Treatment with time-limited venetoclax (Venclexta)-based combination regimens resulted in superior rates of undetectable minimal residual disease (uMRD) in the peripheral blood at 15 months compared with chemoimmunotherapy (CIT) in fit patients with chronic lymphocytic leukemia (CLL), according to findings from the GAIA (CLL13) clinical trial. Moreover, uMRD rates in the bone marrow and complete response rates were significantly higher with 2 of these regimens versus CIT: venetoclax plus obinutuzumab (Gazyva; GVe) and venetoclax, ibrutinib (Imbruvica), and obinutuzumab (GIVe), but not with venetoclax plus rituximab (Rituxan; RVe).
These results were presented at the ASH 2021 Annual Meeting and Exposition by Barbara Eichhorst, MD, Senior Physician, Clinic I for Internal Medicine and Center of Integrated Oncology, University Hospital of Cologne, Bonn, Germany.
“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,” she noted.
For fit patients with CLL, continuous treatment with a Bruton tyrosine kinase inhibitor, such as ibrutinib or acalabrutinib, is replacing CIT as standard of care in the frontline setting, particularly in those with unfavorable prognostic factors. The time-limited combinations of GVe and RVe have produced high rates of uMRD, which is strongly associated with extended progression-free survival.
For frontline therapy, GVe is approved in this setting based on data from the CLL14 trial in an unfit population. However, data from a fit cohort have not yet been available. The GAIA (CLL13) trial evaluated the efficacy and safety of 3 venetoclax plus CD20 antibody-based regimens versus CIT as a frontline treatment for fit patients with CLL.
The study enrolled treatment-naïve and fit patients with CLL who required therapy. “Fit” was defined as having a cumulative illness rating scale score ≤6 and a normal creatinine clearance of ≥70 mL/min. Patients with TP53 mutations/deletions were excluded because they have a poor response to CIT, which would bias the study in favor of the experimental arms.
Patients were randomized in a 1:1:1:1 ratio to receive:
- CIT for 6 cycles: fludarabine (Fludara), cyclophosphamide, and rituximab (FCR) for patients aged ≤65 years and bendamustine (Treanda) plus rituximab for patients aged >65 years;
- RVe: venetoclax (standard ramp-up from cycle 1, day 22, and 400 mg/d of cycles 2-12) and rituximab (375/500 mg/m2 on day 1 of cycles 1-6);
- GVe: venetoclax and obinutuzumab 1000 mg on days 1, 8, and 15 of cycle 1 and day 1 of cycles 2 to 6;
- GIVe: venetoclax plus obinutuzumab and ibrutinib 420 mg/d on cycles 1 to 12 and continued until cycle 36 if MRD is detectable.
Patients were stratified according to country, Binet stage, and age (≤65 years or >65 years). The co-primary end points of the trial were the rate of uMRD (<10–4) by flow cytometry in peripheral blood at month 15 (GVe vs CIT) and progression-free survival (GIVe vs CIT). MRD in bone marrow was evaluated 3 months after the end of treatment (month 9) in patients with clinical complete response. Key secondary end points were investigator-assessed responses according to the International Workshop on CLL 2008 guidelines and safety.
From February 2016 to September 2019, a total of 926 patients were randomized to receive CIT (N = 229 [150 to FCR and 79 to bendamustine plus rituximab]; RVe, N = 237; GVe, N = 229; or GIVe, N = 231). Median age of patients was 61 years. The majority had advanced Binet stage (stage B, 37.8%; stage C, 35.6%), and unmutated IGHV status was present in 56% of patients.
Fourteen (FCR, N = 13; GVe, N = 1) patients did not receive study treatment and were not included in the safety analysis. The data cutoff for the first co-primary end point analysis was February 28, 2021. The median observation time was 27.9 months.
The co-primary end point uMRD in peripheral blood at month 15 was met. The rate of uMRD in the intent-to-treat population was significantly higher with GVe compared with CIT: 86.5% versus 52.0%, respectively (P <.0001). GIVe also showed a superior uMRD rate of 92.2% compared with CIT (P <.0001), whereas RVe (57.0%) did not.
Researchers noted that corresponding bone marrow uMRD rates in the intent-to-treat population were 37.1% (CIT), 43.0% (RVe), 72.5% (GVe), and 77.9% (GIVe). Month 15 overall response rates and complete response rates for the 4 regimens mirrored the pattern for uMRD rates.
The most common grade 3-5 treatment-emergent adverse events in all patients were neutropenia (50.5%), thrombocytopenia (12.2%), tumor lysis syndrome (7.5%), infusion-related reaction (7.2%), febrile neutropenia (6.5%), and pneumonia (5.3%). In addition, atrial fibrillation and bleeding events occurred more frequently in patients treated with GIVe, whereas infusion-related reactions were most common in the GVe arm.
Second malignancies occurred among 33 patients in the CIT arm, 22 patients in the GVe arm, 21 patients in the GIVe arm, and 19 patients in the RVe arm. Fatal adverse events were reported in 5, 7, 6, and 9 patients, respectively.