Myelofibrosis (MF) is a chronic, progressive BCR-ABL1–negative myeloproliferative neoplasm characterized by clonal myeloproliferation, bone marrow fibrosis, splenomegaly, cytopenias, constitutional symptoms, and risk of leukemic transformation. [1-2] It may arise de novo (primary MF) or evolve from polycythemia vera or essential thrombocythemia (secondary MF). [3] The following is a clinically organized summary for emergency medicine and primary care.
1. History
- Key HPI questions: Fatigue (present in ~85%), night sweats, unexplained fevers, unintentional weight loss (>10% in 6 months), early satiety, left upper quadrant pain/fullness, bone pain, pruritus [4-5]
- Symptom characterization: Constitutional symptoms are often insidious; abdominal symptoms relate to progressive splenomegaly; fatigue is typically the most debilitating symptom [2]
- Timing/progression: Symptoms may be absent early (prefibrotic stage) and worsen over months to years; ask about rate of symptom progression and functional decline [6]
- Associated symptoms: Dyspnea on exertion (anemia), easy bruising/bleeding (thrombocytopenia), recurrent infections (leukopenia), peripheral edema, diarrhea [7]
- Important negatives: Absence of erythrocytosis (distinguishes from PV), absence of isolated thrombocytosis (distinguishes from ET) [4]
2. Alarm Features
- Blast phase transformation: ≥20% blasts in peripheral blood or bone marrow — represents leukemic transformation, occurs in ~15% within 5 years [4][8]
- Splenic infarction: Acute severe LUQ pain with peritoneal signs [9]
- Massive splenomegaly complications: Portal hypertension, variceal bleeding, ascites [10]
- Severe cytopenias: Hemoglobin <8 g/dL (median survival ~2.1 years), platelets <50 × 10⁹/L (associated with significantly worse outcomes) [2][11]
- Extramedullary hematopoiesis complications: Spinal cord compression, pulmonary hypertension, pleural effusions [10]
- JAK inhibitor withdrawal syndrome: Fever, respiratory distress, hypotension, multi-organ failure upon abrupt discontinuation — requires urgent recognition [8]
3. Medications
- FDA-approved JAK inhibitors: [12-13]
- Ruxolitinib (Jakafi): First-line for intermediate/high-risk MF with platelets ≥50 × 10⁹/L; ~42% achieve ≥35% spleen volume reduction at week 24 [1][14]
- Fedratinib (Inrebic): Intermediate-2/high-risk MF; effective second-line after ruxolitinib failure [12]
- Pacritinib (Vonjo): Specifically for platelets <50 × 10⁹/L [8][12]
- Momelotinib (Ojjaara): MF with anemia; unique ACVR1 inhibition addresses anemia, splenomegaly, and symptoms simultaneously [2][12]
- Other treatments: Hydroxyurea (cytoreduction), peginterferon alfa-2a, danazol, ESAs (if EPO <500 mU/mL), luspatercept [8]
- Contraindicated/cautions: Abrupt JAK inhibitor discontinuation (withdrawal syndrome risk); danazol requires prostate cancer screening and LFT monitoring; statins with danazol increase rhabdomyolysis risk [8]
- Monitoring on JAK inhibitors: Dermatology exam yearly (non-melanoma skin cancer risk), lipid panel every 6 months, infection surveillance including viral reactivations [8]
4. Diet
- Cachexia management: High-calorie, high-protein diet to counteract the hypercatabolic state and weight loss common in MF [7]
- Early satiety: Small, frequent meals due to mechanical compression from splenomegaly [5]
- Hydration: Adequate hydration, particularly with hydroxyurea use and in the setting of hyperuricemia
- Iron/folate: Address nutritional deficiencies contributing to anemia; iron studies are part of the standard workup [8]
5. Review of Systems
- Constitutional: Fever, night sweats, weight loss (define as >10% in 6 months for prognostic scoring) [8]
- Hematologic: Fatigue, dyspnea, bleeding, bruising, recurrent infections [6]
- GI: Early satiety, abdominal pain/fullness, diarrhea [7]
- MSK: Bone pain, diffuse extremity pain (extramedullary hematopoiesis) [10]
- Cardiovascular: Peripheral edema, exertional dyspnea [9]
- Dermatologic: Pruritus (especially aquagenic), new skin lesions (non-melanoma skin cancer risk on JAK inhibitors) [5][8]
- Neurologic: Symptoms of cord compression (rare but critical) [10]
6. Collateral History and Family History
- Prior MPN diagnosis: History of polycythemia vera or essential thrombocythemia (secondary MF) [8]
- Prior blood count abnormalities: Long-standing thrombocytosis or erythrocytosis may suggest antecedent MPN [4]
- Family history: Familial clustering of MPNs is recognized; first-degree relatives have increased MPN risk
- Transfusion history: Document transfusion dependence — a key prognostic variable [8]
- Medication history: Prior hydroxyurea, interferon, or JAK inhibitor use [8]
7. Risk Factors
- Age: Most commonly diagnosed ages 50–80 [6]
