Each year at the American Society of Hematology (ASH) annual meeting and exhibition, myeloproliferative neoplasms (MPNs) presentations are more visible than the year before. Among them was the long-awaited phase 3 outcomes of the Transform-1 study for myelofibrosis (MF).
What is Transform-1?
This was the first international, multi-center, randomized study that investigated a combination therapy of the novel drug navitoclax with ruxolitinib, an approved JAK inhibitor, in patients who had never taken a JAK inhibitor. The study showed that twice as many patients who received navitoclax plus ruxolitinib versus those who received ruxolitinib plus a placebo had a significant reduction in spleen size (35% or greater) at the end of 24 weeks.
Navitoclax is a BCL-XL inhibitor, which works differently than the JAK inhibitor ruxolitinib, currently the standard therapy for MF treatment. Navitoclax works by blocking a specific protein that helps enable cancer cells to thrive.
Who Participated in the Study?
A total of 252 patients were enrolled in the trial, including people whose disease fell into the intermediate-2 and high-risk MF categories with measurable splenomegaly (enlarged spleen) and evidence of other MF-related symptoms.
Splenomegaly is a key disease feature of MF and can cause serious complications. It is often used as a measurement tool in clinical trials and practice, as it appears to correlate with overall survival.
What Were the Results?
“We set off to improve clinical outcomes for patients by looking at a different pathway,” said the study’s lead investigator, Naveen Pemmaraju, MD, professor of leukemia at the MD Anderson Cancer Center in Houston.
The treatment reduced spleen volume by at least 35% in the majority of patients, and that reduction continued after a median follow-up of nearly 15 months. In some cases, adverse effects were experienced, most specifically thrombocytopenia (low platelet count) and anemia (low red blood cell count), which Dr. Pemmaraju described as “common but manageable” with dose modifications. A total of 83 patients (33%) discontinued the study treatment, with the most common reason being adverse events.
This study is one of two phase 3 clinical trials reported at ASH that offered novel targeted agent combination therapies for previously untreated MF patients. The other study, called MANIFEST-2, combined pelabresib, a novel BET-inhibitor, with ruxolitinib, similarly combining two drugs with different pathways to reduce MF symptoms with the potential for disease modification.
“These results show the feasibility and tolerability of a frontline approach with this promising two-drug combination (navitoclax + ruxolitinib) and potentially opening a new era of combination therapy to modify the course of this disease,” said Dr. Pemmaraju.
What Are the Next Steps?
Statistically, the two-drug combo performed better than ruxolitinib paired with a placebo when considering spleen reduction at just under 15 weeks. However, the addition of the second drug did not improve overall symptom reduction at 24 weeks. “We will continue to monitor this and other key secondary endpoints over time,” Dr. Pemmaraju added. This would include data related to duration of spleen response, reduction of other MF-related symptoms, progression-free and overall survival.
“This is a promising new treatment for patients with intermediate-2 or higher myelofibrosis,” according to Ellen Ritchie, MD, an MPN specialist at Weill Cornell Medicine in New York. “The trial is ongoing and I look forward to more mature results.”
For further perspective she added: “There are many new drugs that are in clinical trial to treat myelofibrosis, and this is very exciting for a field that once had few options. Many of the new treatment options are reaching endpoints of spleen volume reduction and improvement in symptom scores. Many also are showing the ability to decrease the VAF (variant allele frequency) of important mutations such as JAK2.”
Other important endpoints are being evaluated in some but not all trials, including transfusion dependence. “Disease modification as demonstrated by bone marrow biopsy are also not available for some of these drugs,” Dr. Ritchie added. “We need to wait for the data to mature in order to determine the real impact of these new drugs on the natural history and treatment of myelofibrosis.”
An earlier phase 2 trial, reported in 2022, studied the addition of navitoclax to ruxolitinib therapy in MF patients who didn’t receive an optimal response to ruxolitinib alone or who experienced disease progression while on the single-drug therapy.