By Patrick Daly
December 6, 2023
Ruxolitinib combined with navitoclax induced spleen volume reduction of ≥35% at week 24 (SVR35W24) at a rate twice as high as with ruxolitinib and placebo in Janus kinase (JAK) inhibitor–naïve patients with primary, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis (MF), according to authors of the ongoing phase III TRANSFORM-1 study.
The study, 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, according to lead author, Naveen Pemmaraju, MD, of the University of Texas MD Anderson Cancer Center in Houston. Findings were presented at the 65th American Society of Hematology Annual Meeting & Exposition in San Diego, California.
The cohort included 252 patients with a median age of 69 (range, 37–87) and intermediate-2 or high-risk MF with splenomegaly, signs of MF-related symptoms, no prior JAK2 inhibitor therapy, and an Eastern Cooperative Oncology Group performance score of 2 or less.
The primary outcome was SVR35W24, 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 79 of 125 (63.2%) patients in the navitoclax group achieved SVR35W24 compared with 40 of 127 (31.5%) in the placebo group (P<0.0001). Furthermore, 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. 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=0.2852).
Adverse events (AEs) of grade 3 or higher occurred in 85% and 70% of navitoclax and placebo patients, respectively. The most common AEs in greater than 30% of patients on navitoclax were thrombocytopenia, anemia, diarrhea, and neutropenia.
Serious AEs occurred in 26% of patients in the navitoclax and 32% of patients in the placebo group, including anemia in two and one patients, respectively, as well as thrombocytopenia and neutropenia in two and one navitoclax patients. Overall, 39% of navitoclax or placebo discontinuations were due to AEs, and 17% were due to a physician’s decision.
Overall, “the responses were durable; AEs of thrombocytopenia and anemia were common but manageable with dose modification without any clinically significant sequalae,” 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.