CLL18/MOIRAI TRIAL AIMING TO ESTABLISH MEASUREMENT OF INDIVIDUAL RESIDUAL DISEASE FOR ADJUSTMENT OF TREATMENT DURATION TO IMPROVE OUTCOMES IN TREATMENT-NAIVE CLL/SLL

Background: The two major options for the first-line therapy of chronic lymphocytic leukemia (CLL) are a continuous BTK inhibitor treatment given as long as possible for disease control, or a venetoclax-based fixed-duration treatment, which usually leads to deep responses and a treatment-free interval of several years. There is an increased use of fixed-duration venetoclax-based regimens, such as venetoclax plus obinutuzumab (12 cycles) or venetoclax plus ibrutinib or acalabrutinib with/without obinutuzumab. While these combination therapies are more intense compared to monotherapies, the treatment-free interval carries advantages in terms of quality of life, safety and costs. The goal of this phase-III trial is to evaluate if a more individualized, but time-limited treatment duration is beneficial.

Methods: Two treatment arms have a fixed-duration and one arm evaluates a treatment duration based on measurable residual disease (MRD):

— the standard arm A is the established combination of venetoclax and obinutuzumab (Ven-Obi, 12 cycles with a duration of 28 days, Obi only during cycles 1–6),

— arm B evaluates venetoclax plus pirtobrutinib (Ven-Pirto) for 15 cycles (3 cycles pirtobrutinib alone, then 12 cycles combined with venetoclax), and

— in arm C, Ven-Pirto will be administered for at least 15 and up to 36 cycles (as long as there is a deepening of response) until achievement of undetectable MRD (uMRD). To facilitate the transfer to clinical routine, MRD is measured in peripheral blood, by multi-colour flow cytometry and with a cut-off of 10⁻⁴. Two MRD assessments with an interval of 12 weeks both documenting uMRD are needed to allow for a treatment discontinuation and treatment will be continued for an additional 12 weeks after the second uMRD result as a consolidation.

813 patients with previously untreated CLL/SLL irrespective of age, comorbidities or CLL risk-factors will be recruited 1:1:1 to the three arms (271 each) with a stratification according to TP53 deletion and/or mutation, IGHV mutational status, disease type (CLL vs. SLL), and age. The primary endpoint is the investigator-assessed progression-free survival (PFS). The trial is designed to show both superiority of MRD-guided Ven-Pirto over Ven-Obi and over fixed duration Ven-Pirto. Secondary endpoints include iwCLL response, MRD, overall survival and safety parameters.

Results: Recruitment is expected to start at the time of the ICML meeting. The estimated recruitment time of the 813 patients in approximately 160 sites in 16 countries is 20 months. Approximately 41 months after start of recruitment, a sufficient number of PFS events shall be reached for the primary endpoint analysis.

Summary/Conclusion: The CLL18/MOIRAI trial will address the question whether an individualized, MRD-guided first-line treatment with pirtobrutinib and venetoclax improves the outcome of patients with CLL/SLL compared to fixed duration venetoclax with either obinutuzumab or pirtobrutinib.

Research funding declaration: financial support of the trial and provision of study medication by AbbVie, F. Hoffmann-LaRoche, and Lilly

Encore Abstract: EHA 2025

Keywords: minimal residual disease; chronic lymphocytic leukemia (CLL); ongoing trials

Potential sources of conflict of interest:

P. Cramer

Consultant or advisory role: AbbVie and Lilly

Honoraria: AbbVie, F. Hoffmann-LaRoche, and Lilly

Educational grants: AbbVie and F. Hoffmann-LaRoche

Other remuneration: research funding (institution) from AbbVie, F. Hoffmann-LaRoche, and Lilly