Navigating the Growing Landscape of JAK Inhibitors in Myelofibrosis

Although treatment with ruxolitinib (Jakafi) was approved by the FDA in November 2011 for patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis, there remained a gap in care due to the agents’ association with treatment-related anemia and eventual patient progression, according to Ashwin Kishtagari, MD.¹

Recent advances and the FDA approvals of additional JAK inhibitors have helped address that gap, including fedratinib (Inrebic) in 2019, pacritinib (Vonjo) in 2022, and momelotinib (Ojjaara) in 2023.^2-4 However, with the advent of these new agents raises questions about sequencing and factors to inform treatment decisions for patients with myelofibrosis.

“Once a patient has [progressed] on or is intolerant to ruxolitinib, how are we going to manage these patients with myelofibrosis?” Kishtagari said in an interview with OncLive^® following the Vanderbilt Stem Cell Transplant and Cellular Therapy Symposium.

In the interview, Kishtagari discussed the treatment of patients with myelofibrosis following progression on ruxolitinib, highlighted the FDA approval of 3 additional JAK inhibitors that have been added to this treatment arena, and explained the unmet needs that still remain to be addressed within this patient population.

Kishtagari is an assistant professor of medicine in the Department of Hematology and Oncology at Vanderbilt University Medical Center, as well as a clinical research fellow in Bick Lab at Vanderbilt University School of Medicine in Nashville, Tennessee.

OncLive: How has the use of JAK inhibitors in the treatment of myelofibrosis evolved over the past decade?

Kishtagari: The management of myelofibrosis after ruxolitinib failure is an important topic that has been evolving over the past few years. Back in [2011], we had 1 JAK inhibitor approved: ruxolitinib. Over the past 5 years, we have had 3 other JAK inhibitors approved by the FDA for the management of myelofibrosis: [fedratinib, pacritinib, and momelotinib]. How we sequence these agents is an important question for the treatment of patients with myelofibrosis.

Considering JAK inhibitors target the same pathway, what does this mean in regard to sequencing these agents?

All of these agents inhibit JAK2; however, these agents differ in small ways. For example, pacritinib was approved by the FDA in 2022 for the treatment of myelofibrosis in patients with a platelet count less than 50 × 109/L. Pacritinib does not inhibit JAK1. [Due to] the JAK1 sparing effect, it does not cause any thrombocytopenia. In fact, it improves the platelet count.

Pacritinib was studied in the phase 3 PERSIST-2 trial [NCT02055781]. These patients tended to have a platelet count less than 100 x 109 in the clinical trial, and [those treated with pacritinib] experienced an improvement in platelet count. That [trial helped support] the FDA approval of [pacritinib]. Along with the clear improvement in platelet count, pacritinib is safe to use in patients who have thrombocytopenia at the time of diagnosis.

What are the distinguishing features of momelotinib compared with ruxolitinib?

The next agent is momelotinib, which was approved by the FDA in 2023. Anemia was a huge unmet need in management of myelofibrosis. The reason for that is ruxolitinib is a good agent in terms of improving symptoms and splenomegaly. However, the biggest challenge with ruxolitinib has been the development of anemia in patients [being treated with the agent]. We always dose reduce ruxolitinib to mitigate the anemia.

Still, there are a lot of patients who have persistent anemia despite being on the lowest dose of ruxolitinib. In the past, we didn't have a particular agent that we could offer patients, especially if they present with anemia at the time of diagnosis because we know that ruxolitinib is known to cause cytopenias. We were eagerly looking for an agent that could potentially help the patients with improvement in hemoglobin [levels] and, at the same time, control symptoms and splenomegaly. That is the setting where momelotinib was studied in the phase 3 MOMENTUM trial [NCT04173494], data for which were published in 2023.

[Previously], we did not have any FDA-approved agent to help with anemia in myelofibrosis. This is a perfect niche area where momelotinib was studied, and [MOMENTUM] showed that momelotinib improves hemoglobin vs danazol. Momelotinib is approved by the FDA for the treatment of patients with intermediate or high-risk myelofibrosis and anemia.

References

1. Jakafi. Prescribing information. Incyte. January 2023. Accessed May 20, 2024. https://www.jakafi.com/pdf/prescribing-information.pdf
2. FDA approves fedratinib for myelofibrosis. FDA. August 16, 2019. Accessed May 20, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fedratinib-myelofibrosis
3. FDA approves drug for adults with rare form of bone marrow disorder. FDA News release. March 1, 2022. Accessed May 20, 2024. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-adults-rare-form-bone-marrow-disorder
4. 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 May 20, 2024. 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