Background: The CLL2-BAG phase 2 trial was among the first to evaluate venetoclax (Ven) plus obinutuzumab (Obi). Another novelty in this trial was the individualized treatment duration based on measurable residual disease (MRD) in peripheral blood (PB). The primary endpoint analysis demonstrated the regimen´s strong efficacy (Cramer et al, Lancet Oncol. 2018) and laid the foundation for several phase-3 studies, establishing Ven-Obi as one of the most important first-line therapies in CLL. This abstract presents the final analysis with a follow-up of 9 years.

Methods: From May 2015 to January 2016, 66 patients (pts) with CLL, irrespective of prior treatment, fitness, and CLL risk factors, were enrolled. Ven-Obi was administered in an induction (8 cycles of 28 days) and a maintenance phase (up to 8 cycles of 84 days) until achievement of a deep remission with undetectable MRD (uMRD, <10-4) in PB. Two optional cycles of bendamustine debulking (Benda) could be administered for high tumor burden before Ven-Obi. In case of progression requiring treatment per iwCLL criteria ≥6 months (mo) after end of treatment, a retreatment with Ven-Obi could be administered in the clinical trial.

Results: Of the 66 pts enrolled, 3 pts with <2 induction cycles had to be excluded from the efficacy analysis as predefined by protocol. 34 pts (54%) were treatment-naïve and 29 (46%) had relapsed/refractory CLL (median number of prior therapies: 2, range: 1-9). Median age was 59 (range 28-77) years and the median CIRS score was 2 (0-14). 17 of 60 pts (28%) had a TP53 mut/del, 46 of 62 (74%) had an unmutated IGHV and 21 of 62 (34%) a complex karyotype (≥ 3 aberrations).

45 pts (71%) received Benda, 60 pts (95%) completed 8 induction cycles with Ven-Obi and received a median number of 2 (range 1-8) maintenance cycles, leading to a median treatment duration for all 63 pts of 15 (range 4-30) mo. Following the MRD-guided treatment approach, 45 of 60 pts (75%) stopped maintenance treatment due to confirmed uMRD, 5 pts (8%) completed the 8 maintenance cycles, and 10 pts (17%) stopped early due to adverse events (AEs, 6 pts), progression (PD, 2 pts), Richter transformation (RT, 1 pt) or other (1 pt).

Among the 60 pts with maintenance treatment, the overall response rate at the end of maintenance was 95%; 85% had uMRD <10-4in PB (considering the last available assessment during maintenance).

After a median observation time of 107 (range 8-115) mo, the median progression-free survival (PFS) was 57 (95% CI 42-73) mo. It was 78 (95% CI 47-108) mo among pts receiving first-line treatment (57 mo with TP53 mut/del) versus 38 (95% CI 28-48) mo in relapsed/refractory CLL (34 mo with TP53 mut/del). Median time to next treatment was 75 mo. 33 pts (52%) received at least one next treatment line: 11 pts were retreated with Ven-based therapies (including 7 with Ven-Obi in CLL2-BAG, all responded; median PFS after start of 2nd Ven-Obi was 33 mo, see abstract at iwCLL 2025), 8 pts switched to a BTK inhibitor, 5 underwent R-CHOP-like regimen, 3 were treated with a triplet of Ven-Obi plus a BTK inhibitor, and 6 received other therapies. Median overall survival was not reached; 88% of pts were alive at 6 years. Nine of the 11 deaths occurred in previously treated pts; 5 were due to RT, 2 related to PD, 3 were fatal infections, and 1 pt died due to cardiac comorbidity.

A total of 835 AEs were reported in the 66 pts, including 102 (12%) during Benda, 608 (73%) during Ven-Obi (434 induction and 174 maintenance), and 125 (15%) during follow-up (i.e., if applicable, until start of Ven-Obi retreatment) in CLL2-BAG. 221 AEs (26%) were of CTC°3, 38 (5%) of °4 and 7 were fatal AEs. 148 AEs (18%) led to adjustments of study drug. Most common AEs of CTC°3 and higher were cytopenias (121 in 41 pts), especially neutropenia (80 in 33 pts), infections (55 in 29 pts), and second primary malignancies (19 in 16 pts).

Conclusion: The final analysis of the CLL2-BAG phase-2 trial with considerable follow-up showed that time-limited MRD-guided Ven-Obi was well tolerated and achieved deep remissions with prolonged PFS and an impressive OS. This individualized treatment led to long-term disease control, even among pts with high-risk features.

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2025
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