Navitoclax with Ruxolitinib Greatly Improves Spleen Response Versus Placebo in Myelofibrosis

Janus kinase (JAK) inhibitor–naïve patients with myelofibrosis (MF) treated with ruxolitinib, a JAK inhibitor, and navitoclax, an oral inhibitor of multiple antiapoptotic B-cell lymphoma 2 proteins, achieved spleen volume reduction of ≥35% at week 24 (SVR­_35W24), at a rate twice as high as patients treated with ruxolitinib and placebo, according to authors of the ongoing phase III TRANSFORM-1 study.

The study, led by Naveen Pemmaraju, MD, of the University of Texas MD Anderson Cancer Center in Houston, evaluated the doublet therapy to address “a substantial unmet need for therapies that alter disease trajectory, improve outcomes, and enhance survival” in patients with MF. Findings were presented at the 65th American Society of Hematology Annual Meeting & Exposition in San Diego, California.

Researchers enrolled 252 patients with intermediate-2 or high-risk MF with measurable splenomegaly, signs of MF-related symptoms, no prior JAK2 inhibitor therapy, and an Eastern Cooperative Oncology Group performance score of 2 or less. The cohort was 57% male with a median age of 69 (range, 37-87).

The primary outcome was SVR­_35W24, and secondary outcomes included change in Myelofibrosis Symptom Assessment Form total symptom score (TSS) at week 24, SVR­₃₅ at any time, SVR­₃₅ response duration, anemia response, reduction in marrow fibrosis, overall survival, leukemia-free survival, reduction in fatigue, and improvement in physical functioning at the data cutoff of April 13, 2023.

Investigators noted that the primary endpoint was met, as 79 of 125 (63.2%) patients in the navitoclax group achieved SVR­_35W24 versus 40 of 127 (31.5%) in the placebo group (P<.0001). Additionally, 96 (77%) patients on navitoclax achieved SVR­₃₅ at any time compared with 53 (42%) patients on placebo.

The median time to SVR response was 12.3 weeks (range, 10.1-48.3) in the navitoclax group versus 12.4 weeks (range, 11.3-72.3) in the placebo group, and the median duration of SVR response was not reached (NR) in the navitoclax group versus 19.4 months (95% CI, 16.8 to NR) in the placebo group. Furthermore, patients in the navitoclax group had a mean change from baseline in TSS of –9.7 (95% CI, –11.8 to –7.6) at week 24, whereas patients in the placebo group had a mean change of –11.1 (95% CI, –13.2 to –9.1; P=.2852).

Adverse events (AEs) of grade 3 or higher occurred in 85% and 70% of navitoclax and placebo patients, respectively. The most common AEs in the navitoclax group were thrombocytopenia, anemia, diarrhea, and neutropenia. Overall, 39% of navitoclax or placebo discontinuations were due to AEs, and 17% were due to a physician’s decision.

Ultimately, “The responses were durable; AEs of thrombocytopenia and anemia were common but manageable with dose modification without any clinically significant sequalae. Additional evaluation is ongoing,” the authors summarized.

Reference

Pemmaraju N, Mead AJ, Somervaille TCP, et al. A randomized, double-blind, placebo-controlled, multicenter, international phase 3 study of navitoclax in combination with ruxolitinib versus ruxolitinib plus placebo in patients with untreated myelofibrosis. Abstract #620. Presented at the 65th American Society of Hematology Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.