Favorable Activity and Safety Profile of Memory-Enriched CD19-Targeted Chimeric Antigen Receptor T-Cell Therapy in Adults with High-Risk Relapsed/Refractory ALL

Abstract

Purpose: A phase I/II study evaluating the safety and activity of memory-enriched CD19-directed chimeric antigen receptor (CD19-CAR) T cells in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL).

Patients and methods: In phase I, we tested sequentially two cell populations for CAR transduction: (i) central memory (Tcm) or (ii) naïve, stem, and central memory (Tn/mem) T cells. The study employed an activity constrained for toxicity design to determine the recommended phase II dose (RP2D), which was tested in phase II.

Results: The Tcm cohort was closed early due to lack of activity. The 200 ×106 Tn/mem-derived CD19-CAR T-cell dose was found to be safe and active, and was declared the RP2D. At RP2D, 58 participants underwent leukapheresis and 46 received CD19-CAR T cells. Median age for treated participants was 38 years (range, 22-72). Twenty-nine (63%) participants had relapsed post-allogeneic hematopoietic cell transplantation (alloHCT), 18 (39%) had Philadelphia-like (Ph-like) genotype, and 16 (35%) had extramedullary disease (EMD) at lymphodepletion (LD). Three (7%) participants had grade 3 cytokine release syndrome (CRS), and none had grade ≥ 4 CRS. Eight (17%) participants had grade ≥ 3 neurotoxicity, including one fatal cerebral edema. Forty (87%) patients achieved complete remission (CR)/CR with incomplete hematologic recovery, 2 (4%) progressed, and 4 (9%) were unevaluable for response. Among 42 response-evaluable participants, 16/17 with Ph-like ALL and 13/15 with EMD at LD responded. Twenty-one (53%) responders underwent alloHCT consolidation, which was associated with improved relapse-free survival (adjusted HR = 0.16; 95% confidence interval, 0.05-0.48; P = 0.001).

Conclusions: Tn/mem-derived CD19-CAR T cells were safe and active, including in Ph-like ALL and EMD. See related commentary by El Marabti and Abdel-Wahab, p. 694.

Figure 1.. Treatment schema and consort diagram.

A. Patients on both arms of the trial received CAR T cells manufactured from patient or donor apheresis products following lymphodepletion. Patients were followed 3 times/week during the first two weeks post-infusion and then weekly until the end of the dose limiting toxicity (DLT) period before entering short-term follow-up. Patients had the option to proceed to allogeneic hematopoietic cell transplantation (AlloHCT) 28 days post CAR T cell infusion. B. Consort diagram of patients enrolled on the Tn/mem arm. The outcome of all patients (n=58) who were enrolled to receive 200×10⁶ Tn/mem-derived CD19-CAR T cells is depicted.

Figure 2.. Survival outcomes post CD19-CAR T cell therapy.

A. Overall survival and B. Relapse-free survival for the 46 patients treated with Tn/mem-derived CD19-CAR T cells. C. Overall survival and D. Relapse-free survival for the patients who received alloHCT consolidation post-CAR T cell therapy.

Figure 3.. Expansion of Tn/mem-derived CD19-CAR T cells.

A. CAR+ cells were detected using cetuximab in patient blood at the indicated timepoints post infusion of CD19-CAR T cells. Percentage of EGFR+ cells of live CD3+ cells for each UPN are presented. B. CAR+ cells in patient blood were detected by qPCR analysis of the WPRE transgene encoded by the lentiviral vector. Black line indicates median copies of WPRE per µg DNA; purple line indicates the number of subjects at each corresponding timepoint. Correlation between peak copies of CAR+ cells by WPRE and grade of C. neurotoxicity, D. CRS or E. Blasts ≥5% and/or extramedullary disease (EMD) at the time of lymphodepletion. F. Serum cytokines were measured at the indicated timepoints post infusion of CAR T cells. Cytokine levels at Days 0, 4, 7, 14, 21, and 28 were divided by the pre-LD level, and the medians at each time point were plotted as a heatmap to illustrate the median fold change from pre-LD level for each cytokine. We computed the average lower limit of quantification (LLOQ) and average upper limit of quantification (ULOQ) across all plates for each cytokine, by which we imputed the out-of-range (OOR) below, OOR above, and extrapolated values that fall outside of the thresholds.