As reported in The Lancet Oncology by Al-Sawaf et al, 3-year follow-up of the phase III CLL14 trial showed maintained significant improvement in progression-free survival with the fixed-duration regimen of venetoclax/obinutuzumab vs chlorambucil/obinutuzumab in previously untreated patients with chronic lymphocytic leukemia (CLL).
Findings in the CLL14 trial supported the May 2019 U.S. Food and Drug Administration approval of venetoclax for the treatment of adult patients with previously untreated CLL or small lymphocytic lymphoma.
“Two years after treatment cessation, venetoclax plus obinutuzumab continues to significantly improve progression-survival compared with chlorambucil plus obinutuzumab, thereby providing a limited-duration treatment option for patients with previously untreated chronic lymphocytic leukemia.”— Al-Sawaf et al
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Study Details
In the open-label trial, 432 patients were randomly assigned between August 2015 and August 2016 to receive venetoclax plus obinutuzumab (n = 216) or chlorambucil plus obinutuzumab (n = 216). Treatment was given in 28-day cycles and consisted of six cycles of venetoclax/obinutuzumab followed by six cycles of venetoclax, vs six cycles of chlorambucil/obinutuzumab followed by six cycles of chlorambucil. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. The current analysis was performed after all patients had been off study treatment for 24 months or longer.
Key Findings
Median follow-up was 39.6 months.
Median progression-free survival was not reached (95% confidence interval [CI] = not estimable–not estimable) in the venetoclax/obinutuzumab group vs 35.6 months (95% CI = 33.7–40.7 months) in the chlorambucil/obinutuzumab group (hazard ratio [HR] = 0.31, 95% CI = 0.22–0.44, P < .0001). Progression-free survival at 3 years was 81.9% vs 49.5%.
Undetectable minimal residual disease was present in 76% vs 35% of patients (P < .0001) at 3 months after treatment completion and in 47% vs 7% at 18 months after treatment completion.
Second-line treatment after disease progression was received by 4% vs 20% of patients.
Median overall survival was not reached in either group. At time of analysis, 13% vs 13% of patients had died (HR = 1.03, P = .92).
The most common grade 3 or 4 adverse event in both groups was neutropenia (53% vs 48%). Serious adverse events occurred in 54% vs 44% of patients. Venetoclax or chlorambucil treatment-related deaths were reported in one patient in the venetoclax/obinutuzumab group (due to sepsis) and in two patients in the chlorambucil/obinutuzumab group (due to septic shock and metastatic skin squamous carcinoma).
The investigators concluded, “Two years after treatment cessation, venetoclax plus obinutuzumab continues to significantly improve progression-survival compared with chlorambucil plus obinutuzumab, thereby providing a limited-duration treatment option for patients with previously untreated chronic lymphocytic leukemia.”
Michael Hallek, MD, of the German CLL Study Group, University Hospital, University of Cologne, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by F. Hoffmann-La Roche and AbbVie. For full disclosures of the study authors, visit thelancet.com.
