Dr DeAngelo on the Evolving Role of JAK Inhibitors in the Management of Myelofibrosis

Daniel DeAngelo, MD, PhD, professor of medicine, Harvard Medical School, chief, Division of Leukemia, institute physician, Dana-Farber Cancer Institute, discusses the evolving role of JAK inhibitors in the management of myelofibrosis and highlights remaining unmet needs for this patient population.

For patients with higher-risk myelofibrosis or those experiencing symptomatic splenomegaly, JAK inhibition is the current standard of care, DeAngelo explains. Ruxolitinib (Jakafi), the first JAK inhibitor approved, remains a foundational therapy, yet it is associated with notable adverse effects, particularly anemia. Fedratinib (Inrebic), another JAK inhibitor similar to ruxolitinib, also leads to anemia and may therefore have limited tolerability in certain patients, he notes.

More recent approvals have provided additional options for specific subpopulations. Momelotinib (Ojjaara), which is approved for patients with myelofibrosis with anemia or transfusion dependence, addresses an unmet need by potentially reducing anemia-related complications. Pacritinib (Vonjo), which is approved for patients with severe thrombocytopenia (platelet counts below 50,000/µL), provides an alternative for those at risk for bleeding complications who may not be able to tolerate other JAK inhibitors.

Despite these advances, unmet needs persist, particularly for patients who exhibit suboptimal responses in terms of spleen size reduction or have persistent disease-related symptoms. As such, several efforts have been made to improve outcomes through combination therapies.

In the phase 3 TRANSFORM-1 study (NCT04472598) ruxolitinib was combined with navitoclax (ABT-263), a BCL-XL inhibitor, and compared with placebo plus ruxolitinib alone. The combination showed statistically significant improvements in spleen reduction compared with ruxolitinib alone. However, no significant improvement was observed in symptom scores.

DeAngelo concludes that although JAK inhibitors play a central role in alleviating symptoms and managing splenomegaly in the current treatment paradigm for myelofibrosis, there are limits to how much they can achieve in symptom control alone. As such, ongoing research is focused on enhancing treatment efficacy through combination regimens and exploring new therapeutic targets.