The Janus kinase (JAK) inhibitor ruxolitinib plus the B-cell lymphoma 2 protein inhibitor navitoclax may be twice as effective at spleen volume reduction compared with standard-of-care ruxolitinib monotherapy in adult patients with intermediate- or high-risk myelofibrosis, according to new findings presented by Pemmaraju et al at the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition (Abstract 620).
Background
Historically, there have been few U.S. Food and Drug Administration–approved agents for the treatment of myelofibrosis—a rare type of bone marrow cancer.
Current treatment options may provide spleen volume reduction, often a major indicator of clinical improvement in this patient population, and symptom improvement; however, there is still a substantial unmet need for therapies that provide durable spleen reduction and other longer-term clinical benefits. Although allogenic stem cell transplants are an effective treatment option, not all patients qualify for this type of therapy.
Study Methods and Results
In the new, international phase III TRANSFORM-1 trial, researchers randomly assigned 252 patients with intermediate- or high-risk myelofibrosis and measurable spleen enlargement who had not previously received treatment with JAK inhibitors to receive a combination of ruxolitinib plus navitoclax (n = 125) or ruxolitinib plus placebo (n = 127).
After a follow-up of 24 weeks, the researchers found that 63.2% of the patients who received the combination therapy achieved a spleen volume reduction of at least 35% compared with 31.5% of those who received ruxolitinib plus placebo, meeting the trial’s primary endpoint.
Further, spleen volume reduction at any time was achieved by 77% of the patients in the combination therapy group and 42% of the patients in the placebo group. The median time to first spleen volume reduction response was 12.3 weeks and 12.4 weeks in the patients who received ruxolitinib plus navitoclax and those who received ruxolitinib plus placebo, respectively.
The researchers reported no statistically significant differences in myeloproliferative neoplasm symptom assessment between both groups at 24 weeks.
The patients who received the combination therapy experienced 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 the patients in the combination therapy group and 32% of those in the placebo group.
Conclusions
“By adding a second drug to an approved therapy, we were able to improve spleen volume reduction compared [with] the current standard of care. This is an important measurement of the clinical benefits of this novel drug combination because treatments can be less effective when the spleen remains enlarged. If we can treat myelofibrosis earlier on in the disease course, we may have an opportunity to impact overall disease modification, improve patient outcomes and reduce symptom burden,” underscored lead study author Naveen Pemmaraju, MD, Professor of Leukemia at The University of Texas MD Anderson Cancer Center. “This study marks a notable achievement in the field of myelofibrosis, as one of the first reported global phase III frontline randomized combination clinical trials in our field. This data set now opens the door for additional research and investigation into combination therapies to treat myelofibrosis and, importantly, highlights a potential new era of investigating disease modification for patients,” he concluded.
The researchers are currently evaluating additional data from the TRANSFORM-1 trial
Disclosure: The research in this study was funded by AbbVie. For full disclosures of the study authors, visit ash.confex.com.
