Dr Hunter on the Development of Targeted Approaches Beyond JAK Inhibition in Myelofibrosis

“We’re already excited that we’ve got four JAK inhibitors to pick from, but now [we’re] moving beyond that pathway. [This] is great for trying to improve outcomes, [because] we know that JAK inhibitors do have their limitations. The 2 that have had the most press recently are pelabresib and navitoclax.”

Anthony M. Hunter, MD, assistant professor, Department of Hematology and Medical Oncology, Emory University School of Medicine, medical director, Immediate Care Center, Winship Cancer Institute of Emory University, shares his insights on the ongoing development of, and potential future roles for, JAK, BET, and BCL2/BCL-XL inhibitors in myelofibrosis.

Hunter begins by stating that 4 JAK inhibitors have been approved by the FDA for the treatment of patients with myelofibrosis: ruxolitinib (Jakafi), fedratinib (Inrebic), pacritinib (Vonjo), and momelotinib (Ojjaara). However, ongoing research aims to address the limitations associated with this drug class and improve patient outcomes, he notes.

Two inhibitors on the rise for myelofibrosis include the BET inhibitor pelabresib (CPI-0610), and the BCL2 and BCL-XL inhibitor navitoclax (ABT-263), Hunter details. He adds that both pelabresib and navitoclax have been explored in combination with ruxolitinib in prior phase 3 trials, including the MANIFEST-2 (NCT04603495) and TRANSFORM-1 (NCT04472598) studies, respectively.

At the 2024 ASCO Annual Meeting, updated data from the MANIFEST-2 trial were presented, demonstrating a 35% or greater reduction in spleen volume at week 24 (SVR35W24) in 65.9% of patients treated with frontline pelabresib plus ruxolitinib (n = 214) vs 35.2% in those treated with ruxolitinib plus placebo (n = 216).

Similarly, data from the phase 3 TRANSFORM-1 trial have shown that the navitoclax plus ruxolitinib produced significant reductions in spleen volume. At a median follow-up of 14.9 months (range, 0-29.5), 63.2% of patients treated with navitoclax/ruxolitinib had a SVR35W24 compared with 31.5% of those treated with ruxolitinib plus placebo.

The MANIFEST-2 and TRANSFORM-1 trials both met their primary end points of SVR35W24, Hunter explains. Still, significant improvements regarding symptomatology were not established in these trials; therefore, more data and long-term follow-up are needed for both pelabresib and navitoclax, he concludes.