Oncology

Myelofibrosis

Novel Therapies and Investigational Agents for Myelofibrosis

clinical topic updates by Stephen T. Oh, MD, PhD

Overview

Multiple novel therapies are under development for myelofibrosis and are also being evaluated in clinical trials. Notable investigational agents for myelofibrosis include luspatercept alone and in combination with ruxolitinib or momelotinib, as well as imetelstat, pelabresib, and navtemadlin alone and in combination with ruxolitinib.

“This is a very exciting time for novel treatment options for myelofibrosis, and a number of treatments are being evaluated in phase 3 studies. The field is moving very rapidly, and I am optimistic that we are going to have newer and better treatment options available in the near future.”

— Stephen T. Oh, MD, PhD

There is some evidence to support the activity of luspatercept in treating anemia in patients with myelofibrosis from the phase 2 ACE-536-MF-001 trial. Additional agents that are being explored as anemia-directed therapies include the anti-HJV antibody DISC-0974 and other agents that reduce hepcidin production. Whether these treatments could have an even greater benefit when used in combination with JAK inhibitors vs when used alone is something that we are beginning to learn. Luspatercept is now being evaluated in combination with JAK inhibitors in the phase 3 INDEPENDENCE trial and in combination with momelotinib, specifically, in the phase 2 ODYSSEY trial.

Another agent that is being investigated in myelofibrosis is imetelstat, a telomerase inhibitor. An early-phase study suggested that patients receiving a higher dosage of imetelstat may have extended survival, and, because of that, the primary end point of the ongoing phase 3 IMpactMF study is overall survival. This is very unusual for studies in the myelofibrosis field, where the focus is typically on reductions in spleen volume and total symptom score. So, we eagerly await the results of IMpactMF, but it will be some time before we have those results. In the meantime, the phase 1/1b IMproveMF study with imetelstat in combination with ruxolitinib is also ongoing. If it turns out that imetelstat can meaningfully extend survival, that would be a huge advancement for the field.

Pelabresib, a BET inhibitor, has been explored in early-phase studies as monotherapy and in combination with ruxolitinib. The ongoing phase 3 MANIFEST-2 study is examining pelabresib plus ruxolitinib vs ruxolitinib alone. The initial readout from the study was presented at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition in 2023. There was a significant improvement in spleen volume reduction in patients who received the combination, and a lesser degree of symptom improvement. Longer-term follow-up is ongoing to assess if these benefits are meaningful.

Navtemadlin is an MDM2 inhibitor has been in development for a while. There were interesting data presented at ASH 2024 with navtemadlin from the ongoing phase 3 BOREAS trial suggesting that navtemadlin may have some degree of disease-modifying activity. This was supported, in part, by a decrease in circulating peripheral blood CD34+ cell counts and a reduction in driver mutation burdens in some of the patients who were treated with navtemadlin. Another phase 3 study, POIESIS, is evaluating navtemadlin plus ruxolitinib and is currently ongoing.

This is a very exciting time for novel treatment options for myelofibrosis, and a number of treatments are being evaluated in phase 3 studies. The field is moving very rapidly, and I am optimistic that we are going to have newer and better treatment options available in the near future.

References

Bose P, Gerds AT, Gupta V, et al. ODYSSEY: a phase 2 open-label study of momelotinib in combination with luspatercept in patients with transfusion-dependent myelofibrosis. Blood. 2024;144(suppl 1):3191.2. doi:10.1182/blood-2024-205767

Gangat N, Foran JM, Halpern AB, et al. A phase 1b trial of DISC-0974, an anti-hemojuvelin antibody, in patients with myelofibrosis and anemia. Blood. 2023;142(suppl 1):4564. doi:10.1182/blood-2023-174922

Gerds AT, Harrison C, Kiladjian JJ, et al. Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis. Blood Adv. 2024;8(17):4511-4522. doi:10.1182/bloodadvances.2024012939

Kiladjian JJ, Harrison C, Mesa RA, et al. MPN-346 INDEPENDENCE: enrolling phase III trial to study the efficacy and safety of luspatercept versus placebo in patients with myelofibrosis on JAK2 inhibitor (JAK2i) therapy requiring red blood cell transfusions (RBCTs). Clinical Lymphoma Myeloma and Leukemia. 2023;23(suppl 1):S390. doi:10.1016/S2152-2650(23)01234-X

Mascarenhas J, Harrison CN, Kiladjian JJ, et al. Imetelstat in intermediate-2 or high-risk myelofibrosis refractory to JAK inhibitor: IMpactMF phase III study design. Future Oncol. 2022;18(22):2393-2402. doi:10.2217/fon-2022-0235

Mascarenhas J, Komrokji RS, Palandri F, et al. Randomized, single-blind, multicenter phase II study of two doses of imetelstat in relapsed or refractory myelofibrosis. J Clin Oncol. 2021;39(26):2881-2892. doi:10.1200/JCO.20.02864

Mascarenhas J, Kremyanskaya M, Patriarca A, et al. MANIFEST: pelabresib in combination with ruxolitinib for Janus kinase inhibitor treatment-naïve myelofibrosis. J Clin Oncol. 2023;41(32):4993-5004. doi:10.1200/JCO.22.01972

Mascarenhas JO, Bose P, Hou HA, et al. Disease-modifying activity of navtemadlin correlates with clinical responses in a randomized, multicenter, global phase 3 study (BOREAS) in JAK-inhibitor relapsed/refractory myelofibrosis. Blood. 2024;144(suppl 1):483. doi:10.1182/blood-2024-205937

Mascarenhas JO, Otoukesh S, Bradley T, et al. Trial update from IMproveMF, an ongoing, open-label, dose-escalation and -expansion, phase 1/1b trial to evaluate the safety, pharmacokinetics, and clinical activity of the novel combination of imetelstat with ruxolitinib in patients with intermediate-1, intermediate-2, or high-risk myelofibrosis (MF). Blood. 2024;144(suppl 1):998. doi:10.1182/blood-2024-203800

Rampal R, Grosicki S, Chraniuk D, et al. Updated safety and efficacy data from the phase 3 MANIFEST-2 study of pelabresib in combination with ruxolitinib for JAK inhibitor treatment-naïve patients with myelofibrosis. J Clin Oncol. 2024;42(suppl 16):6502. doi:10.1200/JCO.2024.42.16_suppl.6502

Rampal RK, Grosicki S, Chraniuk D, et al. Pelabresib in combination with ruxolitinib for Janus kinase inhibitor treatment-naïve patients with myelofibrosis: results of the MANIFEST-2 randomized, double-blind, phase 3 study. Blood. 2023;142(suppl 1):628. doi:10.1182/blood-2023-179141

Vachhani P, Rampal R, Bradley T, et al. POIESIS: a randomized, double-blind, placebo-controlled, multicenter, global phase 3 study of navtemadlin as add-on to ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis who have a suboptimal response to ruxolitinib. Blood. 2024;144(suppl 1):1808.2 doi:10.1182/blood-2024-200966

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Stephen T. Oh, MD, PhD

Associate Professor and Co-Chief
Division of Hematology
John T. Milliken Department of Medicine
Washington University School of Medicine
St. Louis, MO