High Dose Cyclophosphamide and Pre-Treatment Disease Burden Dictate Response and Survival in a Multicenter Clinical Trial Using CD19-Specific CAR T Cells for Relapsed/Refractory B-ALL

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.

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