Optimizing Myelofibrosis Therapy: A Comprehensive Comparison of JAK Inhibitor Clinical Trials From Design to Outcomes

EP: 1.Advancing Treatment Paradigms in Myeloproliferative Neoplasms: From Molecular Pathogenesis to Patient-Tailored Therapy

EP: 2.Personalized JAK Inhibitor Selection in Myelofibrosis: Clinical Characteristics, Molecular Profiles, and Treatment Sequencing

EP: 3.Myelofibrosis Management: Clinical Approaches and Treatment Algorithms With Case-Based Application

EP: 4.COMFORT Trials: Applying Evidence to Intermediate-Risk Myelofibrosis

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EP: 5.Optimizing Myelofibrosis Therapy: A Comprehensive Comparison of JAK Inhibitor Clinical Trials From Design to Outcomes

EP: 6.Clinical Decision-Making With PERSIST-2: Optimizing Therapy for Anemic Myelofibrosis Patients With Splenomegaly

EP: 7.Strategic JAK Inhibitor Sequencing: Translating SIMPLIFY I/II Outcomes to Optimize Myelofibrosis Management

EP: 8.MOMENTUM Trial Outcomes: Guiding Therapy for Myelofibrosis With Anemia and Splenomegaly

EP: 9.Current Evidence and Clinical Algorithms for Targeted Management of Polycythemia Vera: Applying Trial Insights to Patient Care

EP: 10.Case-Based Discussion: Management Strategies for Hydroxyurea-Resistant Polycythemia Vera

EP: 11.Comparative Analysis of Major Polycythemia Vera Clinical Trials: PROUD-PV, MAJIC-PV, RESPONSE, and CYTO-PV

EP: 12.CYTO-PV Trial Insights: Optimizing Hematocrit Targets and Thrombosis Prevention in Polycythemia Vera

Summary of JAK Inhibitor Clinical Trials and Dosing Strategies in Myelofibrosis

Key Clinical Trials

1. REALIZE: Phase 2 study of ruxolitinib in myelofibrosis patients with anemia (hemoglobin [Hb] <10 g/dL)
   1. Evaluated lower starting dose (10 mg twice daily) with delayed dose escalation after 12-plus weeks
   2. Demonstrated spleen length reduction without increasing transfusion requirements
2. JAKARTA: Phase 3 study of fedratinib vs placebo in higher-risk myelofibrosis
   1. Similar design to COMFORT trials
   2. Investigated 2 different fedratinib doses
3. FREEDOM-2: Study of fedratinib vs best available therapy in previously treated high-risk myelofibrosis
4. PERSIST-2: Three-arm study of pacritinib (400 mg daily vs 200 mg twice daily) vs best available therapy
   1. Unique inclusion of patients with platelets <100,000/μL
   2. Approximately 50% had prior JAK inhibitor exposure
   3. Demonstrated improvement in transfusion burden
5. SIMPLIFY-1: Frontline study of momelotinib vs ruxolitinib
6. SIMPLIFY-2: Momelotinib vs best available therapy (89% ruxolitinib) in previously treated patients
7. MOMENTUM: Study in myelofibrosis patients with spleen symptoms and anemia (Hb <10 g/dL)
   1. Primary end point was symptom-driven
   2. Led to momelotinib approval
   3. Showed improved transfusion burden

Safety Considerations

• Cytopenias: Potential issue with all JAK inhibitors
• Fedratinib: Wernicke’s encephalopathy risk; thiamine supplementation used in FREEDOM-2
• Pacritinib/fedratinib: Gastrointestinal toxicities (likely related to FLT3 inhibition)
• Momelotinib: Some Gastrointestinal toxicity (nausea, diarrhea), dizziness; peripheral neuropathy less prominent in later trials

Ruxolitinib Dosing Strategies for Anemic Patients

Expert Approaches:

• Starting at reduced dose (10 mg twice daily) for patients with Hb <10 g/dL
• Similar approach for patients with platelets 50,000-100,000/μL
• Varying philosophies on dose escalation:
  • Some practitioners rarely escalate beyond 10 mg twice daily
  • Others aim to escalate to 20 mg twice daily for optimal outcomes when tolerated
• Dose escalation typically considered after 12 to 16 weeks
• REALIZE approach demonstrates that lower starting doses with delayed escalation can maintain efficacy without worsening transfusion requirements

The panel emphasized that individualized dosing strategies based on baseline cytopenias are essential for optimizing outcomes while minimizing toxicity in myelofibrosis patients.