Is It Time for Time-limited Therapy in Frontline CLL?

CLL-14 is a randomized phase III clinical trial designed for older/frail patients with chronic lymphocytic leukemia (CLL) requiring first-line treatment. Eligible patients were assigned to either venetoclax-obinutuzimab (VO) or chlorambucil-obinutuzuimab (CO). In both treatment arms, obinutuzumab was administered for six months, while venetoclax and chlorambucil were administered for a one-year fixed duration. The primary endpoint of the trial was progression-free survival (PFS). The median age of participating subjects was 72 years, with 216 patients randomized to each treatment arm. At the time of the report, the median follow-up was 28 months. The probability of remaining in remission at two years from study entry was 88 percent in the VO arm versus 64 percent in the CO arm (p<0.001). VO was also superior for overall response rates (85% vs. 71%), complete response rate (49% vs. 23%), and for minimal residual disease (MRD) negativity in the peripheral blood (75% vs. 35%). There was no difference in overall survival. VO performed well even in higher-risk subgroups such as those with unmutated IgVH genes and 17p deletions.

The management of first-line CLL has changed markedly in the past five years. Historically, the FCR (fludarabine, cyclophosphamide, and rituximab) regimen was recommended for the young healthy patients, the bendamustine-rituximab (BR) regimen for older patients, and chlorambucil-based treatment for the older and frail. Then in 2015, the BTK inhibitor ibrutinib received a frontline indication in CLL based on its superiority to chlorambucil (the “98-lb weakling” of CLL management). The option of targeted oral therapy with a good adverse effect and safety profile provided an intriguing new option for managing CLL. However, randomized data supporting ibrutinib over more potent options such as FCR and BR were lacking until just recently, when ibrutinib was shown to outperform both FCR and BR head-to-head in separate U.S. intergroup trials.^1,2  Armed with these strong new data, ibrutinib has become the preferred frontline option for patients with CLL, both young and old. However, a vexing issue with ibrutinib as frontline therapy is the requirement for continuous and indefinite treatment. Long-term follow up from frontline ibrutinib trials shows responses are maintained in more than 70 percent of patients at five years, but discontinuations due to toxicities can be 25 to 40 percent. For patients with low-grade but chronic toxicities, the cumulative effect can significantly impair quality of life. Additionally, ibrutinib is expensive therapy, and the cost over time is substantial. With these pros and cons in mind, the CLL research community has a substantial interest in developing a time-limited, targeted therapy approach to the initial management of CLL. The CLL-14 trial yields the first report of a novel targeted agent used in a time-limited fashion. The results are impressive, though admittedly the follow up is relatively short, and we do not know how patients will fare at five years with this strategy.