Meeting Coverage
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ASH: Hematology
— Combos with navitoclax or pelabresib led to more patients achieving reductions
by
Mike Bassett, Staff Writer, MedPage Today
December 12, 2023
SAN DIEGO — Combining the Janus kinase (JAK) inhibitor ruxolitinib (Jakafi) with either navitoclax or pelabresib led to more patients with myelofibrosis achieving reductions in spleen volume, two phase III studies showed.
In the TRANSFORM-1 trial, the combination of the BCL-XL/BCL-2 inhibitor navitoclax and ruxolitinib doubled the number of patients who achieved a 35% or greater reduction in spleen volume (SVR35) by week 24 (63.2% vs 31.5%, P<0.0001) compared with patients who were treated with ruxolitinib plus placebo, reported Naveen Pemmaraju, MD, of the University of Texas MD Anderson Cancer Center in Houston.
This difference in response was more pronounced over time, with 76.8% of patients achieving SVR35 at any time on study with the combination compared with 41.7% of patients in the control arm (P<0.0001), Pemmaraju said at the American Society of Hematology annual meeting.
These preliminary data are “encouraging,” and additional evaluations are continuing to assess other outcomes, including overall survival, as well as responses in subgroups, Pemmaraju said.
Results from the MANIFEST-2 study evaluating the bromodomain and extra-terminal (BET) inhibitor pelabresib plus ruxolitinib were similar to those of TRANSFORM-1, with 66% of patients treated with the combination achieving SVR35 at week 24 versus 35% of patients given ruxolitinib and placebo (P<0.001), reported Raajit Rampal, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City.
Patients treated with the combination experienced a reduction in pro-inflammatory cytokines, and improvement in bone marrow fibrosis and anemia response, “addressing the four hallmarks of myelofibrosis,” he said. “We believe these results support a potential paradigm shift in the treatment of patients with myelofibrosis.”
TRANSFORM-1
In explaining the rationale behind the trial, Pemmaraju noted that while JAK inhibitors have “revolutionized” the care of patients with myelofibrosis, they “by and large, have not led to a cure, and response rates — with the primary endpoint usually being spleen volume reduction at 35% at week 24 — of only 29% to 42% in monotherapy trials with JAK inhibitors.”
However, navitoclax in combination with ruxolitinib was shown to have pronounced antitumor activity in patients with myelofibrosis in the phase II REFINE trial.
In the international, randomized, double-blind, multicenter TRANSFORM-1 trial, Pemmaraju and colleagues further evaluated whether the combination could improve clinical outcomes in myelofibrosis patients.
The study included 252 JAK inhibitor-naive patients with intermediate-2- or high-risk myelofibrosis with measurable splenomegaly and evidence of myelofibrosis symptoms.
Median participant age was 69-70 years, and most were men. Most patients in both arms had intermediate-2-risk disease (83% in the combination arm and 87% in the placebo arm). Slightly less than half had high-molecular-risk mutations (48% and 43%, respectively).
