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

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.