Emerging drugs for the treatment of myelofibrosis: phase II & III clinical trials

ABSTRACT

Introduction

Myelofibrosis is a clonal hematologic malignancy with clinical manifestations that include cytopenias, debilitating constitutional symptoms, splenomegaly, bone marrow fibrosis and a propensity toward leukemic progression. While allogeneic hematopoietic stem cell transplantation can be curative, this therapy is not available for the majority of patients. Ruxolitinib and fedratinib are approved JAK2 inhibitors that have produced meaningful benefits in terms of spleen reduction and symptom improvement, but there remain several unmet needs.

Areas covered

We discuss novel therapies based upon published data from phase II or III clinical trials. Specifically, we cover novel JAK inhibitors (momelotinib and pacritinib), and agents that target bromodomain and extra-terminal domain (pelabresib), the antiapoptotic proteins BCL-2/BCL-xL (navitoclax), MDM2 (navtemadlin), phosphatidylinositol 3-kinase (parsaclisib), or telomerase (imetelstat).

Expert opinion

Patients with disease related cytopenias are ineligible for currently approved JAK2 inhibitors. However, momelotinib and pacritinib may be able to fill this void. Novel therapies are being evaluated in the upfront setting to improve the depth and duration of responses with ruxolitinib. Future evaluation of agents must be judged on their potential to modify disease progression, which current JAK2 inhibitors lack. Combination therapy, possibly with an immunotherapeutic agent might serve as key components of future myelofibrosis treatment options.

KEYWORDS:

• Myelofibrosis
• momelotinib
• pacritinib
• pelabresib
• navitoclax
• navtemadlin
• parsaclisib
• imetelstat
• luspatercept

Funding

This paper was not funded.

Declaration of interest

D Tremblay has received clinical trial funding, paid to his institution, from Astellas Pharma. R Hoffman serves on the Data and Safety Monitoring Board for AbbVie and Novartis. The authors have no other relevant affiliation or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this paper has disclosed that they received research support from Incyte, Bristol-Myers Squibb, CTI Biopharma, Blueprint Medicines, Kartos Therapeutics, Constellation Pharmaceuticals, Astellas, Pfizer, NS Pharma and Promedior; and that they have received honoraria from Incyte, Bristol-Myers Squibb, CTI Biopharma, Blueprint Medicines, Kartos Therapeutics, Novartis, Karyopharm, Sierra Oncology and Pharma Essentia. No other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.