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

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

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

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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 Momelotinib Clinical Trials and Second-Line Applications

SIMPLIFY-1 (First-Line Setting)

• Efficacy comparison with ruxolitinib in newly diagnosed myelofibrosis:
  • Spleen response: Momelotinib demonstrated spleen volume reduction
  • Symptom improvement: Not as robust as ruxolitinib
  • Anemia benefit: Preserved transfusion independence at week 24 vs baseline, while ruxolitinib showed slight decline
• Clinical considerations for newly diagnosed myelofibrosis with moderate anemia:
  • Potential benefit of single-agent therapy (avoiding combination with erythropoiesis-stimulating agents)
  • When anemia contributes significantly to symptom burden, momelotinib may be preferable

SIMPLIFY-2 (Second-Line Setting)

• Study design: Effectively a comparison of momelotinib vs ruxolitinib in previously treated patients
  • No washout period between treatments
• Key outcomes:
  • Spleen response: Comparable between momelotinib and control (“a wash”)
  • Anemia: Clear advantage for momelotinib
  • Symptom control: Superior with momelotinib in the second-line setting
• Expert opinion on optimal positioning:
  • Panel indicated greater preference for momelotinib in the second-line setting
  • Particularly valuable in patients with worsening anemia or diminishing spleen response on ruxolitinib
  • Setting appropriate expectations is crucial; emphasize anemia and symptom benefits rather than additional spleen reduction

Clinical Pearls

• Treatment selection should align with the dominant disease manifestation:
  • Match Janus kinase inhibitor characteristics to patient phenotype and symptoms
  • Consider whether symptoms are primarily driven by anemia vs other factors
• Ruxolitinib failure represents a challenging clinical scenario:
  • Important to distinguish between loss of response/refractoriness vs anemia development
  • Momelotinib offers a valuable option, particularly when anemia contributes to symptoms

The panel emphasized the importance of individualized treatment selection based on the patient’s specific needs, with momelotinib finding particular utility in the second-line setting for patients with worsening anemia on ruxolitinib.