Weight based dosing of alemtuzumab as part of an enhanced lymphodepletion regimen may  mitigate the risks of over and underexposure and improve response rates : Analysis of the nathali-01 trial

Abstract Introduction: 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. 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. 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 NatHaLi-01 study, a first-in-human, open-label, dose-finding and dose-expansion study of the dual CAR-T therapy UCART20x22 administered intravenously in subjects with relapsed or refractory B-Cell Non-Hodgkin Lymphoma (B-NHL). Body weight has a significant impact on the overall exposure to alemtuzumab. This results in significant intersubject variability in pharmacokinetics with the potential for some subjects to be highly exposed and some subjects being potentially underexposed based on their body weight when flat dosing was applied. This has implications for both efficacy and toxicity. Weight based dosing of alemtuzumab is being investigated in the NatHaLi-01 study to understand if this approach will allow for the optimization of efficacy while controlling the potential for toxicities due to overexposure. Methods: Based on body weight, the mg/kg exposure to alemtuzumab was calculated in subjects who completed the NatHaLi-01 study. The impact of body weight on alemtuzumab pharmacokinetics, UCART20x22 expansion, host immune reconstitution and toxicities was assessed to determine if there was a relationship between alemtuzumab exposure and outcomes in terms of response assessment and toxicity. PK modeling of multiple weight based doses was performed to identify a potential optimal weight based dose. Results: The data from the NatHaLi-01 study demonstrates significant intersubject variability in exposure to alemtuzumab. Increased weight with resultant lower alemtuzumab exposure appears to be associated with earlier host immune reconstitution and reduced CAR T-cell expansion and therefore, poorer response to treatment. Conversely, lighter patients with resultant increased exposure demonstrated greater UCART20x22 expansion and delayed host immune reconstitution with apparent improvement in response rates. Overall, the best responses appear to be in the subjects with the highest levels of alemtuzumab exposure. While no clear correlation between exposure and toxicity is evident, a dose limiting toxicity was observed in a subject with higher levels of exposure. PK modeling demonstrated the potential for over and underexposure with a flat based dosing schedules. Conclusion: Adequate alemtuzumab exposure is important in achieving adequate lymphodepletion and disease response due to the positive impact on CAR-T cell expansion and the delay in host immune reconstitution. Increased weight with resultant lower alemtuzumab exposure may be associated with early host immune reconstitution and limited CAR T-cell expansion and suboptimal response. However, while adequate exposure is important, overexposure may be also associated with unnecessary toxicities which alters the risk benefit assessment. Therefore, dosing schedules of alemtuzumab which limit the potential for both over and underdosing must be investigated. The feasibility of weight based dosing is being investigated in the NatHaLi-01 study.