Evaluating Safety & Outcomes of Rapid BCL-2 Inhibitor Titration for CLL

Photo Credit: Nemes Laszlo

In a retrospective, single-center study presented at the 2024 ASCO Annual Meeting, researchers explored the safety of rapidly titrating a BCL-2 inhibitor in patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL).

CLL and MCL often exhibit rapid disease progression, necessitating fast therapeutic intervention. When administering the BCL-2 inhibitor venetoclax, clinicians must perform meticulous dose titration to mitigate the risk of tumor lysis syndrome. Standard outpatient titration spans 29 days to achieve the maximum dose, during which low doses provide minimal disease control.

“A common practice at our site is to rapidly titrate venetoclax to 100 mg within 1 week with hospitalization for careful tumor lysis syndrome monitoring and management,” wrote Tijesuni Babalola, MD, and colleagues affiliated with the University of Virginia. “We present the safety and outcomes of 39 identified patients treated as such.”

Rapid Venetoclax Titration Findings

The rapid venetoclax titration protocol involved administering 20 mg for 2 days, then 50 mg for 2 days, then 100mg daily, with tumor lysis syndrome labs monitored every 6 to 8 hours. Based on clinicians’ discretion, patients also received continuous IV hydration and allopurinol, with or without rasburicase. Patients without tumor lysis syndrome were typically discharged after 2 days on venetoclax 100 mg, then continued weekly outpatient dose escalation to 200 mg and subsequently to 400 mg. Patients experiencing disease progression often received BTK inhibitors concurrently with early venetoclax doses.

The CLL/SLL cohort included 22 patients. These patients were an average age of 58 years and predominantly male (68%), and half the group (52%) had Del17p or TP53 mutations. Five patients (23%) experienced laboratory tumor lysis syndrome; two patients with tumor lysis syndrome were considered low risk. Only one patient (4.5%) exhibited clinical tumor lysis syndrome, marked by a Grade 2 creatinine elevation.

“In that specific patient, considered low risk for tumor lysis syndrome, the elevated creatinine did not recover but was subsequently deemed secondary to Richter’s transformation involving the kidneys,” Dr. Babalola and colleagues reported.

Meanwhile, the MCL cohort included 17 patients who were, on average, 65 years old and mostly male (71%). Just under half (43%) had Del17p or TP53 mutations. Six patients (35%) in the MCL group experienced laboratory tumor lysis syndrome, of which three were low-risk. However, no patients in the MCL cohort experienced clinical tumor lysis syndrome.

The researchers reported no unexpected toxicity beyond what is typically associated with venetoclax and anti-CD20 antibodies.

On average, the patients reached a dose of 100 mg venetoclax in 6.5 days (range quartile [Q]1, 5 days; Q3, 10 days), and the mean time to attain the target venetoclax dose was 18.8 days (range Q1, 14 days; Q3, 25 days). A total of 64% of patients achieved the target dose of 400 mg.

Dr. Babalola and coinvestigators concluded that their retrospective analysis underscores the efficacy of rapid venetoclax titration in a controlled environment for patients with high-risk disease who need prompt disease control with a low incidence of clinical tumor lysis syndrome.

“However, lab tumor lysis syndrome occurred in low-risk patients treated in this manner, necessitating hospitalization despite low risk,” the researchers wrote. “No unexpected or additional toxicity was observed.”