- Prior MPN: PV and ET can transform to secondary MF [3]
- Driver mutations: JAK2 V617F (~60%), CALR (~25%), MPL (~5%); ~8–10% are "triple-negative" (worst prognosis) [1][8]
- High-molecular-risk mutations: ASXL1, EZH2, SRSF2, IDH1/2, TP53, U2AF1 Q157 — associated with inferior survival and/or leukemic transformation [8]
- Unfavorable karyotype and complex cytogenetics [8]
- Cardiovascular comorbidities: Contribute to thrombotic risk [4]
8. Differential Diagnosis
- Chronic myeloid leukemia (CML): Must exclude with BCR::ABL1 testing (FISH or RT-PCR) — mandatory in workup [8]
- Polycythemia vera: Distinguished by erythrocytosis; post-PV MF develops after established PV [4]
- Essential thrombocythemia: Distinguished by isolated thrombocytosis and characteristic bone marrow morphology [8]
- Myelodysplastic syndromes (MDS): Can have fibrosis; distinguished by dysplastic morphology and cytogenetics [8]
- Chronic myelomonocytic leukemia (CMML): MF can develop monocytosis mimicking CMML [8]
- Reactive/secondary bone marrow fibrosis: Autoimmune disorders, infections, metastatic malignancy, hairy cell leukemia — must be excluded [8]
- Systemic mastocytosis: If mast cell aggregates seen in bone marrow [8]
9. Past Medical History
- Prior MPN diagnosis (PV, ET) and duration [8]
- Thrombotic/hemorrhagic events: Arterial or venous thrombosis complicates ~10% of cases over 5 years [4]
- Splenectomy history [15]
- Transfusion dependence — key prognostic factor [8]
- Cardiovascular disease, renal/hepatic impairment — affects JAK inhibitor dosing and transplant eligibility [8]
10. Physical Exam
- Vital signs: Low-grade fever, tachycardia (anemia), cachexia/weight loss [7]
- Spleen: Palpate for splenomegaly — present in nearly all patients; can be massive (>15 cm below costal margin); measure distance from left costal margin [4][15]
- Liver: Hepatomegaly from extramedullary hematopoiesis [6]
- Skin: Pallor (anemia), petechiae/ecchymoses (thrombocytopenia), pruritus excoriations, new skin lesions [6]
- Lymph nodes: Generally not prominent (helps distinguish from lymphoma)
- Extremities: Peripheral edema, bone tenderness [7]
- Concerning findings: Peritoneal signs (splenic infarction), ascites (portal hypertension), signs of cord compression [9-10]
11. Lab Studies
- CBC with differential and peripheral smear: Anemia (often severe), leukoerythroblastosis (nucleated RBCs + immature granulocytes), teardrop cells (dacrocytes) — hallmark finding, variable WBC and platelet counts [4][7]
- CMP with LDH, uric acid, LFTs: Elevated LDH (minor criterion for diagnosis), hyperuricemia [8]
- Molecular testing: JAK2 V617F, CALR, MPL mutations; multigene NGS panel for prognostic mutations (ASXL1, EZH2, SRSF2, IDH1/2, TP53, U2AF1) [8]
- BCR::ABL1 testing: FISH or RT-PCR to exclude CML — mandatory [8]
- Serum EPO level: Guides ESA eligibility (use if <500 mU/mL) [8]
- Iron studies: Rule out iron deficiency as contributing cause of anemia [8]
- Coagulation studies: Consider acquired von Willebrand syndrome testing in patients with elevated platelets and unexplained bleeding [8]
- Labs to rule out dangerous conditions: Peripheral blast count (≥10–20% suggests accelerated/blast phase), rapidly falling counts suggest progression [8]
12. Imaging
- First-line: Abdominal ultrasound or CT to quantify spleen and liver size [9]
- Spleen volumetrics: Used to monitor treatment response (≥35% spleen volume reduction is a key endpoint) [1]
- When to image urgently: Acute LUQ pain (splenic infarction on CT with contrast), new neurologic symptoms (MRI spine for extramedullary hematopoiesis/cord compression) [10]
- Chest imaging: If dyspnea — evaluate for pulmonary hypertension, pleural effusions from extramedullary hematopoiesis [10]
- Imaging is unnecessary for routine monitoring if spleen is easily palpable and stable
13. Special Tests
- Bone marrow biopsy: Essential for diagnosis — aspirate with iron stain, biopsy with reticulin and trichrome stain; assess fibrosis grade (0–3), megakaryocyte morphology, cellularity, blast percentage [8]
- Cytogenetics: Karyotype from bone marrow (or peripheral blood if inaspirable — "dry tap" is common) [8]
- Prognostic scoring systems:
- DIPSS/DIPSS-Plus: Clinical variables (age, Hb, WBC, blasts, constitutional symptoms ± karyotype, platelets, transfusion status) [16-17]
- MIPSS70+v2.0: Integrates molecular data for refined prognostication [18]
- GIPSS: Purely genomic-based scoring (karyotype + mutations) [8]
- MTSS: Myelofibrosis Transplant Scoring System for transplant candidacy [8]
- MPN-SAF TSS: 10-item symptom assessment tool for quantifying symptom burden [5][8]
The NCCN diagnostic criteria for primary myelofibrosis are shown below:
14. ECG
