Advancing Treatment Paradigms in Myeloproliferative Neoplasms: From Molecular Pathogenesis to Patient-Tailored Therapy
Panelists discuss how advancements in understanding myeloproliferative neoplasms are shaping treatment approaches through case studies of intermediate-risk myelofibrosis and advanced polycythemia vera, with emphasis on Janus kinase (JAK) inhibitor selection based on genetic profiles and patient-specific factors.
Summary of Myeloproliferative Neoplasms Virtual Tumor Board
This summary outlines key points from a virtual tumor board discussion on myeloproliferative neoplasms (MPNs) led by Pankit Vachhani, MD, along with experts Edward Pearson, MD, and Maureen Thyne, PA.
MPN Overview
- MPNs are classified as Philadelphia chromosome–negative blood cancers including:
- Polycythemia vera (PV
- Essential thrombocythemia (ET)
- Primary myelofibrosis (PMF), including overt PMF and prefibrotic PMF
- Molecular Basis: All MPNs are characterized by hyperactive JAK-STAT pathway signaling
- PV: approximately 95% have JAK2 V617F mutation (exon 14), 2%-3% have exon 12 mutations
- ET and PMF: 50%-65% have JAK2 mutations, approximately 25% have CALR mutations, 5%-10% have MPL mutations
- 10%-15% of cases lack these three driver mutations but typically have other myeloid gene mutations
Treatment Landscape for Myelofibrosis
- 4 FDA-approved JAK inhibitors are available:
- Ruxolitinib (2011)
- Fedratinib
- Pacritinib
- Momelotinib (September 2023)
- Differential Inhibitory Profiles:
- All 4 inhibit JAK2
- Ruxolitinib and momelotinib also inhibit JAK1
- Pacritinib is a JAK1-sparing inhibitor
- Momelotinib and pacritinib inhibit ACVR1, potentially providing anemia benefits
Risk Stratification and Treatment Approach
- Risk Assessment: Using MIPS 70 version 2.0+ to stratify patients from very low to very high risk
- Lower risk (very low/low): Observation may be appropriate if asymptomatic
- Higher risk: Consider allogeneic stem cell transplant if eligible
- Treatment Selection Based on Clinical Presentation:
- Predominant anemia: Consider androgens, danazol, immunomodulatory imide drugs, prednisone, or erythropoiesis-stimulating agents
- Splenomegaly/cytosis without significant cytopenias: Consider hydroxyurea or ruxolitinib
- Anemia with spleen-related symptoms: Consider appropriate JAK inhibitor
- Platelet count <50,000: Pacritinib is FDA approved
- Ruxolitinib failure: Optimize dosing or consider fedratinib or other JAK inhibitors
The discussion planned to cover 2 illustrative cases focusing on intermediate-risk myelofibrosis and advanced polycythemia vera to demonstrate clinical decision-making in the evolving treatment landscape.
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