Venetoclax-based combinations demonstrate elevated levels of uMRD in first-line CLL

Based on the results of the Phase 3 GAIA (CLL13) trial (NCT02950051) which were presented to the American Society of Hematology 2021 Annual Meeting. 1

At 15 months, the uMRD rate (P <.0001 the umrd rate was ci to with give vs. chemoimmunotherapy>P <.0001>

The combination of rituximab (Rituxan) and venetoclax (RVe) was not found to induce statistically significantly higher levels of uMRD compared to chemoimmunotherapy, at 57% (97.5% CI, 49 , 5% to 64.2%) versus 52%, respectively (P = .317).

Venetoclax time-limited therapies have been shown to be highly effective in unfit patients with CLL. The results of the phase 3 CLL14 trial (NCT02242942) demonstrated that median progression-free survival (PFS) was not achieved with the combination of venetoclax and obinutuzumab vs. 36.4 months with chlorambucil and l ‘obinutuzumab (RR: 0.33; 95% CI: 0.25-0.45; P <.0001>2 The 4-year PFS rates were 74% versus 35.4%, respectively.

In the phase 3 CLL10 trial (NCT00769522), the chemoimmunotherapy combination of fludarabine, cyclophosphamide and rituximab (FCR) demonstrated improvement in PFS in older and younger patients compared to 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 over 65 years of age, compared with 38.2 months with BR in patients aged 65 and over. 65 years or less and 48.5 months with BR in patients over 65 years of age.

“The first co-primary endpoint of the uMRD level in peripheral blood at month 15 was achieved by this study, showing a very significantly higher uMRD level with GVe in healthy patients, confirming or even exceeding the results of the CLL14 trial in unfit patients. The triplet combination achieved even higher levels of uMRD, ”said lead study author Barbara Eichhorst, MD, associate professor and attending physician at Cologne University Hospital in Cologne, Germany, during ‘a presentation of the data.

The GAIA trial aimed to determine whether time-limited first-line venetoclax combinations were superior to chemoimmunotherapy.

Healthy patients with CLL with a cumulative incidence assessment scale (CIRS) score of 6 or less and normal creatinine clearance were eligible to participate in the study. Patients must not have hosted TP53 17p mutations or deletions by central screening.

A total of 926 patients were randomized to one of the 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 of age or younger receiving FCR and patients over 65 years receiving BR.

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

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

UMRD was defined as less than 10-4 in peripheral blood and was assessed by 4-color flow.

All treatment regimens were administered 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) had a median age of 61 years (range, 27-84). The median CIRS score was 2 (range, 0-7), and the median creatinine clearance according to 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 11q deletion (n = 162; 17.5%), trisomy 12 (n = 150; 16.2%), and 13q deletion (n = 413; 44.6%) ). In addition, 21.7% of patients (n = 201) presented no cytogenetic abnormalities. Most patients (n = 518; 56%) had 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 stopping treatment included side effects (AEs) or intercurrent disease, 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 the 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 arm, early treatment discontinuations may have been caused by more than one reason and 9 patients were not evaluable for dose modification due to imprecise data.

Additional results compared uMRD levels in peripheral blood versus bone marrow at 15 months. Respectively, the rates were 52% versus 37.1% in the chemoimmunotherapy arm, 57% versus 43% in the RVe arm, 86.5% versus 72.5% in the GVe arm and 92.2 versus 77, 9% in the GIVe arm.

According to the International CLL Criteria Workshop, complete remissions with incomplete bone marrow recovery (CIS) were observed in 61.9% of patients who received GIVe, 56.8% of patients who received of GVe, 49.4% of patients who received RVe and 31% of patients who received GVe. received chemoimmunotherapy. Clinical CRs were observed in 10%, 10.5%, 11.4%, and 30.1% of patients, respectively. Partial responses (PR) were observed in 22.5%, 28.8%, 32.5%, and 19.7% of patients, respectively.

Best responses through Month 15 included CR in 62.3% of patients with GIVe, 56.8% of patients with GVe, 49.4% of patients with RVe, and 39.3% of patients with chemoimmunotherapy . Clinical CRs were reported in 30.7%, 35.4%, 41.8% and 42.8% of patients, respectively. PR was reported in 6.5%, 6.1%, 7.2% and 10% of patients, respectively.

Regarding safety, adverse reactions of any grade 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. Adverse reactions up to grade 3 were observed in 46.3%, 49.6%, 46.8% and 37.5% of patients, respectively. Adverse reactions up to grade 4 were observed in 32%, 32.5%, 21.5% and 38.9% of patients, respectively. Adverse reactions up to grade 5 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. SLT was reported in 6.5%, 8.8%, 10.1%, and 4.2% of patients, respectively.

Twelve patients developed grade 5 AEs during treatment up to day 84 after stopping 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 84 days after stopping treatment; these included pneumonia (n = 2), Richter’s transformation (RT; n = 3), and secondary neoplasia. Other grade 5 AEs included suicide, RT, toxic leukoencephalopathy, cardiac arrest, and respiratory failure.

“Although there were a few serious AEs associated with BTK, the AE profiles otherwise did not show significant differences between the arms,” ​​Eichhorst concluded.

The references

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

2. Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukemia (CLL14): follow-up results from a multicenter, open, randomized 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 the first-line treatment of fit patients treated with FCR versus BR (GCLLSG trial CLL10). Hemisphere. 2020; 4 (1): e336. doi: 10.1097 / HS9. 0000000000000336

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