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Umbralisib/Ublituximab Improves Survival in Chronic Lymphocytic Leukemia

CLL cells.

In patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia (CLL), the combination of umbralisib and ublituximab significantly increases progression-free survival (PFS) compared with obinutuzumab/chlorambucil, according to results of a phase 3 trial recently presented at the American Society of Hematology (ASH) Annual Meeting.

"Umbralisib is an oral, once-daily, novel dual inhibitor of phosphatidylinositol-3-kinase-delta (PI3Kδ) and casein kinase-1ε (CK1ε) that exhibits improved selectivity for the delta isoform of PI3K," write the investigators, led by first author John G. Gribben, MD, DSc, of Barts Cancer Institute at Queen Mary University of London. "Ublituximab is a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity that targets a unique epitope on CD20." Dr. Gribben and colleagues investigated the efficacy of umbralisib/ublituximab in UNITY-CLL, the first randomized phase 3 trial of a PI3K inhibitor compared with chemoimmunotherapy in CLL and the first randomized study of a PI3K inhibitor in patients with treatment-naive CLL.

The trial enrolled 421 patients with untreated or relapsed/refractory CLL who had adequate organ function and an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 and who required treatment based on the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. Of these, 43% had relapsed/refractory disease. Patients were randomized in a 1:1 ratio to receive umbralisib 800 mg orally once daily in combination with intravenous ublituximab 900 mg on Days 1-2, 8, and 15 of Cycle 1; Day 1 of Cycles 2-6; and Day 1 of every third cycle thereafter; or obinutuzumab in combination with chlorambucil. The primary end point was PFS assessed by independent review committee, with secondary end points of overall response, complete response, undetectable minimal residual disease, duration of response, and safety.

At a median follow-up of 36.2 months, median PFS was significantly higher for patients receiving umbralisib/ublituximab compared with obinutuzumab/chlorambucil (31.9 vs 17.9 months), with estimated 24-month PFS rates of 60.8% and 40.4%, respectively. Median PFS was higher for patients receiving umbralisib/ublituximab compared with obinutuzumab/chlorambucil in both the treatment-naive population (38.5 vs 26.1 months) and the relapsed/refractory population (19.5 vs 12.9 months). Umbralisib/ublituximab also produced a higher overall response rate (83.3% vs 68.7%) and a longer median treatment duration (23 vs 5 months) compared with obinutuzumab/chlorambucil.

Grade 3/4 adverse events included neutropenia (30.6% vs 34.7%), thrombocytopenia (3.4% vs 13.1%), diarrhea (12.1% vs 2.5%), infusion-related reaction (1.9% vs 3.5%) elevated aspartate aminotransferase/alanine aminotransferase (AST/ALT) (8.3% vs 2%), colitis (3.4% vs 0%), and pneumonitis (2.9% vs 0%). A higher proportion of patients receiving umbralisib/ublituximab experienced treatment discontinuation due to adverse events compared with those receiving obinutuzumab/chlorambucil (16.5% vs 7.6%).

"Umbralisib/ublituximab exhibited a well-tolerated safety profile and significantly improved PFS versus standard of care chemoimmunotherapy in patients with treatment-naive and relapsed/refractory CLL," conclude Dr. Gribben and colleagues.

For More Information

Gribben JG, Jurczak W, Jacobs R, et al (2020). Umbralisib plus ublituximab (U2) is superior to obinutuzumab plus chlorambucil (O+Chl) in patients with treatment naive (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): results from the phase 3 Unity-CLL study. 62nd American Society of Hematology Annual Meeting & Exposition. Abstract 543.

Image credit: Erhabor Osaro. Licensed under CC BY-SA 4.0

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