Zanubrutinib Combo Meets Primary End Point of Undetectable MRD in CLL/SLL Despite Short Treatment Duration

Patients with chronic lymphocytic leukemia or small lymphocytic leukemia treated with zanubrutinib, obinutuzumab, and venetoclax experienced increased rates of undetectable minimal residual disease in peripheral blood and bone marrow.

Zanubrutinib (Brukinsa) combined with obinutuzumab (Gazyva) and venetoclax (Venclexta) yielding a promising rate of undetectable minimal residual disease (MRD) in peripheral blood and bone marrow for those diagnosed with chronic lymphocytic lymphoma or small lymphocytic lymphoma despite a median treatment duration of 10 months, according to results from a phase 2 study (NCT03824483) published in The Lancet Hematology.

At the median follow-up of 25.8 months, 89% patients had undetectable MRD in blood and bone marrow, meeting the study’s primary end point. After a median time of 15.8 months during surveillance following treatment, 94% of patients had undetectable MRD. The median time to undetectable bone marrow MRD was 8.0 months. Thirty-seven patients had an overall response, 57% of whom had a complete response (CR) or a CR with incomplete marrow recovery.

The patients had a median age of 62 years and were predominantly male. In total, 95% patients underwent at least 2 cycles of treatment and underwent MRD assessment. Of the 39 patients who enrolled on the study, 72% had unmutated immunoglobulin heavy-chain variable-region and 13% had a 17p depletion or TP53 mutation.

Zanubrutinib was administered at a dose of 160 mg orally twice daily on day 1 of cycle 1, and obinutuzumab was given at 1000 mg intravenously on days 1, 8, and 15 of cycle 1 and day 1 of cycles 2 through 8. Venetoclax was given on day 1 of cycle 3 with an increase in dosing starting at 20 mg and increasing to 50 mg, 100 mg, 200 mg, and 400 mg orally per day.

Treatment discontinuation occurred in 55% patients (95% CI, 36%-72%) and a partial response (PR) occurred in 45% patients (95% CI, 28%-64%). Eight percent of patients completed 24 cycles of treatment and finished therapy with detectable bone marrow MRD. Among the 15 patients with an MRD-undetectable PR at discontinuation, 93% had borderline lymphadenopathy or splenomegaly, and 1 patient had substantial intra-abdominal soft tissue measuring at 6.6 × 2.5 cm.

The median progression-free survival was not reached, with only 1 patient developing progressive disease. All 33 patients who met the prespecified undetectable MRD end point had successful treatment discontinuation, and 94% had ongoing undetectable MRD in the blood detected by flow cytometry. Additionally, 2 patients had recurrent detectable MRD, with 1 patient having detectable MRD and progressive lymphadenopathy. Twelve months after treatment, this patient reached peripheral blood undetectable MRD with venetoclax and zanubrutinib after 3 months of treatment.

Grade 3 or higher adverse effects (AEs) included neutropenia (18%), thrombocytopenia (8%), rash (8%), lung infection (8%), and infusion-related reaction (5%). Twenty-three percent of patients received granulocyte colony-stimulating factor for grade 3/4 AEs. Two patients died due to due to intracranial hemorrhage and metastatic adenocarcinoma.

Reference

Soumerai JD, Mato AR, Dogan A, et al. Zanubrutinib, obinutuzumab, and venetoclax with minimal residual disease-driven discontinuation in previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Haematol. 2021;8(12):e879-e890. doi:10.1016/S2352-3026(21)00307-0