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

Abstract

Background: We hypothesised that combining zanubrutinib with obinutuzumab and venetoclax (BOVen) as an initial therapy for chronic lymphocytic leukaemia and small lymphocytic lymphoma would lead to high rates of undetectable minimal residual disease (MRD), and we explored MRD as a biomarker for directing treatment duration.

Methods: This multicenter, investigator-initiated, single-arm, phase 2 trial took place at two two academic medical centres in the USA. Patients were eligible for the primary cohort if they had treatment-naive chronic lymphocytic leukaemia or small lymphocytic lymphoma, required therapy, and were at least 18 years of age with an Eastern Cooperative Oncology Group performance status up to 2. BOVen was administered in 28 day cycles (oral zanubrutinib at 160 mg twice per day starting in cycle 1 on day 1; intravenous obinutuzumab at 1000 mg on day 1 [split over day 1 with 100 mg and day 2 with 900 mg for an absolute lymphocyte count >25 000 cells per μL or lymph nodes >5 cm in diameter], day 8, and day 15 of cycle 1, and day 1 of cycles 2-8; and oral venetoclax ramp up to 400 mg per day starting in cycle 3 on day 1) and discontinued after 8-24 cycles when prespecified undetectable MRD criteria were met in the peripheral blood and bone marrow. The primary endpoint was the proportion of patients that reached undetectable MRD in both the peripheral blood and bone marrow (flow cytometry cutoff less than one chronic lymphocytic leukaemia cell per 10 000 leukocytes [<10-4]) assessed per protocol. This trial is registered at clinicaltrials.gov (NCT03824483). The primary cohort is closed to recruitment, and recruitment continues in the TP53-mutated mantle cell lymphoma cohort.

Findings: Between March 14, 2019, and Oct 10, 2019, 47 patients were screened for eligibility, and 39 patients were enrolled and treated. Median age was 62 years (IQR 52-70) with 30 (77%) of 39 male participants and nine (23%) of 39 female participants. 28 (72%) of 39 patients had unmutated immunoglobulin heavy-chain variable-region and five (13%) of 39 had 17p deletion or TP53 mutation. After a median follow-up of 25·8 months (IQR 24·0-27·3), 33 (89%) of 37 patients (95% CI 75-97) had undetectable MRD in both blood and bone marrow, meeting the prespecified undetectable MRD criteria to stop therapy after a median of ten cycles (IQR 8-12), which includes two cycles of zanubrutinib and obinutuzumab before starting venetoclax. After median surveillance after treatment of 15·8 months (IQR 13·0-18·6), 31 (94%) of 33 patients had undetectable MRD. The most common adverse events were thrombocytopenia (23 [59%] of 39), fatigue (21 [54%]), neutropenia (20 [51%]), and bruising (20 [51%]), and the most common adverse event at grade 3 or worse was neutropenia (seven [18%]) in the intention-to-treat population. One death occurred in a patient with intracranial haemorrhage on day 1 of cycle 1 after initiating intravenous heparin for pulmonary emboli.

Interpretation: BOVen was well tolerated and met its primary endpoint, with 33 (89%) of 37 previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma reaching undetectable MRD in both peripheral blood and bone marrow despite a median treatment duration of only 10 months, owing to our undetectable MRD-driven treatment discontinuation design. These data support further evaluation of the BOVen regimen in chronic lymphocytic leukaemia and small lymphocytic lymphoma with treatment duration guided by early MRD response kinetics.

Funding: Beigene, Genentech (Roche), Grais-Cutler Fund, Lymphoma Research Fund, Lymphoma Research Foundation, American Cancer Society, Farmer Family Foundation, and the National Instititutes of Health and National Cancer Institute.

