Venetoclax has demonstrated substantial efficacy in the treatment of chronic lymphocytic leukemia (CLL). However, the metabolism of venetoclax primarily relies on the cytochrome P450 enzyme CYP3A4, which can be influenced by concurrent administration of strong CYP3A4 inhibitors (ex: ketoconazole). These drugs have the potential to interact with venetoclax by inhibiting its metabolism resulting in elevated venetoclax plasma concentrations. Venetoclax availability in the public setting in Brazil is currently limited, with irregular donations being the only possible source. Therefore, we have made the decision to utilize ketoconazole to save venetoclax tablets in an effort to maximize treatment opportunities for as many patients as possible.

Evaluate the efficacy and safety of the combination therapy of ketoconazole, low-dose venetoclax, and rituximab in the treatment of patients with CLL.

Patients received venetoclax starting on day 22 of cycle 1, with a 5-week dose ramp-up (20 mg, 50 mg, 100 mg, and 200 mg). Subsequently, they received venetoclax 100 mg in combination with ketoconazole 200 mg daily until completion of cycle 12 (for patients in the first line of treatment) or cycle 24 (for patients in further treatment lines). Intravenous rituximab was also administered for six cycles, 375 mg/m2 in cycle 1 and 500 mg/m2 in cycles 2 to 6. All patients included in the analysis had received a minimum of 6 months of treatment at the time of data collection.

A total of 21 treatment regimens for 18 patients were included in this analysis. The median duration of venetoclax treatment was 12 months, ranging from 6 to 24 months. Six patients (29%) received the treatment as a first-line therapy, 5 (24%) as a second-line therapy, 8 (38%) as a third-line therapy, and the remaining patients received it in further lines of treatment. The overall response rate was 100%, with 14 treatments leading to a complete response and 7 treatments to a partial response. Among the partial responders, 4 patients are still receiving treatment, and 2 patients completed six months of treatment and were referred to an allogeneic stem cell transplantation. The most common grade 3 or 4 adverse event observed was neutropenia, which occurred in 12 treatments. Notably, no cases of grade 2 or higher hepatic toxicity related to ketoconazole were reported. Additionally, there were no treatment-related deaths observed in the study. At a median follow-up of 19 months (range: 6-33), the median progression-free survival (PFS) has not been reached, and the PFS at 24 months was 83%. Three cases of disease progression occurred after 26, 30, and 39 months of treatment. All three patients were successfully retreated with the same treatment combination and achieved at least a partial response again. The median overall survival (OS) has not been reached, and the OS at 24 months was 95%. Three deaths were recorded during the study period: one patient died from acute myelogenous leukemia, one patient from a myocardial infarction, and one patient due to an unrelated intestinal bleeding.

Our data indicate that the combination of ketoconazole, low-dose venetoclax, and rituximab showed favorable tolerability and promising effectiveness in patients with CLL. Further studies are warranted to confirm these observations and validate the potential benefits of this combination regimen in the management of CLL in similar settings.