Dr Allan on the Investigation of Obinutuzumab Triplet Consolidation in MRD-Positive CLL

John N. Allan, MD, associate professor of clinical medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, discusses a planned evaluation of obinutuzumab (Gazyva) triplet consolidation therapy for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who remain minimal residual disease (MRD)–positive after initial treatment with zanubrutinib (Brukinsa) and venetoclax (Venclexta).

While BTK and BCL2 inhibitor combinations allow patients to achieve high rates of MRD-negativity, there are 30% to 40% that remain MRD-positive after 1 year of fixed-duration doublet therapy, Allan begins. Current evidence suggests that the use of anti-CD20 agents after this regimen may enhance remission and MRD-negativity in this population, he explains.

The single-center, open-label phase 2 trial (NCT05650723) will assess the ability of this response-adapted consolidation strategy to reduce the use of obinutuzumab, limit toxicity, and maximize MRD negativity, Allan details. The trial will enroll up to50 patients with previously untreated CLL/SLL who meet enrollment criteria according to the 2018 International Workshop on CLL guidelines, he says. Notably, patients with Richter's transformation will be excluded from participation.

The treatment protocol consists of lead-in, combination, and consolidation phases. All patients will receive a 3-cycle lead-in of zanubrutinib monotherapy, followed by the introduction of venetoclax starting from the fourth cycle. Zanubrutinib and venetoclax will be administered daily, and the dose of venetoclax will be increased according to the standard ramp-up schedule. MRD assessment will be conducted after the 16th cycle in both peripheral blood and bone marrow using clonoSEQ.

Patients who achieve MRD negativity in both portions will discontinue therapy. For those who remain MRD-positive, an additional 6 cycles of zanubrutinib and venetoclax will be prescribed, and obinutuzumab will be introduced during the 17th cycle. Obinutuzumab will be administered intravenously and continue monthly until the 22nd cycle.

The trial's primary end point is the rate of MRD negativity in both peripheral blood and bone marrow after the 16th cycle. The co-primary end point evaluates MRD negativity rates following the 23rd cycle in subjects who were MRD positive at cycle 16 and received at least one dose of obinutuzumab.

Key secondary end points include overall response rates, 36-month progression-free survival, 36-month overall survival, 36-month time to next treatment, MRD negativity rates in peripheral blood at 24 and 36 months, tumor lysis risk reduction rates, and safety evaluations.