The pharmacotherapeutic management of patients with myelofibrosis: looking beyond JAK inhibitors

ABSTRACT

Introduction

The approach to myelofibrosis (MF) has been revolutionized in recent years, overcoming the traditional therapies, often not very effective. Janus kinase inhibitors (JAKi – from ruxolitinib up to momelotinib) were the first class of drugs with considerable results.

Areas covered

Ongoing, new molecules are being tested that promise to give hope even to those patients not eligible for bone marrow transplants who become intolerant or are refractory to JAKi, for which therapeutic hopes are currently limited. Telomerase, murine double minute 2 (MDM2), phosphatidylinositol 3-kinase δ (PI3Kδ), BCL-2/xL, and bromodomain and extra-terminal motif (BET) inhibitors are the drugs with promising results in clinical trials and close to closure with consequent placing on the market, finally allowing JAK to look beyond. The novelty of the MF field was searched in the PubMed database, and the recently completed/ongoing trials are extrapolated from the ClinicalTrial website.

Expert opinion

From this point of view, the use of new molecules widely described in this review, probably in association with JAKi, will represent the future treatment of choice in MF, leaving, in any case, the potential new approaches actually in an early stage of development, such as the use of immunotherapy in targeting CALR, which is coming soon.

KEYWORDS:

• Myeloproliferative neoplasms
• myelofibrosis
• Beyond JAKi
• new treatments
• clinical trials

Article highlights

• The treatment for MF is continuously improved, revolutionizing the therapeutic approach

• JAK inhibitors (ruxolitinib, pacritinib, fedratinib, and momelotinib) are currently the central drugs in the treatment of symptomatic MF

• New molecules are being tested for patients who become intolerant or are refractory to JAKi

• The combination approach (JAKi plus another molecule with a different mechanism of action) could be the preferred choice in the future

• A very close turning point will be represented by immunotherapy directed against the mutated calreticulin (CALR) gene

Declaration of interest

A Duminuco reports personal fees from BMS, Incyte, and Eusa Pharma outside the submitted work. G Vetro reports personal fees from Abbvie, BMS, and Jazz outside the submitted work. C Giallongo declares no conflict of interest. G A Palumbo reports personal fees from Abbvie, AOP, Astra Zeneca, BMS, GSK, Incyte, Janssen, MorphoSys, and Novartis outside the submitted work. 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, Kartos, Telios, Morphosys, Ionis, Disc, Cogent, Blueprint, Sumitomo, Geron and Janssen, and honoraria/consulting fees from Incyte, BMS, GSK, CTI, Morphosys, Blueprint, Cogent, Novartis, Abbvie, Pharma Essentia, Karyopharm and Jubilant. Peer reviewers in this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.