Dr Rampal on ​Emerging Therapies Under Investigation in Myelofibrosis

"Among the more exciting [treatments] we have are immunotherapies. We have calreticulin-targeted antibodies. There are 2 in trials currently. Those have the potential to be game changers if they're effective."

Raajit Rampal, MD, director of the Center for Hematologic Malignancies and director of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center, discusses emerging treatments for patients with myelofibrosis.

The therapeutic paradigm for myelofibrosis continues to expand with emerging treatment options, particularly with combination therapies, novel JAK inhibitors, and immunotherapeutic agents, Rampal begins. Among these, pelabresib (CPI-0610), a BET inhibitor, has completed phase 3 trials. Preliminary data from the phase 3 MANIFEST-2 trial (NCT04603495), which were presented in December 2023, demonstrated improved spleen responses and a trend toward better symptom management with the combination of pelabresib and ruxolitinib (Jakafi) vs placebo plus ruxolitinib in patients with JAK inhibitor–naive myelofibrosis. Updated findings from MANIFEST-2 were published in Nature Medicine in March 2025. 

Beyond pelabresib, several other agents are currently in phase 3 trials for patients with myelofibrosis, Rampal says. Selinexor (Xpovio), which is currently FDA approved for the treatment of patients with relapsed/refractory multiple myeloma, is being studied in combination with ruxolitinib in patients with myelofibrosis in the phase 3 XPORT-MF-034 trial (NCT04562389). Additionally, navtemadlin (KRT-232), an MDM2 inhibitor, is undergoing clinical evaluation in patients with myelofibrosis. Notably, these trials are ongoing, and no conclusive data are available at this time, Rampal emphasizes.

The development of next-generation JAK inhibitors also represents a promising area of investigation, according to Rampal. These newer inhibitors are anticipated to demonstrate greater potency and selectivity compared with existing agents, though they remain in early-phase clinical trials, he notes.

Rampal states that one of the most exciting advancements in this setting is the emergence of immunotherapies. Calreticulin-targeted antibodies are currently being evaluated in clinical trials, and 2 candidates are in development, he reports. If these agents prove effective, they could significantly alter the treatment paradigm, he concludes.