The combination of the JAK inhibitor ruxolitinib with the BCL-xL inhibitor navitoclax was twice as effective in reducing spleen enlargement – a key indicator of clinical improvement – compared with standard ruxolitinib monotherapy for adult patients with intermediate- or high-risk myelofibrosis, a rare cancer of the bone marrow, according to results of the Phase III TRANSFORM-1 trial reported by researchers from the University of Texas MD Anderson Cancer Center.
Data from the global, randomized, placebo-controlled clinical trial were presented today at the American Society of Hematology (ASH) 2023 Annual Meeting by Naveen Pemmaraju, MD, professor of Leukemia. At the time of the data cut-off, 63.2% of patients receiving ruxolitinib and navitoclax achieved a reduction in spleen volume of at least 35% within 24 weeks, compared with 31.5% of patients receiving ruxolitinib plus placebo; which meets the primary endpoint of the study.
By adding a second drug to an approved treatment, we were able to improve spleen volume reduction compared to the current standard of care. This is an important measure of the clinical benefits of this new drug combination, because treatments may be less effective when the spleen remains enlarged. If we can treat myelofibrosis earlier in the disease course, we may have an opportunity to affect overall disease modification, improve patient outcomes, and reduce symptom burden.”
Naveen Pemmaraju, MD, Professor of Leukemia
Currently, there are few drugs approved by the Food and Drug Administration to treat myelofibrosis. Available options provide patients with splenic and symptomatic improvement, but there remains a substantial unmet need for therapies that provide durable reduction in spleen size and other long-term clin. Allogeneic stem cell transplants are an effective treatment option, but not all patients qualify.
This international trial involved 252 patients with intermediate- or high-risk myelofibrosis and measurable splenomegaly who had not received prior JAK inhibitor treatment. The trial randomized 125 patients to receive the combination of navitoclax and ruxolitinib and 127 patients to receive ruxolitinib plus placebo. Most patients were male (57%) and the median age was 69.
The trial met its primary endpoint of spleen volume reduction at 24 weeks. Spleen volume reduction at any time was achieved by 77% of patients in the combination arm and 42% of patients in the control arm. The median time to first spleen volume reduction response was 12.3 weeks with the combination and 12.4 weeks with monotherapy. At 24 weeks, there were no significant differences between the groups on a myeloproliferative neoplasm symptom score, a secondary endpoint of the study.
Patients treated with the combination therapy had side effects that were manageable and consistent with previous trials. The most common treatment-related adverse events were thrombocytopenia, anemia, diarrhea, and neutropenia. Serious adverse events were experienced by 26% of patients in the combination arm and 32% in the control arm.
“This study marks a remarkable achievement in the field of myelofibrosis, as one of the first global first-line Phase III randomized combination clinical trials reported in our field,” said Pemmaraju. “This data set now opens the door for additional research and exploration of combination therapies to treat myelofibrosis and, importantly, highlights a potential new era of disease-modifying investigation for patients. Additional data from the TRANSFORM-1 study are being evaluated.”
The trial was funded by AbbVie. Pemmaraju receives research support from AbbVie.