- Indications: Baseline ECG before starting anagrelide (phosphodiesterase III inhibitor properties — risk of tachycardia, cardiac insufficiency) [8]
- Pre-transplant: Standard cardiac evaluation including ECG as part of HCT workup [8]
- Dangerous patterns: Tachyarrhythmias in the setting of severe anemia; signs of pulmonary hypertension (right heart strain pattern)
- Not routinely required for JAK inhibitor initiation unless cardiovascular comorbidities are present
15. Assessment
- Clinical summary: MF is a heterogeneous disease with survival ranging from >15 years (low-risk) to ~1.3 years (high-risk) depending on prognostic scoring [16-17]
- Severity stratification: Risk-stratify all patients using DIPSS-Plus or MIPSS70+v2.0; this directly guides treatment decisions including transplant referral [8]
- Typical presentation: Insidious fatigue, progressive splenomegaly, anemia, constitutional symptoms in a patient aged 50–80 [6]
- Atypical presentations: Asymptomatic with incidental splenomegaly or cytopenias; isolated thrombocytosis mimicking ET; presentation with thrombotic event [4]
- Complications: Leukemic transformation (~15–23% at 5 years), portal hypertension, splenic infarction, cord compression, severe transfusion-dependent anemia [4][10][19]
The NCCN treatment algorithms for lower-risk and higher-risk MF are shown below:
16. Treatment Plan
Initial stabilization (ED setting)
- Transfuse PRBCs for symptomatic anemia or hemodynamic instability
- Manage splenic infarction with analgesia, IV fluids, and surgical consultation if peritoneal signs
- Do NOT abruptly discontinue JAK inhibitors — risk of withdrawal syndrome (fever, hypotension, respiratory distress, multi-organ failure); consider corticosteroids if withdrawal syndrome suspected [8]
Risk-stratified treatment per NCCN Guidelines: [8]
- Lower-risk, asymptomatic: Observation with monitoring every 3–6 months
- Lower-risk, symptomatic: Hydroxyurea, ruxolitinib, peginterferon alfa-2a, pacritinib (if platelets <50 × 10⁹/L), or momelotinib (category 2B)
- Higher-risk, platelets ≥50 × 10⁹/L: Ruxolitinib (category 1), fedratinib (category 1), momelotinib, or pacritinib (category 2B); transplant candidates should proceed to allogeneic HCT
- Higher-risk, platelets <50 × 10⁹/L: Pacritinib (category 1, preferred) or momelotinib (category 2B)
- MF-associated anemia: Momelotinib (category 1, preferred if splenomegaly/symptoms present); ESAs, danazol, luspatercept as alternatives [8]
- Accelerated/blast phase: HMA ± JAK inhibitor, HMA + venetoclax, or intensive chemotherapy; transplant if eligible [8]
Only curative therapy: Allogeneic hematopoietic cell transplant (HCT) — recommended for DIPSS-Plus intermediate-2/high-risk or MIPSS70 high-risk patients; JAK inhibitors should be used ≥2 months pre-transplant for spleen/symptom control [8][20]
17. Disposition
- Admission criteria: Symptomatic severe anemia requiring transfusion, splenic infarction, variceal bleeding/portal hypertension complications, suspected blast transformation, JAK inhibitor withdrawal syndrome, cord compression [8-10]
- Observation: New diagnosis with moderate cytopenias pending hematology consultation; post-transfusion monitoring
- Discharge criteria: Hemodynamically stable, no acute complications, established hematology follow-up, stable medication regimen
- Specialist consultation triggers: All patients with suspected or confirmed MF should be referred to hematology/oncology; transplant-eligible patients need early HCT referral; interventional radiology for splenic artery embolization if massive splenomegaly refractory to JAK inhibitors [8]
18. Follow Up / Return Precautions
- Follow-up timing: Hematology within 1–2 weeks for new diagnoses; every 3–6 months for stable lower-risk patients; more frequently for higher-risk or actively treated patients [8]
- Bone marrow reassessment: At diagnosis and as clinically indicated with worsening symptoms or signs of progression; include NGS and karyotype [8]
- Symptoms requiring immediate reassessment:
- Severe LUQ pain (splenic infarction)
- New bleeding or significant bruising
- Fever or signs of infection (immunocompromised)
- Neurologic symptoms (cord compression)
- Symptoms after stopping JAK inhibitor (withdrawal syndrome)
- Increasing fatigue, new transfusion requirement
- Patient counseling: MF is a chronic condition; JAK inhibitors control symptoms but are not curative; never stop JAK inhibitors abruptly; yearly dermatology exams on JAK inhibitors; report new skin lesions [8]
- Expected course: Variable — low-risk patients may have near-normal life expectancy; high-risk patients have median survival of ~1.3–2 years without transplant; leukemic transformation is a major cause of mortality [2][14][16]
