Tumor burden-guided dosing contributes to mitigation of immunotoxicities following treatment with obecabtagene autoleucel in adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia.

Obecabtagene autoleucel (obe-cel) is a CD19-targeted autologous chimeric antigen receptor T-cell therapy (CAR T) with a fast off-rate binding domain, administered as split-dose infusions guided by pre-lymphodepletion tumor burden (low-tumor- burden [TB] group: ≤20%; high-TB group: >20% bone marrow [BM] blasts). Obe-cel treatment in adult relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) was investigated in the phase Ib/II FELIX trial. Here, we report pharmacokinetics, safety, and efficacy outcomes in patients with low or high tumor burden and discuss the evidence/rationale justifying the spilt-dose strategy and threshold used to classify the groups. Tumor burden at lymphodepletion was a critical driver of CAR T-cell expansion; a 50% increase, e.g., 70% versus 20% BM blasts, was associated with a 1.9-fold increase (95% confidence interval: 1.4-2.6) in maximal expansion of CAR T cells. Robust CAR T-cell expansion was observed in both tumor burden groups. The incidence of grade ≥3 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome was minimal in both the low- and high-TB groups (2% vs. 3% and 4% vs. 9%, respectively). Although the overall remission rate was higher in the low-TB group (85%), it also remained high in the high-TB group (73%). Evidence from FELIX suggests that use of tumor burden--guided dosing may mitigate the typical effects of immunotoxicity while maintaining substantial efficacy. Although further study is needed to better characterize the effects of the split-dosing strategy, the clinical evidence supports its use when administering obe-cel for the treatment of R/R B-ALL. Trial registered at www.clinicaltrial. gov (clinicaltrials gov. Identifier: NCT04404660).