Conflict of interest statement

Declaration of interests JDS reports consulting fees from Abbvie, AstraZeneca, Beigene, Bristol Myers Squibb, TG Therapeutics, and Verastem, and research funding from Adaptive Biotechnologies, Beigene, BostonGene, Genentech (Roche), GSK, Moderna, and TG Therapeutics. ARM reports consulting fees from Curio, Dava, Medscape, GenMab, PeerView, AstraZeneca, Abbvie, Adaptive, Beigene, Genentech, LOXO, Janssen, Pharmacyclics, and TG Therapeutics, research funding from DTRM, Nurix, GenMab, AstraZeneca, Abbvie, Adaptive, Beigene, Genentech, LOXO, Janssen, Pharmacyclics, and TG Therapeutics, and Data Safety Monitoring Board membership for TG Therapeutics. AD reports consulting fees from Physician's Education Resource, Seattle Genetics, Takeda, EUSA Pharma, and Abbvie, and research funding from Roche and Takeda. EJ reports consulting fees from AstraZeneca and Epizyme. EH reports consulting fees from Leuko and Intervention Insights. JSA reports consulting fees from Abbvie, Bayer, Celgene, Gilead, Juno Therapeutics, Kite Pharma, Genentech, Amgen, Novartis, Karyopharm, Verastem, Janssen, Merck, and Seattle Genetics. CLB reports consulting fees from Life Sci, GLG, Juno (Celgene), Seattle Genetics, Kite, Karyopharm, TG Therapeutics, and ADC Therapeutics, honoraria from Dava Oncology, TouchIME, and Medscape, stock ownership in BMS, Pfizer, Viatris, Regeneron, Moderna, and Novavax, and research funding from Autolus, Bayer, Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, and Genentech (Roche). MJM reports consulting fees from Genentech (Roche), Merck, Bayer, Juno, Teva, Rocket Medical, Seattle Genetics, Daiichi Sankyo, Takeda, honoraria from Genentech (Roche), GSK, Bayer, Pharmacyclics, Janssen, Seattle Genetics, Immunovaccine Technologies, and Takeda, travel, accommodation, or other expenses from Genentech (Roche), Bayer, and Seattle Genetics, and research funding from Genentech (Roche), Bayer, GlaxoSmithKline, IGM Biosciences, Rocket Medical, Seattle Genetics, Janssen, Pharmacyclics, and Immunovaccine Technologies, and minority ownership interest in Merck. AN reports consulting fees from Epizyme, Janssen, Pharmacyclics, Medscape, Targeted Oncology, and Morphosys, and research funding from Pharmacyclics and Rafael Pharma. MLP reports consulting fees from Beigene, Celgene, Novartis, Merck, and Synthekine, research funding from Pharmacyclics, Genentech, Juno, and Regeneron, and an immediate family member who receives royalties from Juno and Seres. AK reports consulting fees from Kite Pharmaceuticals, AstraZeneca, and Janssen, and research funding from Abbvie, Adaptive, Celgene, Pharmacyclics, Seattle Genetics, and AstraZeneca, and serves on a steering committee for mantle cell lymphoma Registry for AstraZeneca. LER reports consulting fees from Abbvie, AstraZeneca, Beigene, Janssen, Loxo Oncology, Pfizer, Pharmacyclics, TG Therapeutics, and Vaniam Group, minority ownership interest in Abbott Laboratories and Abbvie, and research funding from Pfizer. MT reports honoraria from the Massachusetts Medical Society, the Brazilian Association of Haematology, MJH Life Sciences, Curio Science, and VJHemeOnc. MR reports consulting fees from Celgene, Auron Therapeutics, and Physician's Education Resource, research funding from Cellularity, NGM, Genentech, and Beat AML, and ownership or equity interest in Auron Therapeutics. JH reports employment from Beigene. JB reports employment from Genentech. QW reports employment from Genentech. AJ reports employment from Adaptive Biotechnologies. OA-W reports consulting fees from H3 Biomedicine, Envisagenics, Janssen, and Merck. ADZ reports consulting fees from Adaptive Biotechnologies, Abbvie, Amgen, AstraZeneca, Beigene, Bristol Myers Squibb, Celgene, Genentech (Roche), Gilead, MEI Pharma, MorphoSys, NCCN, Novartis, and Verastem, data safety monitoring committee membership for BMS, Celgene, and Juno, data safety monitoring committee membership chair for Beigene, and research funding from MEI Pharma, Gilead, Beigene, and Roche. All other authors declare no competing interests.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Figures

Figure 1:

Study profile

Figure 2:. MRD and iwCLL response

(A) MRD response as assessed by flow cytometry in evaluable patients. (B) iwCLL response in evaluable patients. MRD=minimum residual disease. iwCLL=lnternational Workshop for Chronic Lymphocytic Leukaemia. *One patient was initially ascertained as having peripheral-blood undetectable MRD, but subsequent serial testing confirmed MRD positivity at the threshold of detection, so the patient was excluded from the proportion of patients reaching undetectable MRD. †All 33 patients who reached bone marrow undetectable MRD met the prespecified endpoint, with undetectable MRD confirmed in both peripheral blood and bone marrow.

Figure 3:. Patient-level outcomes

Swimmer’s plot of patient-level outcomes. iwCLL response was inclusive of initial complete response, complete response with incomplete marrow recovery, or partial response. iwCLL=lnternationai Workshop for Chronic Lymphocytic Leukaemia. MRD=minimal residual disease. *As assessed by flow cytometry.