Recent advances in JAK2 inhibition for the treatment of myelofibrosis

ABSTRACT

Introduction

Myelofibrosis (MF) is a BCR-ABL-negative myeloproliferative neoplasm characterized by splenomegaly, constitutional symptoms, cytopenias, a potential for leukemic transformation, and increased mortality. Patients who are ineligible for stem cell transplant rely on pharmacologic therapies of noncurative intent, whose cornerstone consists of JAK inhibitors (JAKi). While current JAKi are efficacious in controlling symptoms and splenic volume, none meaningfully reduce clonal burden nor halt disease progression, and patients oftentimes develop JAKi intolerant, relapsed, or refractory MF. As such, there remains an urgent necessity for second-line options and novel therapies with disease-modifying properties.

Areas Covered

In this review, we delineate the mechanistic rationale, along with the latest safety and efficacy data, of investigational JAKi-based MF treatment strategies, with a focus on JAKi monotherapies and combinations of novel agents with approved JAKi. Our literature search consisted of extensive review of PubMed and clinicaltrials.gov.

Expert Opinion

A myriad of promising MF-directed therapies are in late-phase studies. Following their approval, treatment selection should be tailored to patient-specific treatment goals and disease characteristics, with an emphasis on combination therapies of JAKi with novel agents of differing mechanistic targets that possess anti-clonal properties, in attempt to alter disease course and concurrently limit dose-dependent JAKi toxicities.

KEYWORDS:

• JAK inhibitors
• myelofibrosis
• myeloproliferative neoplasm
• MPN
• MF

Article highlights

• Abnormal JAK-STAT activity represents the root of myelofibrosis (MF) pathogenesis, and underlies the rationale for JAK inhibition in this setting

• Four JAK inhibitors (JAKi) – including ruxolitinib, fedratinib, and the less myelosuppressive pacritinib and momelotinib – are approved by the United States Food and Drug Administration for use in MF, and are effective at reducing symptom burden and splenic volume

• There is an urgent unmet need for MF-directed therapies with disease-modifying and life prolonging properties

• A vast number of early and late phase studies exploring investigational JAKi monotherapies and combinations of novel agents with approved JAKi demonstrate promising preliminary outcomes

Declaration of interest

M Kremyanskaya declares: Consulting for Protagonist Therapeutics, Constellation/Morphosys, Incyte, Abbvie, Silence Therapeutics, Agios.

The authors have no other relevant affiliations 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 manuscript has disclosed that they have received research support from Incyte, BMS, CTI (now Sobi), Morphosys, Kartos, Telios, Disc, Ionis, Geron, Janssen, Sumitomo, Karyopharm, Blueprint, Cogent. They have also received honoraria/consulting fees from Incyte, BMS, CTI (now Sobi), GSK, Abbvie, Morphosys, Ionis, Disc, Geron, Karyopharm, Sumitomo, Pharma Essentia, Morphic, Jubilant, Novartis, Blueprint and Cogent. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.