Dr. Brian Hill, MD, PhD, from the Cleveland Clinic presented a study conducted through the Alliance and US cooperative groups, including ECOG and SWOG, called the A041702 study. This randomized phase 3 trial focused on previously untreated CLL patients over the age of 70. The study aimed to determine whether the addition of Venetoclax to Ibrutinib and Obinutuzumab would improve progression-free survival through a response-adapted use of Venetoclax for one year of therapy.
The study compared two treatment arms. In the standard arm, patients received Ibrutinib and Obinutuzumab for one year, with Ibrutinib continued afterward. In the experimental arm, patients received Ibrutinib, Obinutuzumab, and Venetoclax for one year. Patients achieving an undetectable minimal residual disease (MRD) state had all therapy discontinued, while those with detectable MRD continued on indefinite therapy with Ibrutinib.
The study revealed toxicities associated with both treatments, exacerbated by the COVID-19 pandemic during the study period. The experimental arm had a higher number of deaths, with 19 out of 28 deaths attributed to COVID-19, compared to 11 out of 23 deaths in the standard arm. Overall survival was 87.5% in the standard arm and approximately 85% in the experimental arm.
The study results showed that the hazard ratio favored the doublet therapy (Ibrutinib and Obinutuzumab) over the triplet therapy (Ibrutinib, Venetoclax, and Obinutuzumab). This finding highlighted the significant impact of COVID-19 on older patients with CLL, as the risks of lympho-depleting and myelosuppressive therapies outweighed the benefits during the pandemic.
However, Dr. Hill noted that with the availability of better vaccines and treatments for COVID-19, a repeat study conducted in the more modern era might not observe the same imbalance of deaths due to COVID-19. He emphasized that the field has rapidly evolved in terms of COVID-19 treatment and supportive care.
In conclusion, the study demonstrated that triplet therapy with Ibrutinib, Venetoclax, and Obinutuzumab was not superior and possibly inferior to doublet therapy with Ibrutinib and Obinutuzumab in older CLL patients. Future investigations are exploring other triplets, including different BTK inhibitors, and comparing them to Venetoclax and Obinutuzumab.
Dr. Hill highlighted the potential for personalized treatment based on response-adapted therapy, where the depth of remission determined by MRD assessment would dictate whether treatment continued or not. He emphasized the exciting advancements in CLL treatment, the availability of novel therapeutics, and the ongoing need for perspective phase 3 trials to test different combinations and treatment strategies for optimal outcomes in all CLL patients.