BENDAMUSTINE, FOLLOWED BY OBINUTUZUMAB, ACALABRUTINIB AND VENETOCLAX IN PATIENTS (PTS) WITH RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): CLL2‐BAAG TRIAL OF THE GCLLSG

Abstract

Introduction: The CLL2-BAG trial had shown very favourable response and minimal residual disease (MRD) rates with a sequential treatment consisting of an optional bendamustine (B) debulking, followed by a doublet combination of obinutuzumab (G) and venetoclax (V) [Cramer et al, Lancet Oncol. 2018]. Following these results, the triplet combination adding the BTK inhibitor (BTK-I) acalabrutinib (A) was tested in the CLL2-BAAG trial to further improve efficacy. Methods: An optional debulking with 2 cycles of B was recommended in pts with lymphocyte counts ≥25.000/μl and/or lymph nodes ≥ 5cm (70mg/m2 d1&2 q28 days). In the induction, G (1000mg) was administered 3 times in cycle 1 (days 1/2, 8 & 15) and every 4 weeks in cycles 2-6. A (100mg bid) was added in cycle 2 followed by V in cycle 3 with a dose ramp-up (to 400mg daily) over 5 weeks. In the maintenance therapy, A and V remained unchanged while intervals of G were increased to 3 months. The primary endpoint was the rate of undetectable MRD (uMRD) in PB at the end of induction therapy (defined as <10-4 by flow cytometry, assessed centrally). Sample size was estimated with the objective to test against the null hypothesis of ≤70% using a onesided one-sample binomial test on the basis of an assumed improvement of uMRD rate to ≥90%. Secondary endpoints included iwCLL responses, safety and survival parameters. Results: Between January 2019 and June 2020, 46 pts were enrolled, 1 pt with a violation of inclusion/exclusion criteria and ≤2 induction cycles was excluded from the analysis. The 45 evaluable pts had relapsed/refractory (r/r) CLL with a median of one prior therapy (range 1-4), 21 pts (47%) had already received a targeted agent, including 8 pts with a BTK-I, 7 pts with V-based therapies, 3 pts with both and 3 pts with idelalisib. Fourteen pts (32%) had a del(17p)/ TP53 mutation, 34 (76%) had an unmutated IGHV status and 12 (30%) a complex karyotype. 18 pts (40%) received B debulking, 27 (60%) pts immediately started with the induction with G, A and V. 44 pts (98%) received 6 induction cycles and 32 pts (71%) have thus far started with the maintenance treatment. At the end of the induction all pts responded, 8 pts (18%) had a CR/ CRi and 37 pts (82%) a PR. With an uMRD rate in PB of 76% (34 pts), the primary endpoint was not met (95% CI 61%-87%, p = 0.258). As of February 25th 2021, 430 adverse events (AEs) were reported, including 29 SAEs (7%) and 69 AEs (16%) of CTC3-4. Most common were gastrointestinal AEs, cytopenias and infections. Conclusion: Sequential treatment with B debulking, followed by the triplet combination of G, A and V was well tolerated. Although the primary endpoint was not met with given sample size, the ORR of 100% and a rate of uMRD of 76% in PB at the end of induction phase compare favourably to other regimens for r/r CLL. The lower uMRD rate may be explained by the redistribution phenomenon caused by BTK-I and could improve with continued maintenance treatment in the long run.