Increased Understanding of the Mechanisms of Myelofibrosis Helps Usher in New Treatments and Novel Agents

Research providing a growing understanding of the molecular mechanisms of myelofibrosis has helped facilitate the development of new treatments for this patient population, and novel agents are poised to continue emerging in this space, according to Gaby Hobbs, MD.

In February 2022, the FDA approved pacritinib (Vonjo) for the treatment of patients with intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 10⁹/L.¹ Additionally, the regulatory agency approved momelotinib (Ojjaara) for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis, and anemia in September 2023.² Both agents inhibit ACVR1, and their approvals are examples of how the growing understanding of the biology of myelofibrosis is informing drug development.

“We have a better understanding of several mechanisms that are involved in the development and the pathophysiology of myelofibrosis,” Hobbs said in an interview with OncLive^® following a State of the Science Summit™ (SOSS) on hematology, which she chaired.

In the interview, Hobbs discussed how further research into the biology of myelofibrosis has propelled the development of novel therapies for this patient population, expanded on ongoing and upcoming investigations of various agents, and highlighted the role that biomarkers play in the diagnosis, prognosis, and treatment response evaluation for these patients. Hobbs is a hematology-oncology physician, the clinical director of Leukemia Service, and an assistant in medicine at the Massachusetts General Hospital in Boston.

OncLive: Your presentations at the SOSS centered around the evolving treatment landscape of myelofibrosis and current standards of care. What were the key points you aimed to highlight during these discussions?

Hobbs: There have been a lot of changes in the therapies available for [patients with myelofibrosis] over the last couple of years. The first presentation focused on providing a brief overview of the current standard of care and new therapies that are available for [treating patients with] myelofibrosis.

The second talk [focused] an area where there's still a lot of unmet need, which is anemia, [and I wanted to] give the audience an idea or approach on how to manage anemia for these patients, especially [after] the approval momelotinib.

What is the current understanding of the molecular mechanisms of myelofibrosis? How has this influenced the development of personalized treatment strategies for this patient population?

[The increased understanding of the mechanisms of myelofibrosis] has helped with some of the new drug approvals, including pacritinib and momelotinib. We were [previously] focused mostly on the JAK/STAT signaling pathway; now we appreciate that there are other signaling pathways that may also be involved in the pathophysiology of this disease.

For example, momelotinib and pacritinib also inhibit the ACVR1 pathway, which leads to an improvement in anemia. That's a very clear way in which we've had improvement in therapies based on better understanding of the biology of [myelofibrosis].

Beyond momelotinib and pacritinib, are there any other agents currently under investigation in myelofibrosis that are intriguing?

There are many different agents that are currently being studied. The one that is most likely closest to being available to patients is luspatercept-aamt [Reblozyl], as that is already approved for patients with myelodysplastic syndrome, and that specifically will help patients with anemia. With regards to other novel therapeutics, there are many agents that are currently under development, including drugs like the telomerase inhibitor imetelstat, the BCL-2/BCL-XL inhibitor navitoclax, the BET inhibitor pelabresib [CPI-0610], the MDM2 inhibitor navtemadlin [formerly KRT-232], and the XPO1 inhibitor selinexor [Xpovio].

There are many agents under development now that [could] change the field of myelofibrosis from just having single-agent JAK inhibitors to having combination therapies that could hopefully help our patients live with less symptoms and also live longer.

What role do biomarkers play in the diagnosis, prognosis, and treatment response evaluation for patients with myelofibrosis?

When you say biomarkers in myelofibrosis, we rely significantly on genetic mutations and a variety of different risk scores to prognosticate for our patients. We know that patients with JAK2 mutations have different outcomes than those with CALR mutations. More specifically, we know that having additional mutations outside of JAK/STAT mutations also contribute to a negative prognosis, and those include mutations such as ASXL1, IDH, SRSF2, and EZH1. Those genetic mutations help us to understand prognosis with these patients, when taken into conjunction with other clinical variables that are included in [risk] scores.

References

1. CTI BioPharma announces FDA accelerated approval of VONJO™ (pacritinib) for the treatment of adult patients with myelofibrosis and thrombocytopenia. CTI BioPharma Corp. News release. February 28, 2022. Accessed November 8, 2023. https://www.prnewswire.com/news-releases/cti-biopharma-announces-fda-accelerated-approval-of-vonjo-pacritinib-for-the-treatment-of-adult-patients-with-myelofibrosis-and-thrombocytopenia
2. Ojaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia. News release. GlaxoSmithKline. September 15, 2023. Accessed November 8, 2023. https://www.gsk.com/en-gb/media/press-releases/ojjaara-momelotinib-approved-in-the-us-as-the-first-and-only-treatment-indicated-for-myelofibrosis-patients-with-anaemia