According to 6-year results from the Phase III CLL14 trial (NCT02242942), fixed-duration venetoclax (Venclexta) plus obinutuzumab (Gazyva) therapy resulted in a 60% reduction in the risk of progression or death compared to chlorambucil plus obinutuzumab, with benefit seen regardless of TP53 or IGHV mutation status.
At the 17th Annual International Conference on Malignant Lymphoma, Othman Al-Sawaf, MD, of the Division of Haematology, Immunology, Infectiology, Intensive Care and Oncology at the University of Cologne in Germany, presented the findings.
Results revealed that venetoclax had a 6-year progression-free survival (PFS) rate of 53.1% compared to chlorambucil’s PFS rate of 21.7% . Venetoclax and chlorambucil had median PFS of 76.2 months and 36.4 months, respectively.
The FDA approved the regimen in 2019 for the first treatment of individuals with CLL/small lymphocytic lymphoma based on the findings of the main analysis. Data from a five-year follow-up were revealed at the EHA Congress in 2022.
Patients with treatment-naive chronic lymphocytic leukemia (CLL) who also had comorbid illnesses as determined by the Cumulative Illness Rating Scale (CIRS) above 6 and/or a creatinine clearance < 70 mL/min were included in the trial. For a total of one year of therapy, patients were randomized 1:1 to receive either 6 cycles of venetoclax and obinutuzumab followed by another 6 cycles of venetoclax, or 6 cycles of chlorambucil and obinutuzumab followed by another 6 cycles of chlorambucil.
PFS was the trial’s main measure of success. Response, minimum residual disease (MRD), and overall survival (OS) were considered secondary end goals.
The median estimated creatinine clearance was 65.2 mL/min in the venetoclax arm (n = 216), and the median age was 72 years. The median CIRS score was 9 (range, 0-23). A (21%), B (35%), and C (44%), together with the tumor lysis syndrome (TLS) risk categories of low (13%), intermediate (64%), and high (22%), were all represented by the Binet stages. The median age in the chlorambucil arm (n = 216), the median CIRS score (range, 1-28), and the median estimated creatinine clearance (mL/min) were all 71 years old. The distribution of TLS low (12%), intermediate (68%), and high (20%) risk, as well as Binet stage A (20%), B (37%), and C (43%) illness, was identical to that of the experimental arm.
The majority of patients in the venetoclax arm (61%), had unmutated IGHV; 12% had 17p deletion and/or TP53 mutation; and 34% had just 13q deletion. In the chlorambucil group, 36% of patients only had a 13q deletion whereas 12% had a 17p deletion and/or TP53 mutation. In the investigational and control groups, respectively, 24% and 20% of individuals showed no abnormalities.
The median period of observation was 76.4 months.
Additional findings demonstrated that patients without TP53 mutation/17p deletion experienced improved progression-free survival (PFS) regardless of the intervention. In the venetoclax group, the median PFS for patients without these markers was 76.6 months, compared to 51.9 months for those with the markers (HR, 2.29; 95% CI, 1.37-3.83; P = .001). In the chlorambucil group, median PFS was 38.9 months for patients without the markers and 20.8 months for those with them (HR, 1.66; 95% CI, 1.05-2.63; P = .03).
Patients with mutated IGHV had a median PFS that was not reached (NR) with venetoclax, while those with unmutated IGHV had a median PFS of 64.8 months (HR, 0.38; 95% CI, 0.23-0.61; P < .001). In the chlorambucil group, patients with mutated IGHV had a median PFS of 62.2 months, whereas those with unmutated IGHV had a median PFS of 26.9 months (HR, 0.33; 95% CI, 0.23-0.47; P < .001).
Notably, the presence of TP53 mutation/17p deletion did not appear to negatively impact PFS in patients with IGHV mutations who received venetoclax. The 6-year PFS rates were 47.2% and 31.3% in patients without and with TP53 deletion/mutation, respectively.
The median time to next treatment was NR with venetoclax and 52.9 months with chlorambucil, with 6-year rates of 65.2% and 37.1%, respectively (HR, 0.44; 95% CI, 0.33-0.58; P < .0001). Most patients in both groups received targeted agents as second-line therapy, with BTK inhibitors being the most common choice, followed by BCL-2 inhibitors.
Median overall survival (OS) was NR in both groups, with 6-year rates of 78.7% and 69.2% for venetoclax and chlorambucil, respectively (HR, 0.69; 95% CI, 0.48-1.01; P = .052).
Minimal residual disease (MRD) evaluated through next-generation sequencing in peripheral blood was sustained at less than 10-4 in 1.9% of patients who received chlorambucil and 7.9% of those who received venetoclax. MRD status at the end of treatment correlated with long-term PFS and OS (HR, 3.42; 95% CI, 1.65-7.06; P < .001).
In terms of safety, post-treatment toxicity was infrequent in both groups. In the venetoclax group, grade 3 or greater adverse effects included neutropenia (3.8%), thrombocytopenia (0.5%), anemia (1.9%), febrile neutropenia (0.9%), and pneumonia (3.3%). In the chlorambucil group, these adverse effects included neutropenia (1.9%), anemia (0.5%), febrile neutropenia (0.5%), pneumonia (1.4%), and infusion-related reaction (0.5%).
The rate of second primary malignancies was 14.2% with venetoclax and 8.4% with chlorambucil, including cases of melanoma, solid organ tumors, hematologic malignancies, and other malignancies.
