Dr Gangat on the Evolution of JAK Inhibitors in Myelofibrosis

Naseema Gangat, MBBS, hematologist/oncologist, education chair and program director, Division of Hematology, Department of Medicine, Mayo Clinic Rochester, discusses the evolution of JAK inhibitors within the treatment landscape for patients with myelofibrosis.

Notably, the identification of the JAK2 mutation in 2005 catalyzed intensive efforts toward developing inhibitors targeting the JAK/STAT pathway, Gangat begins. Ruxolitinib (Jakafi) emerged as the pioneering medication in this domain, becoming the first JAK inhibitor approved in this space in 2011. Subsequent years led to the introduction of three additional JAK inhibitors: fedratinib (Inrebic) in 2019, pacritinib (Vonjo) in 2022, and momelotinib (Ojjaara) in 2023.

Aiming to build on the efficacy displayed by these JAK inhibitors as single-agent treatment, numerous ongoing clinical trials are investigating the activity and safety of combining JAK inhibitors with other agents with different mechanisms of action, Gangat explains. One noteworthy endeavor includes assessing the combination of ruxolitinib with the BCL-xL inhibitor navitoclax in the phase 3 TRANSFORM-1 trial (NCT04472598), where the combination elicited an improvement in spleen volume reduction of 35% or more (SVR35) compared with ruxolitinib plus placebo. Additionally, the phase 3 MANIFEST-2 trial (NCT04603495) is evaluating pelabresib (CPI-0610) in combination with ruxolitinib vs ruxolitinib plus placebo, and data from this study also demonstrated an improvement in SVR35 with the combination vs the placebo regimen.

Although these novel combinations show promise in enhancing spleen response, their potential disease-modifying activity and impact on survival remain under scrutiny, Gangat explains. Additionally, concerns regarding heightened toxicity with the combination regimens underscore the necessity for continued evaluation.

The current landscape of treatment for patients with myelofibrosis delineates 3 primary domains: single-agent utilization of approved JAK inhibitors, ongoing exploration of combination therapies in clinical trials, and investigation into agents with novel mechanisms of action, she continues Notable among the latter are interventions targeting anemia, including luspatercept-aamt (Reblozyl) and therapies such as the anti-hemoglobin antibodies and ALK inhibitors.

Collectively, these advancements signify a critical juncture in myelofibrosis therapeutics, marked by a burgeoning array of treatment modalities, Gangat explains. However, the translation of experimental combinations into tangible clinical benefits, particularly in terms of disease modification and survival enhancement, necessitates continued scrutiny and rigorous evaluation, she adds.

Gangat concludes that the multifaceted landscape of treatment for patients with myelofibrosis underscores the imperative for tailored therapeutic strategies informed by evolving evidence and patient-specific considerations.