MRD Kinetics Identify High-risk CLL in Study of Zanubrutinib, Venetoclax, Obinutuzumab

Findings from an abstract presented at the 2021 American Society of Hematology Meeting & Exposition suggest that early minimal residual disease (MRD) kinetics after treatment with zanubrutinib, venetoclax, and obinutuzumab can identify a high-risk cohort of patients with delayed bone marrow undetectable MRD (uMRD) and early MRD recurrence after treatment.

Venetoclax and obinutuzumab (O-Ven) is an FDA-approved combination for first-line treatment of patients with chronic lymphocytic leukemia (CLL). The fixed-duration regimen spans 1 year and has been shown to induce uMRD and durable remissions in treatment-naïve patients with CLL. In a trial of venetoclax and the Bruton tyrosine kinase (BTK) inhibitor ibrutinib in relapsed or refractory CLL (CLARITY), peripheral blood MRD kinetics were predictive of bone marrow uMRD and progression-free survival. The abstract explores the potential for MRD as a biomarker for treatment duration in an ongoing phase 2 trial of O-Ven plus the BTK inhibitor zanubrutinib (BOVen) in patients with CLL and small lymphocytic leukemia.

Eligible patients received BOVen in 28-day cycles. During cycle 1, they received 160 mg of oral zanubrutinib twice daily starting on day 1. Intravenous obinutuzumab (1000 mg) was given on days 1, 8, and 15 of cycle 1 and on day 1 of each cycle thereafter. On day 1 of cycle 3, oral venetoclax dosing began and ramped up to a target dose of 400 mg daily.

Patients received 8 to 24 cycles, and treatment duration was informed by MRD criteria. Flow cytometry (MRD-FC) and immunosequencing (MRD-IS) were used to analyze MRD, and the uMRD threshold was as 10^-4 or lower for MRD-FC and 10^-5 or lower for MRD-IS.

Thirty-nine patients were eligible for the study and were evaluated for treatment toxicity, and 37 were evaluated for efficacy. At 26 or more months median follow-up, 95% of patients achieved peripheral blood uMRD-FC, and 94% of those patients also achieved uMRD-IS. Eighty-nine percent also achieved bone marrow uMRD at a median of 8 months and discontinued treatment at a median of 10 months. Therapy was discontinued by 3 patients who still had detectable bone marrow MRD after 24 cycles.

A 400-fold or greater reduction in peripheral blood MRD-IS after 4 cycles of treatment was predictive of a patient reaching bone marrow uMRD in 8 months of treatment or less. Patients who reached this level of MRD reduction by cycle 4 had a median therapy duration of 8 months compared with 13 months in patients who did not.

Of the 33 patients who met the uMRD criteria and discontinued therapy, 94% were still at uMRD-FC at a median 15 months after therapy discontinuation. MRD-IS failure–free survival was longer in patients who had reached a 400-fold or greater reduction in peripheral blood MRD-IS after 4 cycles, despite their generally shorter treatment duration. Neutropenia, thrombocytopenia, diarrhea, infusion-related reaction, and bruising were the most common adverse events (AEs). Neutropenia was the most common grade 3 or higher AE, at 15%.

Overall, the results show that most patients given a BOVen regimen achieved durable uMRD, and at posttreatment follow-up, most still showed uMRD-FC. The 40% of patients who did not reach a 400-fold or greater reduction in peripheral blood MRD-IS after 4 cycles of treatment were prone to delayed bone marrow MRD clearance and earlier MRD recurrence. This outcome warrants further research as a biomarker to inform treatment duration.

Reference

Soumerai J, Mato A, Dogan A, et al. Zanubrutinib, obinutuzumab, and venetoclax in chronic lymphocytic leukemia: early MRD kinetics define a high-risk patient cohort with delayed bone marrow undetectable MRD and earlier post-treatment MRD recurrence. Paper presented at: 63rd American Society of Hematology Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 3753. Accessed January 13, 2022. https://ash.confex.com/ash/2021/webprogram/Paper150961.html