STOCKHOLM—The PI3K delta inhibitor umbralisib can “augment or resurrect” responses to ruxolitinib in patients with myelofibrosis (MF), according to a speaker at the 23rd Congress of the European Hematology Association (EHA).
Results of a phase 1 study showed that adding umbralisib to treatment with ruxolitinib could induce responses in MF patients who had a suboptimal or lost response to ruxolitinib.
Of the 23 patients who received the combination, 2 achieved a complete remission (CR), 11 had clinical improvement, and 8 had stable disease.
In addition, umbralisib plus ruxolitinib was considered well-tolerated. The most common adverse event (AE) was anemia.
Tamara K. Moyo, MD, PhD, of Vanderbilt University Medical Center in Nashville, Tennessee, presented these results at the EHA Congress as abstract S133. The research was sponsored by TG Therapeutics.
Dr Moyo reported results in 23 MF patients who had a suboptimal response, lost a response, or had no response while on a stable dose of ruxolitinib for at least 8 weeks. Their median age was 67 (range, 49-83), and 61% were male.
Patients had primary MF (30%), post-essential thrombocythemia (ET) MF (43%), or post-polycythemia vera (PV) MF (26%). Forty-three percent of patients had JAK2 V617F, 30% had CALR mutations, 17% had MPL mutations, and 13% were triple-negative. One patient had co-occurring CALR and MPL mutations.
Most patients had an ECOG performance score of 0 (39%) or 1 (52%). All had intermediate-1 (35%), intermediate-2 (35%), or high-risk disease (30%) according to DIPSS Plus.
Sixty-one percent of patients had splenomegaly.
In stage 1, the patients received stable ruxolitinib and escalating umbralisib. In stage 2, patients received escalating ruxolitinib and umbralisib at the maximum tolerated dose (MTD) established from stage 1.
Patients could then proceed to expansion cohorts in which they would receive any dose of ruxolitinib and umbralisib at the MTD. The expansion cohorts include patients with treatment-naïve MF, PV, chronic myelomonocytic leukemia, and myelodysplastic syndromes/myeloproliferative neoplasms.
However, Dr Moyo reported only on the 23 ruxolitinib-experienced MF patients.
There were 2 dose-limiting toxicities of asymptomatic, grade 3 amylase/lipase elevations. One occurred in a patient receiving 800 mg of umbralisib daily and 10 mg of ruxolitinib twice daily. The other occurred in a patient receiving 800 mg of umbralisib daily and 15 mg of ruxolitinib twice daily.
Therefore, 600 mg daily was deemed the MTD of umbralisib.
Seventeen patients had at least 1 AE. There were 17 grade 3 or higher AEs in 13 patients.
AEs of any grade included anemia (n=10), neutrophil decrease (n=2), platelet decrease (n=5), AST increase (n=6), ALT increase (n=3), amylase increase (n=3), lipase increase (n=3), diarrhea (n=2), colitis (n=1), dyspnea (n=1), upper respiratory infection (n=2), pneumonia (n=4), other infections (n=6), and sepsis (n=1).
Grade 3 AEs included anemia (n=3), neutrophil decrease (n=2), amylase increase (n=2), lipase increase (n=2), diarrhea (n=2), colitis (n=1), dyspnea (n=1), pneumonia (n=1), and other infections (n=2). The case of sepsis was the only grade 4 AE.
Dr Moyo noted that anemia—the most common AE—was commonly attributed to disease rather than study treatment.
The case of colitis, which was grade 3, was deemed possibly related to treatment, so the patient was removed from the study.
Thirteen patients had discontinued study treatment at the time of analysis. Aside from the patient who discontinued due to colitis, 2 patients went off study due to dose-limiting toxicities, 3 due to progressive disease, 6 due to physician or patient decision, and 1 due to transplant.
Two patients could not be assessed for efficacy, and 8 had stable disease on umbralisib and ruxolitinib.
The combination produced clinical improvement—reduction in spleen volume, increase in hemoglobin, and improvement in MF-related symptoms—in 11 patients (48%).
And 2 patients (9%) achieved a CR. Dr Moyo said there were “few commonalities” between these 2 patients.
Both had intermediate-1-risk disease as well as persistent or progressive MF-related symptoms and thrombocytosis at baseline. However, 1 patient had post-ET MF, and 1 had post-PV MF.
The post-ET MF patient had an MPL driver mutation. She received ruxolitinib at 20 mg twice daily and umbralisib at 400 mg daily. The patient achieved a CR at cycle 15 and remained on study 2 years before proceeding to transplant. The patient is now about 1 year from her transplant with no evidence of disease.
The post-PV patient had a JAK2 V617F driver mutation. She received ruxolitinib at 15 mg twice daily and umbralisib at 600 mg daily. The patient achieved a CR at cycle 5 and remains on study, currently receiving cycle 12 of treatment.
Dr Moyo said these results suggest “the addition of umbralisib to ruxolitinib can augment or resurrect a response in MF patients who have had suboptimal or lost response to ruxolitinib alone, and this treatment combination warrants further investigation.”