Recent Data from ASH 2023 in Leukemia

This is a synopsis of a Peer Exchange series featuring James K. McCloskey, MD, and Lori A. Leslie, MD, of John Theurer Cancer Center, Hackensack University Medical Center.

In this discussion on recent updates in the treatment of myelofibrosis, James K. McCloskey, MD, Chief of the Leukemia Division at the John Theurer Cancer Center, notes that while JAK inhibitors like ruxolitinib have offered symptom control and spleen volume reduction for myelofibrosis patients, substantial unmet needs remain regarding disease modification and survival improvement. However, data presented at the 2022 ASH Annual Meeting highlighted synergistic JAK inhibitor combinations that may finally offer disease modification.

Specifically, Dr. McCloskey discusses results from the double-blinded, placebo-controlled, phase 3 TRANSFORM-1 trial evaluating ruxolitinib plus navitoclax (a BCL-2 protein inhibitor) versus ruxolitinib plus placebo in JAK inhibitor-naïve patients with primary or secondary myelofibrosis. With a median 14 month follow-up of the 252 enrolled patients, the primary endpoint of ≥35% spleen volume reduction (SVR35) at week 24 occurred in 63% of the navitoclax arm versus 31% of placebo arm. Importantly, 77% of navitoclax patients achieved SVR35 at any timepoint compared to only 42% for placebo. Thus, the combination exhibited the most robust spleen responses observed to date.

Comparable results were seen in trials adding BET inhibitors like pelabresib to ruxolitinib, with twice the SVR35 rates versus ruxolitinib alone. However, neither the navitoclax or pelabresib trials showed clear improvements in symptom score reduction, contrasting the FDA’s traditional emphasis on patient-reported outcomes. As Dr. McCloskey notes, while symptom improvements remain critical in myelofibrosis management, the implications of symptom scores may need to be reweighted for combinatorial agents versus single agents.

In summary, these randomized trials finally demonstrate profound spleen responses from JAK inhibitor combinations, constituting a potential breakthrough for disease modification in myelofibrosis. Further analyses of clinical implications are still needed, especially regarding if enhanced spleen control translates into survival benefits. Additionally, refinements in managing adverse effects like cytopenias remain important for successful adoption into real-world clinical practice. Overall though, these combination strategies represent the most exciting advance for myelofibrosis treatment in years.

*Video synopsis is AI-generated and reviewed by OncLive editorial staff.