Authors
Paula Cramer, Ellinor Görgen, Léa Mazot, Miriam Schüler-Aparicio, Sandra Robrecht, Christina Paulitschek, Aline Zey, Antonia Albrecht, Julia Blau, Laura Jung, Sophia Reidel1, Othman Al-Sawaf, Francesc Bosch, Caspar da Cunha-Bang, Michael Doubek, Emadoldin Feyzi, Anna-Maria Fink, Paolo Ghia, Michael Gregor, Romain Guieze, Krzysztof Jamroziak, Ann Janssens, Arnon P. Kater, Sabina Kersting, Petra Langerbeins, Mark-David Levin, Vesa Lindström, Mattias Mattsson, Carsten U. Niemann, Anne Quinquenel, Matthias Ritgen, Lydia Scarfò, Philipp Staber, Stephan Stilgenbauer, Tamar Tadmor, Patrick Thornton, Eugen Tausch, Loïc Ysebaert, Kirsten Fischer, Barbara Eichhorst, Michael Hallek.
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 fixedduration 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.
Aims
To evaluate if a more individualized approach is beneficial in the context of time-limited therapy, we have designed this pan-European, academic phase III trial with three arms – two evaluating a fixed-duration regimen and one evaluating a treatment duration based on measurable residual disease (MRD), using a treatment duration tailored to the depth of remission.
Methods
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), while arm B evaluates venetoclax plus pirtobrutinib (Ven-Pirto) for 15 cycles (3 cycles pirtobrutinib alone, then 12 cycles combined with venetoclax). 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 or 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, type of disease (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
At the time of submission of this abstract, the CLL18 / MOIRAI protocol was approved by the competent authorities of 13 of the 16 participating countries and recruitment was about to start. 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.
Keywords : firstline, MRD-guided
Please indicate how this research was funded.: academic IIT trial with research support by the pharmaceutical companies
Please indicate the name of the funding organization. : Lilly, AbbVie and Roche