Advances in pharmacotherapy for myelofibrosis: what is the current state of play?

ABSTRACT

Introduction

The introduction of the first JAK inhibitor (JAKi) ruxolitinib 10 years ago represented a pivotal advancement in myelofibrosis (MF) treatment, mostly in terms of spleen and symptoms response. Nowadays three more JAKi, fedratinib, pacritinib, and momelotinib, are available for both ruxolitinib-resistant and naïve patients. Moreover, many drugs are currently being investigated, both alone and in combination with JAKi.

Areas covered

In this review we discuss the long-term data of ruxolitinib and more recent evidence coming from clinical trials of fedratinib, pacritinib, and momelotinib, used as first- or second-line MF therapy. More, focus is set on data from non-JAKi drugs, such as the quite extensively studied BET-inhibitors (pelabresib) and BCL-inhibitors (navitoclax), novel target therapies, and drugs aimed to improve anemia, still representing a major determinant of reduced survival in MF.

Expert opinion

It’s now evident that JAKi monotherapy, though clinically effective, is rarely able to change MF natural history; novel drugs are promising but long-term data are inevitably lacking. We feel that soon MF treatment will require clinicians to select the most appropriate JAKi inhibitor, based on patient characteristics, associating either front-line or in case of early suboptimal response, non-JAKi drugs with the aim to pursue disease modification.

KEYWORDS:

• Myelofibrosis
• JAK inhibitors
• combinational therapy
• pharamacotherapy
• anemia improvement

Article highlights

• More than 10 years after its first approval, ruxolitinib still represents the most commonly used JAK inihibitor (JAKi) in the treatment of patients with myelofibrosis (MF).

• An indirect comparison of all available trials suggests that efficacy of frontline ruxolitinib and fedratinib is similar in terms of spleen and symptom response, and slightly superior to that of pacritinib and momelotinib; the latter drugs may be preferentially used in thrombocytopenic and anemic patients, respectively.

• A prognostic model named RR6 is able to distinguish three groups of patients with distinct survival probabilities based on response after 6 months of treatment with ruxolitinib, thus guiding the optimal timing for treatment switch.

• Many novel agents have been investigated in combination with JAKi: besides increasing spleen and symptoms response, these agents seem able to exert biological disease-modifying effects, for example by reducing bone marrow fibrosis or the allelic burden of driver mutations.

• Drugs acting as activin receptor-ligand trap or ALK2 inhibitors are in development with the aim of improving anemia linked to ineffective erythropoiesis or induced by treatment with JAKi.

• In patients refractory or intolerant to multiple JAKi, promising results come from novel drugs like the telomerase inhibitor imetelstat, the LSD1 inhibitor bomedemstat and the MDM2 inhibitor navtemadlin.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.