Patients with previously untreated chronic lymphocytic leukemia (CLL) who receive one-year fixed-duration treatment with venetoclax-obinutuzumab (Ven-Obi) experience sustained long-term survival, undetectable measurable residual disease (uMRD), and quality-of-life (QoL) benefits. Othman Al-Sawaf, MD, a hematologist at the University Hospital of Cologne in Germany, and colleagues published the six-year results of the randomized phase III CLL14 study in Blood.
The study reinforces the benefits of using fixed-duration, targeted treatment in patients with previously untreated CLL. Fixed-duration targeted treatment of CLL combines the BCL2 inhibitor Ven with the anti-CD20 antibody Obi and has become a standard of care in the first-line treatment of CLL.
“This is the longest observation we have for this regimen,” said Dr. Al-Sawaf, describing the CLL14 study. The new analysis included patients (median age of 72 years at enrollment) with previously untreated CLL and coexisting conditions (unfit patients) who received first-line therapy with either Ven-Obi or chemoimmunotherapy with chlorambucil (Clb)-Obi. All of the patients in the study had been off treatment for at least five years (median age = 77 years).
The study enrolled 432 patients, 59.8% of whom had unmutated IGHV status, and 11.8% had del(17p) and/or TP53 mutation. The new data reveal that treatment with one-year fixed-duration Ven-Obi was associated with durable treatment-free remissions, a six-year progression-free survival (PFS) rate of 53%, and a six-year time-to-next-treatment rate of 65%. In both treatment arms, patients with del(17p) and/or TP53 mutation had a shorter PFS than patients without del(17p) and/or TP53 mutation.
“One year of fixed-duration treatment provides long-term remissions,” Dr. Al-Sawaf said. Moreover, he explained that the vast majority of patients did not require the next line of treatment, and because patients were already in their seventies when they received their first treatment, they may only need one treatment in their lives. “The time to next treatment is very positive,” Dr. Al-Sawaf said, describing the results as “very encouraging.”
Dr. Al-Sawaf and his colleagues also found that end-of-treatment MRD status was associated with PFS and overall survival. Moreover, at six years, the number of patients in the Ven-Obi arm with uMRD in peripheral blood dropped to an MRD < 10-4 rate of 8%. The investigators noted a significant difference in patient-reported outcomes in patients treated with Ven-Obi versus Clb-Obi, such that patients in the Ven-Obi arm had a significantly longer time until definitive deterioration in global health status/QoL compared to the Clb-Obi arm (median 82.1 vs. 65.1 months, respectively). The researchers also calculated follow-up adjusted second primary malignancy incidence rates of 2.3 per 1,000 patient months in the Ven-Obi arm and 1.4 per 1,000 patient months in the Clb-Obi arm.
Dr. Al-Sawaf noted that the study found no long-term toxicity associated with the fixed-duration treatment. This is likely due to the fact that exposure to treatment is limited to just one year. Nevertheless, it is currently unclear which group of patients benefits most from fixed-duration Ven-Obi or other targeted approaches, such as continuous Bruton tyrosine kinase inhibition or an oral fixed-duration regimen of venetoclax-ibrutinib. Dr. Al-Sawaf’s team is currently performing another study comparing the continuous and fixed duration paradigms. They also intend to look more closely at MRD to determine if it can be used as an indication to extend or shorten treatment.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Al-Sawaf O, Robrecht S, Zhang C, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the phase 3 CLL14 study [published online ahead of print, 2024 July 10]. Blood. doi: 10.1182/blood.2024024631.
