Personalized JAK Inhibitor Selection in Myelofibrosis: Clinical Characteristics, Molecular Profiles, and Treatment Sequencing
Panelists discuss how treatment selection among Janus kinase (JAK) inhibitors for myelofibrosis involves considering specific patient characteristics such as cytopenia profiles, mutation status, risk stratification using MIPS criteria, and balancing potential transplant candidacy with careful timing of JAK inhibitor therapy.
Summary of JAK Inhibitor Selection and Transplant Considerations in Myelofibrosis
JAK Inhibitor Landscape
- All 4 JAK inhibitors (ruxolitinib, fedratinib, pacritinib, momelotinib) are approved in a line-agnostic fashion
- Specific approval nuances exist:
- Pacritinib: Approved for patients with platelets <50,000/μL
- Momelotinib: Approved for intermediate/high-risk myelofibrosis with anemia (EU label specifies hemoglobin <10 g/dL)
- Important safety considerations include drug interactions and unique concerns (eg, fedratinib’s black box warning for Wernicke encephalopathy)
Treatment Selection Factors
- Molecular testing is now standard of care:
- Next-generation sequencing panels (typically 50+ genes) help guide risk stratification
- Integration with clinical factors through tools like MIPS is essential
- Results provide both prognostic and transplant selection guidance
- Cytopenia vs proliferative phenotype influences JAK inhibitor selection:
- Low platelets: Pacritinib may be preferred
- Anemia: JAK inhibitors with ACVR1 inhibition (momelotinib, pacritinib) may be preferred
- Thrombocytosis: Ruxolitinib may help control elevated platelets
- Symptom control considerations:
- All JAK inhibitors provide constitutional symptom relief
- Ruxolitinib noted as particularly effective for symptom management
- Symptom relief typically occurs quickly after initiating therapy
- Spleen response varies between agents
Transplant Evaluation and Timing
- Transplant decisions remain challenging due to:
- Survival benefit curves crossing only years after transplant
- Significant upfront morbidity
- General approach to transplant consideration:
- Most patients under age 60 should at least consult with transplant team
- Higher-risk myelofibrosis patients with low comorbidity burden are optimal candidates
- Initial human leukocyte antigen typing and donor availability assessment is low risk
- Patient fitness, age, and motivation are important considerations
- Transplant remains the only curative option
The panel emphasized the importance of standardized risk assessment incorporating molecular data and the need to weigh patient-specific factors when selecting between JAK inhibitors.
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