Venetoclax-Based Combos Demonstrate High Rates of uMRD in Frontline CLL

High rates of undetectable minimal residual disease were found in fit patients with chronic lymphocytic leukemia who were treated with venetoclax plus either obinutuzumab or ibrutinib vs chemoimmunotherapy.

Fit patients with chronic lymphocytic leukemia (CLL) had significantly higher rates of undetectable minimal residual disease (uMRD) when treated with venetoclax (Venclexta) plus obinutuzumab (Gazyva; GVe) or ibrutinib (Imbruvica; GIVe) compared with chemoimmunotherapy, according to results from the phase 3 GAIA (CLL13) trial (NCT02950051) that were presented at the 2021 American Society of Hematology Annual Meeting. 1

At 15 months, the rate of uMRD (< 10-4) was 86.5% (97.5% CI, 80.6%-91.1%) with GVe compared with 52% (97.5% CI, 44.4%-59.5%) with chemoimmunotherapy (P < .0001). The rate of uMRD was 92.2% (97.5% CI, 87.3%-95.7%) with GIVe vs 52% with chemoimmunotherapy (P < .0001).

The combination of rituximab (Rituxan) and venetoclax (RVe) was not found to induce statistically significantly higher rates of uMRD compared with chemoimmunotherapy, at 57% (97.5% CI, 49.5%-64.2%) vs 52%, respectively (P = .317).

Venetoclax-based, time-limited therapies have demonstrated high efficacy in unfit patients with CLL. Findings from the phase 3 CLL14 trial (NCT02242942) demonstrated that the median progression-free survival (PFS) was not reached with the combination of venetoclax and obinutuzumab vs 36.4 months with chlorambucil and obinutuzumab (HR, 0.33; 95% CI, 0.25-0.45; P < .0001).2 The 4-year PFS rates were 74% vs 35.4%, respectively.

In the phase 3 CLL10 trial (NCT00769522), the chemoimmunotherapy combination of fludarabine, cyclophosphamide, and rituximab (FCR) demonstrated improved PFS in older and younger patients compared with bendamustine/rituximab (BR).3 The median PFS was 57.6 months with FCR in patients 65 years of age or younger and 57.9 months with FCR in patients older than 65 years of age compared with 38.2 months with BR in patients 65 years of age or younger and 48.5 months with BR in patients older than 65 years of age.

“The first co-primary end point of uMRD rate in peripheral blood at month 15 was met by this study, showing a highly significantly superior uMRD rate with GVe in fit patients, confirming or even exceeding the results of the CLL14 trial in unfit patients. The triplet combination achieved even higher rates of uMRD,” said lead study author Barbara Eichhorst, MD, an associate professor and attending physician at the University Hospital Cologne in Cologne, Germany, during a presentation of the data.

The GAIA trial aimed to determine whether venetoclax-based, time-limited, frontline combinations were superior to chemoimmunotherapy.

Fit patients with CLL whose Cumulative Incidence Rating Scale (CIRS) score was 6 or less and had normal creatinine clearance were eligible to enroll on the study. Patients must not have harbored TP53 mutations or 17p deletions by central screening.

Overall, 926 patients were randomized to 1 of 4 arms: chemoimmunotherapy (FCR, n = 150; BR, n = 79 or BR; total, n = 229), RVe (n = 237), GVe (n = 229), or GIVe (n = 231). Chemoimmunotherapy was given based on age with patients 65 years or younger receiving FCR and patients older than 65 receiving BR.

Patients were stratified by age, disease stage, and region.

The co-primary end points of the study were uMRD at 15 months in the GVe vs chemoimmunotherapy arms and PFS in the GIVe vs chemoimmunotherapy arms. However, the PFS interim analysis was postponed because of a low number of events; the results are expected in quarter 1 of 2022.

uMRD was defined as less than 10-4 in the peripheral blood and was assessed by 4-colour-flow.

All treatment regimens were given in 28-day interval cycles. Notably, patients randomized to the GIVe regimen were eligible to continue ibrutinib for up to 36 cycles if they had detectable MRD.

Patients in the intention-to-treat (ITT) cohort (n = 926) were a median age of 61 years (range, 27-84). The median CIRS score was 2 (range, 0-7), and the median creatinine clearance by the Cockcroft-Gault equation was 85.7 mL/min (range, 39.5-268.3). Binet stages ranged from stage A (n = 246; 26.6%), stage B (n = 350; 37.8%), and stage C (n = 330; 35.6%).

Risk factors in the overall ITT population included deletion 11q (n = 162; 17.5%), trisomy 12 (n = 150; 16.2%), and deletion 13q (n = 413; 44.6%). Moreover, 21.7% of patients (n = 201) did not have any cytogenetic abnormalities. Most patients (n = 518; 56%) had unmutated IGHV; 41.1% (n = 380) of patients had mutated IGHV and 2.9% (n = 27) were not evaluable.

