The phase II ERADIC trial has revealed that a combination of ibrutinib and venetoclax (IV), guided by measurable residual disease (MRD), demonstrates superior efficacy compared to the standard fludarabine, cyclophosphamide, and rituximab (FCR) regimen in select patients with intermediate-risk chronic lymphocytic leukemia (CLL). The findings, presented at the 2024 ASH Annual Meeting, suggest a potential shift in first-line treatment strategies for CLL, emphasizing the importance of MRD assessment and patient-specific risk profiles.
ERADIC Trial Design and Results
The ERADIC study, conducted by the French organization, randomized 120 patients to either six cycles of FCR or a combination of ibrutinib and venetoclax (IV). The IV arm involved a three-month lead-in phase with ibrutinib alone, followed by the combination. The duration of the IV combination was determined by bone marrow MRD results at month nine. Patients with undetectable MRD continued for six months, stopping at month 15, while others continued for 18 months, stopping at month 27. The primary endpoint was the rate of undetectable MRD in the bone marrow at month 27.
While the difference in bone marrow MRD negativity rates between the two arms did not reach statistical significance (55% for FCR vs. 68% for IV), the IV arm demonstrated a significantly higher rate of undetectable MRD in peripheral blood (85%). Furthermore, the IV arm showed superior progression-free survival (95%) compared to the FCR arm (82%).
Safety Considerations
Safety profiles differed between the two regimens. FCR was associated with myelosuppression, while IV showed cardiological toxicity and metabolic disorders. There were three deaths in each arm: for FCR, one due to myelodysplasia, one due to acute myeloid leukemia, and one due to septic shock; for IV, two were cardiac-related deaths and one was related to COVID-19.
Implications for Clinical Practice
According to Dr. Anne Sophie Michallet, MD, PhD, of Centre Léon Bérard Hospital, Lyon, France, the ERADIC trial indicates that IV is superior to FCR in terms of depth of response and progression-free survival. However, she emphasized the importance of selecting appropriate patients for IV therapy: "We have to take strict account to the profile of the patient for IV: young, fit, and without comorbidity, particularly cardiovascular."
The study underscores the evolving landscape of CLL treatment, where targeted therapies and MRD-guided approaches are becoming increasingly important. The results suggest that IV can be a highly effective first-line treatment for CLL, provided that patients are carefully selected to minimize the risk of cardiac complications.
