Abstract
Relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) may occur in the central nervous system (CNS). Most clinical trials of CAR T-cell therapy excluded patients with active CNS leukemia, partially for concerns of neurotoxicity. Here, we report an international study of fifty-five children and adolescents who received CAR T-cell therapy for relapsed BCP-ALL with CNS involvement at the time of referral. All patients received bridging therapy, 16 still having active CNS disease at the time of lymphodepletion. Twelve patients received CD28-based CAR T-cells, 9 being subsequently treated with allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Forty-three patients received 4-1BB-based CAR T-cells. Cytokine-release syndrome (CRS) and neurotoxicity occurred in 65% and 38% of patients, respectively, more frequently following treatment with CD28-based CARs. Fifty-one of 54 evaluable patients (94%) achieved complete response following this therapy. Relapse occurred in 22 patients: 19/43 following 4-1BB-based CARs (12 CNS relapses), and 3/12 after CD28-based CARs with subsequent HSCT (no CNS relapse). Patients treated with tisagenlecleucel for an isolated CNS relapse had a high incidence of a subsequent CNS relapse (6 of 8). CAR T-cells were found to be effective in this cohort, though the risk of CNS relapse was not completely mitigated by this approach.
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Funding
This work was done on behalf of the international BFM Resistant Disease study group. This study was funded by the Dotan research center in hemato-oncology and by the Israel Cancer Association.
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EJ, JPB and AB conceived the study and oversaw the project; EJ, SG, BV, BDM, NB, OM, AY, JB, RE, BB, SR, ED, MM, CR, AT, AVS, FL, PB, JPB and AB collected patient data. EJ and MZ performed statistical analysis, EJ, MZ and AB analyzed and interpreted data; EJ, AB, SG, BV and BDM wrote and significantly revised the manuscript. All authors approved the manuscript.
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This study was not supported by phama but by a NPO grant (ICA to Dr. Jacoby). EJ reports participation of advisory boards for Novartis and Lonza and speaker’s fee from Novartis. SG reports honoraria and conference support from Novartis. BDM reports participation of advisory boards for Novartis, NB reports speaker’s fee from Novartis. JB has received personal fees, advisory board/steering committee honoraria, and nonfinancial support from Novartis; and advisory board honoraria from Pfizer, Kite, and Janssen. MM reports speaker’s fee from Miltenyi. CR reports participation in advisory boards by Amgen, BMS, Celgene, Novartis and Pfizer. AB reports participation on advisory boards and travel from Servier, Celgene, Novartis, Jazz, AstraZeneca, and being an investigator on trials from Novartis, Kite, Celgene and Cellectis. BV, OM, AY, RE, BB, SR, ED, AT, AVS, FL, PB, and JPB report no conflict of interests.
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Jacoby, E., Ghorashian, S., Vormoor, B. et al. CD19 CAR T-cells for pediatric relapsed acute lymphoblastic leukemia with active CNS involvement: a retrospective international study. Leukemia 36, 1525–1532 (2022). https://doi.org/10.1038/s41375-022-01546-9
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DOI: https://doi.org/10.1038/s41375-022-01546-9
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