Dr DeAngelo on the Current Treatment Paradigm for Myelofibrosis

Daniel DeAngelo MD, PhD, professor, medicine, Harvard Medical School; physician, chief, Division of Leukemia, Dana-Farber Cancer Institute, discusses current treatment strategies for patients with myelofibrosis, highlighting how ongoing and recently presented studies have affected these treatment decisions.

The current standard of care for managing myelofibrosis is tailored based on risk assessment, DeAngelo begins. For patients identified as high risk or those exhibiting symptomatic disease, including symptomatic splenomegaly, the initiation of JAK inhibition is recommended, he explains. DeAngelo states that ruxolitinib (Jakafi) has historically been the primary treatment option for these patients, but 3 additional JAK inhibitors have recently gained FDA approval for patients with myelofibrosis. One of these, fedratinib (Inrebic), shares similarities with ruxolitinib; however, both medications are known to cause anemia as a common adverse effect, he reports.

Momelotinib (Ojjaara), approved by the FDA in 2023, is indicated for patients with primary or secondary myelofibrosis who experience anemia or require red blood cell transfusions, DeAngelo expands. Lastly, pacritinib (Vonjo) was FDAapproved in 2022 for patients with intermediate- or high-risk myelofibrosis and severe thrombocytopenia, defined as having a platelet count of less than 50,000 per microliter, he emphasizes.

Recent studies have contributed significantly to the development of ruxolitinib-containing regimens for myelofibrosis, according to DeAngelo. Two notable combination trials were recently presented, DeAngelo continues. The phase 3 TRANSFORM-1 study (NCT04472598) investigated the efficacy of combining ruxolitinib with navitoclax (previously ABT-263), a BCL-XL inhibitor, in a placebo-controlled setting, he says. The results demonstrated a statistically significant improvement in spleen volume reduction (SVR) with the addition of navitoclax vs ruxolitinib alone, although there was no corresponding change in the total symptom score (TSS).

Similarly, the phase 3 MANIFEST-2 study (NCT04603495) randomly assigned treatment-naive patients to receive pelabresib (CPI-0610), a BET inhibitor, combined with ruxolitinib or a placebo, DeAngelo reports. This study found that although the combination of pelabresib and ruxolitinib led to improved SVR vs pelabresib plus placebo, it did not result in significant enhancements in TSS, he adds. Overall, the findings from TRANSFORM-1 and MANIFEST-2 indicate that althoughthe addition of navitoclax or pelabresib to ruxolitinib may improve SVR, ruxolitinib remains a challenging benchmark to overcome regarding myelofibrosis symptom management, DeAngelo concludes.