Early results from the CLL17 trial show that fixed-duration doublet regimens with venetoclax are noninferior to continuous ibrutinib therapy, with similar 3-year progression-free survival rates, for patients with chronic lymphocytic leukemia (CLL), according to findings presented at the 67th American Society of Hematology (ASH) Annual Meeting and Exposition (Abstract 1).
This study, which was also simultaneously published in The New England Journal of Medicine, challenges the common idea that patients need to remain on treatment indefinitely for the greatest impact.
“As clinicians, we often assume that continuous treatment will always be more effective because you’re simply giving more treatment, but this study shows that is not necessarily the case,” said lead study author Othman Al-Sawaf, MD, PhD, Hematologist and Medical Oncologist at the University of Cologne in Germany. “The results provide the first evidence that fixed-duration treatment, which patients often prefer, is indeed noninferior to continuous treatment, suggesting clinically equal efficacy.”
Study Design
Investigators initiated a prospective, international, randomized phase III trial to directly compare two standard approaches used for the treatment of patients with CLL: continuous BTK inhibition or fixed-duration treatment with a BCL2 inhibitor and a CD20 antibody or a BTK inhibitor. The CLL17 trial enrolled 909 patients with CLL who were randomly assigned 1:1:1 to receive either continuous ibrutinib, fixed-duration venetoclax plus obinutuzumab, or fixed-duration venetoclax plus ibrutinib. Patients were stratified by IGHV status, del(17p)/TP53 mutation, and patient fitness, which was defined by cumulative illness rating score > 6 and/or creatinine clearance < 70 mL/min.
The trial was designed to examine the noninferiority of fixed-duration venetoclax/obinutuzumab vs continuous ibrutinib and fixed-duration venetoclax/ibrutinib vs continuous ibrutinib monotherapy. Up to an 8% reduction in 3-year progression-free survival rate, the primary endpoint, was considered a not clinically meaningful difference. Secondary endpoints included overall response rate, undetectable minimal residual disease (< 10-4), overall survival, and safety.
Key Findings
At 3 years, the progression-free survival rate in the fixed-duration venetoclax/obinutuzumab arm was 81.1% vs 81.0% in the continuous ibrutinib arm (hazard ratio [HR] = 0.87; 98.3% confidence interval [CI] = 0.54–1.41). In the venetoclax/ibrutinib arm, the 3-year progression-free survival rate was 79.4% (HR = 0.84; 98.0% CI = 0.53–1.32). The upper limit of each adjusted CI was below the predefined noninferiority margin, demonstrating noninferiority for each comparison.
At the final staging, the overall response rate was 84.2% in the venetoclax/obinutuzumab arm, 88.5% in the venetoclax/ibrutinib arm, and 86.0% in the continuous ibrutinib monotherapy arm; complete response rates were 51.5%, 46.2%, and 8.3%, respectively. Undetectable minimal residual disease in the peripheral blood in the intention-to-treat population was found in 73.3% of patients in the venetoclax/obinutuzumab arm and in the bone marrow in 62% of patients; in the venetoclax/ibrutinib arm, it was detected in 47.2% in the peripheral blood and in 40% in the bone marrow; in the continuous ibrutinib monotherapy arm, the undetectable minimal residual disease rate was 0% in both the peripheral blood and in the bone marrow.
The 3-year overall survival rate was 91.5% in the fixed-duration venetoclax/obinutuzumab arm vs 95.7% in the continuous ibrutinib arm (HR = 1.67; 95% CI = 0.86–3.28). In the fixed-duration venetoclax/ibrutinib arm, the overall survival rate at 3 years was 96% (HR = 0.96; 95% CI = 0.45–2.05).
“The secondary endpoints are surrogate parameters for us to assume long-term efficacy,” said Dr. Al Sawaf. “With the fixed-duration paradigm, we see higher rates of complete response and minimal residual disease responses, and with the continuous single-agent treatment we see lower complete response and minimal residual disease responses.”
The most commonly seen adverse events were infections/infestations (76.3% with venetoclax/obinutuzumab, 80.2% with venetoclax/ibrutinib, 79.9% with ibrutinib), gastrointestinal disorders (59.7% with venetoclax/obinutuzumab, 74.3% with venetoclax/ibrutinib, 63.4% with ibrutinib), and blood and lymphatic system disorders (59.0% with venetoclax/obinutuzumab, 42.9% with venetoclax/ibrutinib, 28.5% with ibrutinib). Adverse events of interest included COVID-19 infection in 38.3% of patients in the fixed-duration venetoclax/obinutuzumab arm, 42.2% of patients in the venetoclax/ibrutinib arm, and in 39.3% of patients from the continuous ibrutinib monotherapy arm; cardiac disorders in 13.9%, 23.8%, and 34.6%, respectively; and secondary cancers in 11.5%, 11.2%, and 18.5%.
Disclosure: The study was investigator-initiated under sponsorship of the University of Cologne; AbbVie Inc., Janssen Pharmaceuticals, and Roche Pharmaceuticals provided the study drugs and funding to support the trial conduct; parts of the analyses and research staff were supported by the German Research Foundation (Deutsche Forschungsgemeinschaft). Dr. Al-Sawaf reported consultancy, including expert testimony, for AbbVie, Janssen, Roche, BeiGene, Genmab, Lilly, AstraZeneca, and research funding from AbbVie, Janssen, Roche, BeiGene, Genmab, Lilly, and AstraZeneca. For full disclosures of the study authors, visit meetings-api.hematology.org.
