What is the recommended treatment algorithm for myelofibrosis, including assessment for allogeneic hematopoietic stem‑cell transplantation, first‑line JAK‑1/2 inhibitor (ruxolitinib) dosing based on platelet count, second‑line options, anemia management, and splenomegaly management?

Myelofibrosis Treatment Algorithm

Immediate Assessment for Allogeneic Hematopoietic Stem Cell Transplantation

All patients with myelofibrosis should be evaluated for allogeneic hematopoietic stem cell transplantation (alloSCT) at diagnosis, as this remains the only curative therapy. 1

• AlloSCT is the sole curative option for primary myelofibrosis (PMF) and post-polycythemia vera/post-essential thrombocythemia myelofibrosis (PPV-/PET-MF), making early assessment critical 1
• Patients with intermediate-2 or high-risk disease by International Prognostic Scoring System should be prioritized for transplant evaluation 2
• Ruxolitinib can serve as effective bridge therapy to transplant, reducing splenomegaly (median 41% reduction), improving performance status, and ameliorating symptoms in 71% of patients prior to alloSCT 2
• Pre-transplant ruxolitinib exposure (median 6.5 months) may improve transplant outcomes through cytokine downregulation, potentially reducing graft failure and acute GVHD rates 2

First-Line JAK1/2 Inhibitor Therapy: Ruxolitinib Dosing

Treatment with ruxolitinib is palliative and guided by predominant symptoms—splenomegaly and constitutional symptoms—rather than curative intent. 1

Starting Dose Based on Platelet Count

• Platelets >200 × 10⁹/L: Start ruxolitinib 20 mg twice daily 3
• Platelets 100-200 × 10⁹/L: Start ruxolitinib 15 mg twice daily 3
• Platelets 50-100 × 10⁹/L: Start ruxolitinib 5 mg twice daily with dose-escalation approach 3
• Platelets <50 × 10⁹/L: Ruxolitinib is not recommended 3

Critical Dose Management Principles

Maintain maximum tolerated doses and avoid extended treatment interruptions to prevent loss of treatment responses. 3

• Close monitoring of blood counts during the first 8-12 weeks is essential, as myelosuppression peaks during this period 3
• Most patients with baseline anemia (hemoglobin <10 g/dL) or thrombocytopenia (platelets ≤100 × 10⁹/L) tolerate and maintain doses ≥10 mg twice daily for nearly 2 years 4
• In real-world practice, 88.3% of anemic patients and 83.1% of thrombocytopenic patients maintained ruxolitinib doses ≥10 mg twice daily, with only 1.1% discontinuing for cytopenias 4
• Dose reductions should follow prescribing information based on platelet counts, but premature discontinuation should be avoided in patients who would otherwise benefit 3

Splenomegaly Management

Ruxolitinib has superseded hydroxyurea as first-line therapy for symptomatic splenomegaly. 1

• Hydroxyurea previously achieved 40% overall response for symptomatic splenomegaly, but approximately 80% of patients required alternative therapy after 1 year 1
• Ruxolitinib effectively reduces splenomegaly and improves quality-of-life measures, with emerging evidence suggesting potential survival benefit in intermediate- or high-risk disease 5
• Splenectomy is indicated for patients with transfusion-dependent anemia refractory to drug therapy, but requires careful consideration due to 50% complication rate and 5-10% mortality 1, 6

Post-Splenectomy Management (If Performed)

• Initiate therapeutic anticoagulation with low molecular weight heparin immediately postoperatively 6
• If platelet count rises above 400 × 10⁹/L, immediately start cytoreductive therapy with hydroxyurea 6
• Begin lifelong prophylactic antibiotics (phenoxymethylpenicillin 250-500 mg twice daily or erythromycin 500 mg twice daily if penicillin-allergic) immediately postoperatively 6
• Educate patients that any fever >38°C requires immediate emergency department evaluation for overwhelming post-splenectomy infection 6

Anemia Management Algorithm

Hemoglobin <10 g/dL typically triggers treatment consideration, though individual variations exist based on age and comorbidities. 1

First-Line Anemia Therapies

Erythropoiesis-stimulating agents (ESAs) are the first option for anemia management. 1

• ESAs produce improvements in 23-60% of patients 1
• Response is often restricted to patients with erythropoietin levels <125 mU/mL, less frequent splenomegaly, and non-transfusion-dependent patients 1
• If no response occurs at 3 months, ESA treatment should be stopped 1

Second-Line Anemia Therapies

Androgens (danazol preferred) should be used when ESAs fail. 1

• Danazol 400-600 mg daily achieves 35% overall response rate with less toxicity than other androgens 1
• Maintain danazol for at least 6 months, then progressively reduce to minimum necessary dose 1
• Alternative androgens (nandrolone, fluoxymesterone, methandrostenolone, oxymetholone) improve anemia in 30-60% of patients 1

Third-Line Anemia Therapies

Immunomodulating drugs may be useful but are frequently withdrawn early due to toxicity. 1

• Low-dose thalidomide combined with oral prednisone provides 23-29% response 1
• Lenalidomide combined with low-dose prednisone taper produces 19% response 1
• Lenalidomide as single agent is the treatment of choice for myelofibrosis patients with 5q deletion 1

Fourth-Line Anemia Therapies

• Corticosteroids alone may be used for refractory anemia in patients unresponsive to above drugs and ineligible for alloSCT or splenectomy 1
• Corticosteroids often result in modest hemoglobin increases and improvements in patient well-being 1
• Splenectomy can be useful for transfusion-dependent anemia refractory to drug therapy 1

Second-Line Options After Ruxolitinib

Treatment remains palliative after ruxolitinib failure, with options guided by predominant symptoms. 1

• For persistent splenomegaly: Consider splenectomy if patient is surgical candidate 1
• For persistent anemia: Follow the anemia management algorithm above (ESAs → androgens → immunomodulators → corticosteroids) 1
• Re-evaluate for alloSCT eligibility, as this remains the only curative option 1

Critical Pitfalls to Avoid

• Do not prematurely discontinue ruxolitinib for early cytopenias—most patients with baseline anemia or thrombocytopenia tolerate therapy long-term with appropriate dose management 4, 3
• Do not use dose-escalation approach at therapy initiation except for patients with platelets 50-100 × 10⁹/L—other platelet ranges should start at recommended doses 3
• Do not continue ESAs beyond 3 months without response—this represents treatment failure requiring alternative approaches 1
• Do not overlook alloSCT evaluation—this is the only curative therapy and should be assessed at diagnosis for all patients 1