At a median follow-up of 27.9 months (range 0-49), 81.5% (n = 176) of patients who received chemoimmunotherapy completed at least 12 cycles of treatment vs 92.4% (n = 219) of patients who received RVe, 93.9% (n = 214) of patients who received GVe, and 85.3% (n = 197) of patients who received GIVe. Reasons for treatment discontinuation included adverse effects (AEs) or intercurrent illness, progressive disease, and other reasons. Dose intensity reductions were required in 14.8% (n = 32), 19.3% (n = 44), 21.5% (n = 47), and 36.5% (n = 81) of patients, respectively.

Overall, 19% of patients (n = 35) completed at least 12 cycles of treatment, 72% (n = 135) completed 13 to 15 cycles of treatment with ibrutinib alone, and 10% (n = 18) completed 16 to 36 cycles of treatment with ibrutinib alone.

In the ibrutinib-containing arm, early treatment discontinuations may have been caused by more than 1 reason and 9 patients were not evaluable for dose modification because of unclean data.

Additional results compared uMRD rates in the peripheral blood vs bone marrow at 15 months. Respectively, the rates were 52% vs 37.1% in the chemoimmunotherapy arm, 57% vs 43% in the RVe arm, 86.5% vs 72.5% in the GVe arm, and 92.2 vs 77.9% in the GIVe arm.

Per International Workshop on CLL criteria, complete remissions with incomplete bone marrow recovery (CRis) were observed in 61.9% of patients who received GIVe, 56.8% of patients who received GVe, 49.4% of patients who received RVe, and 31% of patients who received chemoimmunotherapy. Clinical CRis were observed in 10%, 10.5%, 11.4%, and 30.1% of patients, respectively. Partial responses (PRs) were observed in 22.5%, 28.8%, 32.5%, and 19.7% of patients, respectively.

Best responses until month 15 included CRis in 62.3% of patients with GIVe, 56.8% of patients with GVe, 49.4% of patients with RVe, and 39.3% in patients with chemoimmunotherapy. Clinical CRis were reported in 30.7%, 35.4%, 41.8%, and 42.8% of patients, respectively. PRs were reported in 6.5%, 6.1%, 7.2%, and 10% of patients, respectively.

Regarding safety, any-grade AEs were reported in 98.7% of patients who received GIVe, 98.7% of patients who received GVe, 96.6% of patients who received RVe, and 98.6% of patients who received chemoimmunotherapy. Maximum grade 3 AEs were observed in 46.3%, 49.6%, 46.8%, and 37.5% of patients, respectively. Maximum grade 4 AEs were observed in 32%, 32.5%, 21.5%, and 38.9% of patients, respectively. Maximum grade 5 AEs were observed in 3.9%, 2.6%, 3%, and 2.3% of patients, respectively.

The most common grade 3 or higher AEs included anemia, neutropenia, thrombocytopenia, febrile neutropenia, infections, tumor lysis syndrome (TLS), bleeding events, and atrial fibrillation. Of these, febrile neutropenia was reported in 7.8% of patients with GIVe, 3.1% of patients with GVe, 4.2% of patients with RVe, and 11.1% of patients with chemoimmunotherapy. Infections were reported in 22.1%, 14%, 11.4%, and 19.9% of patients, respectively. TLS was reported in 6.5%, 8.8%, 10.1%, and 4.2% of patients, respectively.

Twelve patients developed grade 5 AEs during therapy until day 84 after end of treatment; these included infections other than COVID-19 (n = 4), COVID-19 (n = 2), and secondary neoplasia (n = 4). Fifteen patients developed grade 5 AEs after 84 days following end of treatment; these included pneumonia (n = 2), Richter transformation (RT; n = 3), and secondary neoplasia. Other grade 5 AEs included suicide, RT, toxic leukoencephalopathy, cardiac arrest, and respiratory failure.

“Although there were some severe BTK-associated AEs, the AE profiles did not otherwise show significant differences between arms,” concluded Eichhorst.


1. Eichhorst B, Niemann CU, Kater AP, et al. A randomized phase III study of venetoclax-based time-limited combination treatments (RVE, GVE, GIVE) vs standard chemoimmunotherapy (CIT: FCR/BR) in frontline chronic lymphocytic leukemia of fit patients: first co-primary endpoint analysis of the international intergroup GAIA (CLL13) trial. Presented at 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 71.

2. Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020; 21(9):1188-1200. doi:10.1016/S1470-2045(20)30443-5

3. Kutsch N, Bahlo J, Robrecht S, et al. Long-term follow-up data and health-related quality of life in frontline therapy of fit patients treated with FCR versus BR (CLL10 trial of the GCLLSG). Hemasphere. 2020;4(1):e336. doi:10.1097/HS9. 0000000000000336