Umbralisib Triplet May Benefit BTK-Naïve Population With R/R MCL


Umbralisib in combination with ublituximab and venetoclax appears tolerable and yields responses in a small cohort of patients with mantle cell lymphoma.

"The combination of umbralisib, ublituximab and venetoclax was an effective and safe time-limited option in BTK inhibitor­–naïve patients," according to the authors of a phase 2 trial (NCT03379051) published in Leukemia & Lymphoma.

"The combination of umbralisib, ublituximab and venetoclax was an effective and safe time-limited option in BTK inhibitor­–naïve patients," according to the authors of a phase 2 trial (NCT03379051) published in Leukemia & Lymphoma.

A time-limited combination of the PI3Kδ/CK1ε inhibitor umbralisib (Ukoniq), anti-CD20 antibody ublituximab (Briumvi), and venetoclax (Venclexta) safely prolonged survival in a cohort of patients with relapsed/refractory mantle cell lymphoma (MCL) naïve to Bruton tyrosine kinase (BTK) inhibition, according to findings from a phase 2 trial (NCT03379051) published in Leukemia & Lymphoma.

Among 16 evaluable patients who were included in the study’s efficacy analysis, the overall response rate (ORR) to the triplet therapy was 62% (95% CI, 36%-84%), the complete response (CR) rate was 50% (95% CI, 28%-72%), and the partial response (PR) rate was 13% (95% CI, 2.2%-40.0%) after a median follow-up of 21 months. Discontinuation of treatment following a CR occurred in 7 patients. Median progression-free survival (PFS) was 21.2 months (95% CI, 3.2-not evaluable [NE]). A total of 39.0% (95% CI, 19.6%-78.3%) of the population remained in remission at 30 months.

All patients who were naïve to BTK inhibition experienced responses (n = 9; 95% CI, 63%-100%); the same was true in 1 of 7 patients (14%; 95% CI, 0.75%-58%) who were not BTK inhibitor naïve. Median PFS was not reached vs 2.4 months (95% CI, 1.4-NE) in BTK inhibitor naïve and non-naïve patients, respectively.

“Despite the small cohort, these results support the observed preclinical data suggesting synergy with the inhibition of BCL2 and the PI3K/AKT/mTOR axis,” the investigators wrote.

“Importantly, this triplet regimen was administered in a time-limited fashion for only a year in patients who experienced a [CR], avoiding the long-term risks associated with PI3K inhibitors. There were no instances of severe colitis, pneumonitis, or hepatitis, which have been reported with other PI3K inhibitors. While further exploration of this combination is not planned due to class-wide safety concerns with PI3K inhibitors, given these results reassessment of these therapies in a time-limited manner may be warranted.”

In total, the trial included 18 patients with a median age of 70 years (range, 51-85) who had received a median of 3 (range, 1-7) prior lines of therapy. Of this group, 9 were refractory to previous therapy, 7 were refractory to previous BTK inhibition, and 3 experienced progressive lymphoma following prior CAR T-cell therapy. Half of these patients had undergone prior BTK inhibition.

Prior autologous stem cell transplantation was reported in 3 patients. One patient was found to have a TP53 mutation; this was the only patient in whom investigators assessed mutation status.

The population received oral umbralisib at a dose of 800 mg daily and intravenous ublituximab at a dose of 900 mg on days 1, 8, and 15 of the first 28-day cycle, initiated prior to oral venetoclax to reduce the risk of tumor lysis syndrome. This treatment was followed by daily umbralisib plus ublituximab on the first day of cycles 2 through 6. Patients also began treatment with venetoclax in cycle 2 via the standard weekly ramp-up to a maximum dose of 400 mg.

Patients with a confirmed CR could halt treatment after the twelfth cycle, and those without a CR remained on umbralisib. At the discretion of the investigators, those remaining on umbralisib could receive further combination treatment with venetoclax.

The study’s primary end point was safety, and secondary end points included ORR, CR rate, and PFS.

Grade 1/2 infusion reactions due to ublituximab were the most common adverse effects (AEs), affecting 50% of patients. The other common grade 1/2 AEs included anemia (33%), fatigue (33%), cough (28%), lymphocytopenia (28%), thrombocytopenia (22%) and nausea (22%).

Regarding grade 3/4 toxicities, there were 2 patients with thrombocytopenia and increased alanine transaminase as well as 1 patient each with high-grade fatigue, lymphocytopenia, neutropenia, increased aspartate aminotransferase, pneumonia, peripheral edema, bleeding, and hypotension.

“The combination of umbralisib, ublituximab and venetoclax was an effective and safe time-limited option in BTK inhibitor­–naïve patients. It did not overcome the poor outcomes currently seen for patients with relapsed or refractory [MCL] who have progressed following BTK inhibitor therapy, despite the available pre-clinical data,” the investigators concluded. “This trial further highlights the critical ongoing need for new treatment options for these patients.”


Wallace DS, Rowland C, Hill BT, et al. Phase 2 trial of umbralisib, ublituximab, and venetoclax in patients with relapsed/refractory mantle cell lymphoma. Leuk Lymphoma. Published online June 21, 2023. doi:10.1080/10428194.2023.2223743

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