The combination of 2 novel medications, umbralisib and ublituximab, has been well-tolerated and has demonstrated promising activity in the treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL).1 This combination, referred to as U2, combines the novel anti-CD20 monoclonal antibody ublituximab and the novel PI3K delta inhibitor umbralisib. Researchers presented results of the UNITY-CLL trial, in which U2 was compared with Gazyva (obinutuzumab) plus Leukeran (chlorambucil) (G+L) in the treatment of patients with both treatment-naïve and relapsed or refractory CLL.
The multicenter, randomized, phase 3 UNITY-CLL trial enrolled adult patients with treatment-naïve or relapsed or refractory CLL requiring treatment.2 Patients were stratified according to prior treatment and deletion 17p status. Patients were randomized to receive 1 of 4 regimens: U2, G+L, umbralisib monotherapy, or ublituximab monotherapy. Once U2 had been compared with monotherapy, patients were randomized to receive combination therapy with U2 or G+L.
Between February 2016 and October 2017, 421 patients were randomized to receive treatment with either U2 or G+L. The median age of enrolled patients was 67 years, 66% were male, and 57% of patients were treatment-naïve. Of enrolled patients, 43% had relapsed or refractory CLL. A 17p deletion was present in 10% of patients, 11q deletion in 20%, and unmutated IGHV in 56%. Demographic characteristics were well-balanced between treatment groups.
At median follow-up of 36.2 months, treatment with U2 was found to significantly prolong progression-free survival (PFS) compared with treatment with G+L (31.9 months vs 17.9 months). The estimated 24-month PFS rate in the U2 treatment group was 60.8%, compared with 40.4% in the G+L group. Improvement in PFS was greater with U2 treatment compared with G+L across all subgroups, including treatment-naïve patients and patients with relapsed or refractory CLL.
The median treatment duration was 21 months for patients in the U2 group and 5 months for the G+L group. Adverse events led to discontinuation of treatment in 34 patients (16.5%) in the U2 treatment group and 16 patients (7.6%) in the G+L group. Grade 3/4 adverse events of note occurring in each treatment arm included neutropenia (30.6% in the U2 group, 34.7% in the G+L group), thrombocytopenia (3.4% vs 13.1%), diarrhea (12.1% vs 2.5%), infusion-related reaction (1.9% vs 3.5%), elevated AST/ALT (8.3% vs 2%), colitis (3.4% vs 0%), and pneumonitis (2.9% vs 0%). Neutropenia was more common in patients who had been previously treated, occurring in 40.0% of previously treated patients compared with 24.1% of treatment-naïve patients.
Researchers conclude that U2 significantly improved PFS in patients with treatment-naïve and relapsed or refractory CLL when compared with standard-of-care chemoimmunotherapy. U2 demonstrated a well-tolerated safety profile in the UNITY-CLL trial, which is the first randomized phase 3 trial comparing a PI3K inhibitor with chemoimmunotherapy, as well as the first randomized study of a PI3K inhibitor in patients with treatment-naïve CLL.
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