References
1. Myelofibrosis. — Passamonti F, Mora B. Blood. 2023.
2. Momelotinib Versus Danazol in Symptomatic Patients With Anaemia and Myelofibrosis (MOMENTUM): Results From an International, Double-Blind, Randomised, Controlled, Phase 3 Study. — Verstovsek S, Gerds AT, Vannucchi AM, et al. Lancet. 2023.
3. How I Treat Myelofibrosis. — Cervantes F. Blood. 2014.
4. Primary Myelofibrosis and the Myeloproliferative Neoplasms: The Role of Individual Variation. — Stein BL, Moliterno AR. The Journal of the American Medical Association. 2010.
5. Patient (pt) interview–based content validation of the Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0). — Cardellino A, Zhang S, Phiri K, et al. Journal of Clinical Oncology. 2024.
6. Primary myelofibrosis. — National Library of Medicine (MedlinePlus) 2014.
7. Myelofibrosis with Myeloid Metaplasia. — Tefferi A. The New England Journal of Medicine. 2000.
8. Myeloproliferative Neoplasms. — Updated 2026-01-22. National Comprehensive Cancer Network.
9. Guideline for the Diagnosis and Management of Myelofibrosis. — Reilly JT, McMullin MF, Beer PA, et al. British Journal of Haematology. 2012.
10. Janus Kinase-1 and Janus Kinase-2 Inhibitors for Treating Myelofibrosis. — Martí-Carvajal AJ, Anand V, Solà I. The Cochrane Database of Systematic Reviews. 2015.
11. Pacritinib Versus Best Available Therapy for the Treatment of Myelofibrosis Irrespective of Baseline Cytopenias (PERSIST-1): An International, Randomised, Phase 3 Trial. — Mesa RA, Vannucchi AM, Mead A, et al. The Lancet. Haematology. 2017.
12. FDA Orange Book. — FDA Orange Book. 2026.
13. How I Individualize Selection of JAK Inhibitors for Patients With Myelofibrosis. — Masarova L, Chifotides HT. Blood. 2025.
14. JAK Inhibition with Ruxolitinib versus Best Available Therapy for Myelofibrosis. — Harrison C, Kiladjian JJ, Al-Ali HK, et al. The New England Journal of Medicine. 2012.
15. Indication and Management of Allogeneic Haematopoietic Stem-Cell Transplantation in Myelofibrosis: Updated Recommendations by the EBMT/ELN International Working Group. — Kröger N, Bacigalupo A, Barbui T, et al. The Lancet. Haematology. 2023.
16. Primary myelofibrosis: 2013 update on diagnosis, risk‐stratification, and management. — Tefferi A. American Journal of Hematology. 2013.
17. Primary myelofibrosis: 2014 update on diagnosis, risk‐stratification, and management. — Tefferi A. American Journal of Hematology. 2014.
18. Primary Myelofibrosis. — Douglas Tremblay, Sangeetha Venugopal, John Mascarenhas, et al. Cancer Consult. 2023.
19. Long term follow-up results of phase II clinical trial evaluating ruxolitinib (RUX) and azacitidine (AZA) combination therapy in patients (pts) with myelofibrosis (MF). — Arora S, Senapati J, Masarova L, et al. Journal of Clinical Oncology. 2024.
20. How I Treat Transplant-Eligible Patients With Myelofibrosis. — Kröger N, Wolschke C, Gagelmann N. Blood. 2023.