Increased alemtuzumab exposure correlates with improved responses in heavily pretreated R/R ALL patients: Analysis of the balli-01 trial

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Abstract Chimeric Antigen Receptor T-cell (CAR-T) therapy has revolutionized treatment of refractory hematologic cancers, particularly B-cell malignancies. A critical preparative step for CAR-T infusion is lymphodepletion (LD) which creates a more permissive immune environment to improve CAR-T expansion, engraftment and efficacy. Clinical trials across multiple B-cell cancers have demonstrated that the intensity and composition of the LD regimen can significantly influence patient outcomes after CAR-T therapy. In order to optimize the clinical outcome in the allogeneic CAR-T setting, alemtuzumab is being investigated as a means to enhance existing LD regimens. Alemtuzumab is a humanized IgG1 monoclonal antibody directed against CD52, a 21–28 kDa glycoprotein abundantly expressed on most lymphocytes. Alemtuzumab-enhanced lymphodepletion produces a very deep and longer lasting immunosuppressive state. The benefit for CAR-T therapy is a maximally permissive environment for the CAR-T cells to expand. LD regimens with alemtuzumab are currently being investigated in multiple clinical studies including the BALLI-01 study in R/R ALL. Studies have consistently demonstrated that alemtuzumab pharmacokinetics are weight-dependent but there have been no studies to date to understand whether individual exposure to alemtuzumab based on body weight may result in an improved response. This was investigated in the BALLI-01 study Methods: BALLI-01 is a first-in-human, open-label, dose escalation and expansion study of UCART22 administered intravenously to patients with relapsed or refractory B-cell acute Lymphoblastic Leukemia (B-ALL). The purpose of this study is to evaluate the safety and clinical activity of UCART22 and determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D). Fludarabine, cyclophosphamide and alemtuzumab (FCA) was investigated as an LD regimen. A flat dose of alemtuzumab of 60mg given over 3 days was used. In a cohort of 17 patients, the pharmacokinetic profile of alemtuzumab was analysed to understand the overall AUC and whether a correlation with CAR-T expansion and response was present. Additionally, the impact of exposure on toxicity was assessed. Results: A clear correlation between alemtuzumab exposure and response was observed. Patients with a day 28 response assessment of progressive disease (PD) had overall lower exposure to alemtuzumab. With increased exposure, deepening of response to MLFS and to CR with the highest levels of exposure was observed. Additionally, the exposure level above which a CR was more likely to be observed was determined and was not associated with an increase in observed toxicities. Lower exposure to alemtuzumab was also associated with lower UCART22 expansion and earlier host T-cell reconstitution. Conclusion: Alemtuzumab is a critical component of the LD regimen in the BALLI-01 trial. For this allogeneic CAR-T therapy, it is important to ensure adequate exposure to alemtuzumab in order to optimize cell expansion and mitigate the risk of early host T cell reconstitution which may compromise response in these heavily pretreated ALL patients with few, if any, alternative treatment options.

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