SOHO State of the Art Updates and Next Questions: Novel Therapies in Development for Myelofibrosis

Abstract Myeloproliferative neoplasms (MPN) research has entered a dynamic and exciting era as we witness exponential growth of novel agents in advanced/early phase clinical trials for myelofibrosis (MF). Building on the success and pivotal role of ruxolitinib, many novel agents, spanning a wide range of mechanisms/targets (epigenetic regulation, apoptotic/intracellular signaling pathways, telomerase, BM fibrosis) are in clinical development; several are in registrational trials and hold great potential to expand the therapeutic arsenal/shift the treatment paradigm if regulatory approval is granted. Insight into MF pathogenesis/molecular underpinnings, preclinical studies demonstrating synergism of ruxolitinib with investigational agents, urgent unmet clinical needs (cytopenias, loss of response to JAK inhibitors); and progressive disease fueled the rapid rise of innovative therapeutics. New strategies include pairing ruxolitinib with erythroid maturation agents to manage anemia (luspatercept), designing rational combinations with ruxolitinib to boost responses in both the frontline and suboptimal response settings (pelabresib, navitoclax, parsaclisib), treatment with non-JAK inhibitor monotherapy in the second-line (navtemadlin, imetelstat), novel JAK inhibitors tailored to subgroups with challenging unmet needs (momelotinib and pacritinib for anemia and thrombocytopenia, respectively); and agents potentially enhancing longevity (imetelstat). Beyond typical endpoints evaluated in MF clinical trials (SVR≥35%, TSS≥50%) thus far, emerging ones include overall survival, progression-free survival, transfusion independence, anemia improvement, bone marrow fibrosis and driver mutation allele burden reduction. Novel biomarkers and additional clinical features are being sought to assess new agents and tailor emerging therapies to appropriate patients. New strategies are needed to optimize the design of clinical trials comparing novel combinations to standard agent monotherapy.