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

Helen T Chifotides; Prithviraj Bose; Lucia Masarova; Naveen Pemmaraju; Srdan Verstovsek

doi:10.1016/j.clml.2021.10.002

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

Clin Lymphoma Myeloma Leuk. 2022 Apr;22(4):210-223. doi: 10.1016/j.clml.2021.10.002. Epub 2021 Oct 13.

Authors

Helen T Chifotides¹, Prithviraj Bose¹, Lucia Masarova¹, Naveen Pemmaraju¹, Srdan Verstovsek²

Affiliations

¹ Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX.
² Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX. Electronic address: sverstov@mdanderson.org.

PMID: 34840087
DOI: 10.1016/j.clml.2021.10.002

Abstract

Myeloproliferative neoplasms 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, bone marrow fibrosis) are in clinical development; several are studied 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 and its 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 setting (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 (spleen volume reduction ≥ 35%, total symptom score reduction ≥ 50%) thus far, emerging endpoints include overall survival, progression-free survival, transfusion independence, anemia benefits, 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.

Keywords: Imetelstat; Luspatercept; Momelotinib; Myelofibrosis; Navitoclax; Navtemadlin; Pacrtitinib; Pelabresib.

Publication types

Review

MeSH terms

Anemia* / drug therapy
Epigenesis, Genetic
Humans
Janus Kinase 2 / genetics
Janus Kinase Inhibitors* / therapeutic use
Myeloproliferative Disorders* / genetics
Primary Myelofibrosis* / etiology
Primary Myelofibrosis* / genetics
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use

Substances

Janus Kinase Inhibitors
Protein Kinase Inhibitors
Janus Kinase 2