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

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