The 6-year follow-up of a landmark study has revealed significant treatment-free remissions and safety findings in elderly patients with chronic lymphocytic leukemia (CLL) and coexisting medical conditions.1
Long-term results of the CLL14 trial, presented during the European Hematology Association (EHA) 2023 Hybrid Congress,1 showed that 53% of previously untreated patients who received a fixed duration of the combination of the BCL2 inhibitor venetoclax plus the monoclonal antibody obinutuzumab are still in remission after more than 6 years without therapy. More than 60% of patients treated with fixed-duration venetoclax plus obinutuzumab have not required the next line of treatment.
“These findings show that a significant proportion of patients experience long-term remission and have not required further treatment, which has important implications for their overall health and quality of life,” said Othman Al-Sawaf, MD, a hematologist and medical oncologist at the University Hospital Cologne and German CLL Study Group investigator for this trial.
The prospective, multicenter, open-label, randomized phase III CLL14 trial, which was conducted in collaboration with the German CLL Study Group, was designed to evaluate the efficacy and safety of a fixed duration of venetoclax plus obinutuzumab compared with chlorambucil plus obinutuzumab for patients with CLL and coexisting conditions. The trial included 432 patients, all of whom were previously untreated, with a median age of 72 years and various risk profiles.
Patients were treated for 1 year. Then all patients stopped treatment regardless of measurable residual disease (MRD) or response.
6-Year Follow-up Results
As Dr. Al-Sawaf reported, patients treated with fixed-duration venetoclax plus obinutuzumab continued to experience improved progression-free survival (hazard ratio [HR] = 0.40) and higher rates of undetectable MRD compared with those who received chlorambucil plus obinutuzumab (53.1% vs 21.7%, respectively). The median progression-free survival was 76.2 months.
The data also showed significantly improved rates of time to next treatment with venetoclax plus obinutuzumab at 65.2% (HR = 0.44) compared with chlorambucil plus obinutuzumab at 37.1%. According to Dr. Al-Sawaf, the observed differences in progression-free survival and time to next treatment benefits between venetoclax-based treatment and chemoimmunotherapy were maintained across all risk groups, including patients with high-risk molecular features of CLL.
“Subgroup analyses showed that patients with high-risk factors, such as TP53 aberrations or unmutated IGHV status, also benefited from treatment with venetoclax plus obinutuzumab. However, their progression-free survival was shorter compared with that of patients who did not have these high-risk factors,” he explained.
Findings also showed a correlation between end-of-treatment MRD status and both progression-free survival and overall survival. Patients with high MRD levels at the end of treatment had significantly shorter survival outcomes, said Dr. Al-Sawaf.
In terms of safety, the study revealed a low incidence of posttreatment toxicity in both treatment groups, with no new safety signals identified. The most frequently occurring grade 3 (≥ 2%) adverse events in patients receiving the venetoclax-based combination were neutropenia, thrombocytopenia, infusion-related reaction, anemia, febrile neutropenia, pneumonia, and leukopenia. Rates of secondary malignancy were numerically higher in certain solid organ tumors and melanoma in the venetoclax arm, said Dr. Al-Sawaf, but these differences were not statistically significant. Importantly, the incidence rate was similar between both arms, suggesting that there is no clinical difference in the risk of second malignancies.
“These results confirm the treatment benefits of a fixed duration of venetoclax and obinutuzumab for previously untreated patients with CLL who have coexisting conditions,” said Dr. Al-Sawaf. “Clinicians treating elderly patients with CLL should be encouraged by these findings, as they demonstrate the potential for long-term disease control with a targeted-therapy approach.”
Expert Point of View
Jennifer R. Brown, MD, PhD, Director of the Chronic Lymphocytic Leukemia (CLL) Center at Dana-Farber Cancer Institute, told The ASCO Post that the updated CLL14 data continue to demonstrate “the excellent efficacy of 1 year of venetoclax plus obinutuzumab therapy for patients with CLL.”
“This is a very effective strategy, and many of us believe that time-limited therapy like this has the advantage that patients are unlikely to be resistant when they relapse—hence, they could be retreated with the same regimen,” Dr. Brown continued. “However, we are still awaiting a head-to-head comparison of this strategy against continuous Bruton’s tyrosine kinase (BTK) inhibitors (as well as against combinations of a BTK inhibitor and a BCL2 inhibitor).”
Jennifer R. Brown, MD, PhD
Catherine C. Coombs, MD
Catherine C. Coombs, MD, Associate Clinical Professor of Hematology/Oncology at UCI Health, told The ASCO Post that having an additional year of follow-up is “incredibly useful when talking to patients about what to expect.”
Although updated median progression-free survival for higher-risk populations, including unmutated IGHV and TP53, has changed slightly and is shorter than in the overall study population, added Dr. Coombs, this patient population still maintains significant time off therapy following the course of this regimen. “My confidence continues with this regimen, but I make sure to discuss expectations with all my patients, especially with respect to their underlying risk features,” she added. With respect to future clinical research, Dr. Coombs said she was eager to see response rates and durability of response to retreatment with venetoclax.
DISCLOSURE: Dr. Al-Sawaf reported financial relationships with AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Gilead Sciences, Janssen Pharmaceuticals, Eli Lilly, and Roche. Dr. Brown has served as a consultant for AbbVie, Acerta/Astra-Zeneca, Alloplex Biotherapeutics, BeiGene, Genentech/Roche, Grifols Worldwide Operations, Hutchmed, iOnctura, Kite, Loxo/Lilly, Merck, Numab Therapeutics, Pfizer, Pharmacyclics; and has received research funding from BeiGene, Gilead, iOnctura, Loxo/Lilly, MEI Pharma, SecuraBio, TG Therapeutics. Dr. Coombs reported no conflicts of interest.
REFERENCE
1. Al-Sawaf O, Robrecht S, Zhang C, et al: Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia. EHA2023 Hybrid Congress. Abstract S145. Presented June 8, 2023.
