50,000, first-line or post-ruxolitinib. BLACK-BOX: encephalopathy, serious and fatal including Wernicke encephalopathy, measure thiamine before/during and supplement.
• Pacritinib (Vonjo), Feb 28, 2022: MF with platelet count <50,000/uL (any prior therapy). JAK2 plus IRAK1 plus FLT3 inhibitor, less myelosuppressive, usable despite severe thrombocytopenia (but anemia and thrombocytopenia still occur, monitor counts). PERSIST-2 (Mascarenhas JAMA Oncol 2018; FDA basis), evaluated pacritinib vs best available therapy including ruxolitinib in patients with platelets ≤100,000/uL, SVR35 22% vs 3%; PACIFICA (NCT03165734) is the required confirmatory phase 3 in platelets <50k, still ongoing; accelerated approval Feb 2022 was based on PERSIST-2.
• Momelotinib (Ojjaara), Sept 15, 2023: int/high-risk MF (PMF or post-PV/ET MF) plus anemia in adults, naive or previously treated. JAK1/2 plus ACVR1 inhibitor (suppresses hepcidin, mobilizes iron, ↑ Hb). SIMPLIFY-1 (Mesa JCO 2017, non-inferior SVR vs rux but better anemia in JAKi-naive), SIMPLIFY-2 (Harrison Lancet Haematol 2018), MOMENTUM (Verstovsek Lancet 2023; pivotal, vs danazol post-JAKi: TSS50 25% vs 9%, transfusion independence 30% vs 20% at week 24).
• Ruxolitinib pearls: works whether or not a JAK2 mutation is present; effective for splenomegaly and constitutional symptoms but does not reliably reverse marrow fibrosis or eradicate the clone (fibrosis can stabilize or improve in a subset); not curative. Discontinue gradually (do not stop abruptly, withdrawal syndrome: cytokine surge, fever, BP instability). Cytopenias (anemia, thrombocytopenia) are the main dose-limiting toxicity. Increased herpes zoster and skin cancer risk. May benefit patients even with lower-risk symptomatic disease/splenomegaly.
• Fedratinib boxed warning: Wernicke encephalopathy, check thiamine before/during therapy and supplement.
• Pacritinib for thrombocytopenia: also inhibits IRAK1; less myelosuppressive. Use when platelets <50k make ruxolitinib problematic.
• Momelotinib for anemia: ACVR1 inhibition, ↓ hepcidin, ↑ iron mobilization, improved Hb. Choose for anemic MF.
• Choosing a JAK inhibitor: anemia, momelotinib; thrombocytopenia <50k, pacritinib; rux-failure, fedratinib (or trial); standard symptomatic with adequate counts, ruxolitinib.
• MPN-SAF TSS: NCCN incorporates the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (fatigue, inactivity, early satiety, abdominal pain, night sweats, etc.) to monitor symptoms during therapy.

Treatment by Risk

• Low / Int-1 risk: observation if asymptomatic; erythropoiesis-stimulating agents (ESA) if anemic; lenalidomide if del(5q); hydroxyurea if symptomatic splenomegaly.
• Int-2 / High risk: allogeneic stem cell transplant; ruxolitinib or fedratinib (especially for splenomegaly or symptoms). Investigational options as appropriate.
• Splenomegaly: hydroxyurea, JAK inhibitor, splenectomy, or splenic radiation.
• Portal hypertension: transjugular intrahepatic portosystemic shunt (TIPS).
• Extramedullary hematopoiesis: low-dose radiation is the treatment of choice for symptomatic EMH at sites other than spleen and liver, and for pulmonary-EMH-associated pulmonary hypertension specifically (low-dose whole-lung RT; not other causes of PH in MF); a JAK inhibitor can be continued for systemic control while radiation provides local control.

Other Therapies & Allo-HSCT

• Anemia management: ESA (if EPO <500), danazol, lenalidomide (especially with del(5q)), thalidomide plus prednisone, transfusions. Luspatercept: phase 3 INDEPENDENCE (transfusion-dependent MF on JAKi) missed its primary transfusion-independence endpoint; not FDA approved for MF.
• Splenectomy: for symptomatic splenomegaly, transfusion-dependent anemia, or refractory disease; high morbidity (bleeding, thrombosis, blast transformation).
• Splenic radiation: palliative for refractory splenomegaly when surgery is not feasible.
• Allo-HSCT: only curative therapy. Indications: int-2/high risk per DIPSS or MIPSS; high molecular risk; transformation; younger (<70) patients. RIC preferred. Outcomes ~50% long-term survival in selected patients.
• Pelabresib (BET inhibitor) plus ruxolitinib: MANIFEST-2 phase 3 (Rampal NEJM/Nature Medicine 2025), SVR35 at wk 24 65.9% vs 35.2% (PELA plus RUX vs PBO plus RUX, P<.001) met; TSS50 52.3% vs 46.3% (P=.22) NOT met. FDA path uncertain given key secondary TSS50 not met; investigational.
• Navitoclax (BCL2/BCL-XL) plus ruxolitinib: TRANSFORM-1 (Pemmaraju Blood 2024), SVR35 met (63.2% vs 31.5%) but symptom score endpoint not met; AbbVie discontinued navitoclax development for MF in 2024. Selvigaltin (Gal-3 inhibitor) and others now in earlier-phase trials.
• Selinexor plus ruxolitinib: SENTRY/XPORT-MF-034 phase 3 in JAKi-naive MF (topline March 2026): SVR35 met (50% vs 28% at week 24) but Abs-TSS co-primary NOT met; investigational.

Transformation & Outcomes

• Leukemic transformation: ~10 to 20% over 10 years. Predictors: HMR mutations (especially ASXL1), TP53, complex karyotype, transfusion dependence. Prognosis post-transformation poor (~3 to 6 mo median OS without transplant).
• Median OS by risk: low risk ~10 to 15 yr; int-1 ~5 to 7 yr; int-2 ~3 yr; high ~1.3 yr (DIPSS-plus).