Novel treatments for myelofibrosis: beyond JAK inhibitors

Douglas Tremblay, Ruben Mesa

Research output: Contribution to journalReview articlepeer-review

Abstract

Myelofibrosis is a chronic hematologic malignancy characterized by constitutional symptoms, bone marrow fibrosis, extramedullary hematopoiesis resulting in splenomegaly and a propensity toward leukemic progression. Given the central role of the JAK-STAT pathway in the pathobiology of myelofibrosis, JAK inhibitors are the mainstay of current pharmacologic management. Although these therapies have produced meaningful improvements in splenomegaly and symptom burden, JAK inhibitors do not significantly impact disease progression. In addition, many patients are ineligible because of disease-related cytopenias, which are exacerbated by JAK inhibitors. Therefore, there is a continued effort to identify targets outside the JAK-STAT pathway. In this review, we discuss novel therapies in development for myelofibrosis. We focus on the preclinical rationale, efficacy and safety data for non-JAK inhibitor therapies that have published or presented clinical data. Specifically, we discuss agents that target epigenetic modification (pelabresib, bomedemstat), apoptosis (navitoclax, navtemdalin), signaling pathways (parsaclisib), bone marrow fibrosis (AVID200, PRM-151), in addition to other targets including telomerase (imetelstat), selective inhibitor of nuclear transport (selinexor), CD123 (tagraxofusp) and erythroid maturation (luspatercept). We end by providing commentary on the ongoing and future therapeutic development in myelofibrosis.

Original languageEnglish (US)
Pages (from-to)645-658
Number of pages14
JournalInternational journal of hematology
Volume115
Issue number5
DOIs
StatePublished - May 2022
Externally publishedYes

Keywords

  • BCL-2/xL
  • BET
  • CD123
  • LSD1
  • MDM2
  • Myelofibrosis
  • PI3K
  • PRM-151
  • SINE
  • TGFb
  • Telomerase

ASJC Scopus subject areas

  • Hematology

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