Abstract
Background: CD19-specific chimeric antigen receptor (CAR) T cells have demonstrated significant clinical impact in patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). Several factors have been implicated in successful application including conditioning chemotherapy, CD4/8 ratio, CAR T cell expansion, and persistence. We undertook a multi-center clinical trial to test the feasibility of exporting this technology to other centers, determine the toxicity following infusion, and establish requisite factors for optimal response.
Methods: Pediatric and young adult patients with R/R B-ALL were treated with CD19-specific CAR (19-28z) T cells. Patients received cyclophosphamide based conditioning chemotherapy prior to infusion of CAR T cells.
Results: A total of 25 pediatric/young adult patients were treated with 19-28z CAR T cells. Based on conditioning chemotherapy 17 patients received high dose (3000mg/m2) cyclophosphamide (HD-Cy) and 8 patients received low dose (1500mg/m2) cyclophosphamide (LD-Cy) prior to CAR T cell infusion. Among evaluable patients (n = 24) complete response (CR) was demonstrated in 94% and 38% for HD-Cy vs LD-Cy cohorts respectively (p=0.01). Overall survival was significantly longer in the HD-Cy cohort as compared to the LD-Cy cohort (median survival = 585 days vs. 138 days; p=0.004) - Figure 1. Based on disease status at time of CAR T cell infusion 14 patients had minimal residual disease (MRD; <5% blasts in bone marrow) and 10 patients had morphologic evidence of disease (≥5% blasts in bone marrow). Complete response was 93% (13/14) and 50% (5/10) in the MRD and morphologic cohort respectively (p=0.05). Overall survival was significantly longer in the MRD cohort as compared to the Morphologic cohort (median survival = 585 days vs. 129 days; p=0.01) - Figure 2. Minimal residual disease as assessment by multi-parameter flow cytometry was assessed for all responders and was achieved by 89% of responding patients (16/18). MRD-negative status in the cohort subsets included 93% (14/15) in HD-Cy cohort, 66% (2/3) in LD-Cy cohort, 92% (12/13) in MRD cohort, and 80% (4/5) in Morphologic cohort. The rate of CR did not differ significantly when analyzed by target dose, fludarabine as part of conditioning chemotherapy, or ex-vivo fold growth of CAR T cells during production. Expectedly, CAR T cell peak and persistence correlates with response as measured by q-PCR and/or flow cytometry in the peripheral blood or bone marrow. The most common treatment-related adverse events were cytokine release syndrome (CRS) and neurotoxicity consistent with finding previously reported. Overall, CRS of any grade occurred in 80% patients (20/25) with severe CRS (grade III/IV) occurring in 20% (5/25) of patients treated. Neurologic symptoms of any grade occurred in 72% (18/25) with severe neurotoxicity (grade III/IV) occurring in 24% (6/25) of patients treated. All toxicity was reversible and was managed with supportive care and/or immunomodulation (IL-6R blockade or corticosteroids).
Conclusions: The use of HD-Cy or treatment with low disease burden positively correlated with complete response and overall survival for pediatric/young adult patients with R/R B-ALL treated with CD19-specific CAR T cells.
Curran: Juno Therapeutics: Research Funding; Novartis: Consultancy. Kernan: Gentium: Other: Received grants from Gentium during the conduct of the study and research was supported by The National Cancer Institute of the National Institutes of Health under award number P30 CA 008748, Research Funding. Park: Amgen: Consultancy. Smith: Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: BCMA targeted CAR T cells, Research Funding. O'Reilly: Atara: Patents & Royalties, Research Funding. Brentjens: Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.
