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 1/2 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). Experimental Design: In phase 1, we tested sequentially two cell populations for CAR transduction: 1) central memory (Tcm) or 2) naïve, stem and central memory (Tn/mem) T cells. The study employed an activity constrained for toxicity design to determine the recommended phase 2 dose (RP2D), which was tested in phase 2. Results: The Tcm cohort was closed early due to lack of activity. The 200x10 6 Tn/mem-derived CD19-CAR T cell dose was found to be safe, 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 (22-72). Twenty-nine (63%) participants had relapsed post-allogeneic hematopoietic cell transplantation (alloHCT), 18 (39%) had Philadelphia-like genotype and 16 (35%) had extramedullary disease (EMD) at lymphodepletion. 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 Philadelphia-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 (aHR=0.16, 95%CI:0.05-0.48; P =0.001). Conclusion: Tn/mem-derived CD19-CAR T cells were safe and active, including in Philadelphia-like ALL and EMD.

Sequencing antigen‐targeting antibodies and cellular therapies in adults with relapsed/refractory B‐cell acute lymphoblastic leukemia

“…In the ELIANA study, the 3‐year RFS was 76% for patients who responded to tisagenlecleucel and received no subsequent therapy 71 . Nonetheless, several studies in adults supported the benefit of alloHCT consolidation post‐CD19 CAR T‐cell therapy 26,62,64,66 . Median duration of remission for patients who received brexucabtagene in the ZUMA‐3 study was 14.6 and 18.6 months, respectively, if outcomes were censored or not to subsequent alloHCT 32 .…”

“…Nonetheless, efficacy and safety were observed with tisagenlecleucel in children and young adults with r/r ALL in the CNS 69 . Other investigational CD19 CAR T‐cell products have also documented efficacy in adults with CNS involvement 66,70 . However, increased risk of neurotoxicity is a concern if the CNS disease was not controlled 68,70 .…”

“…71 Nonetheless, several studies in adults supported the benefit of alloHCT consolidation post-CD19 CAR T-cell therapy. 26,62,64,66 Median duration of remission for patients who received brexucabtagene in the ZUMA-3 study was 14.6 and 18.6 months, respectively, if outcomes were censored or not to subsequent alloHCT. 32 Since a subset of patients with r/r ALL have durable remissions post-CD19 CAR T-cell therapy, this is the preferred salvage option when alloHCT is not possible.…”

“…69 Other investigational CD19 CAR Tcell products have also documented efficacy in adults with CNS involvement. 66,70 However, increased risk of neurotoxicity is a concern if the CNS disease was not controlled. 68,70 One could consider a regimen such as mini-HCVD and inotuzumab as cytoreduction therapy to reduce disease burden before CD19 CAR T-cell consolidation, or as a therapeutic option for patients with EMD if CD19 CAR T-cell therapy is not a viable option.…”

The feasibility of additional CD19‐targeted cellular therapy in relapsed/refractory B‐ALL with re‐emergence of CD19 antigen after prior CD19‐negative relapse

“…Studies have documented high response rate of CD19 CAR T-cells in R/R B-ALL patients previously treated with blinatumomab, especially if they were previously responders. [2][3][4] Nonetheless, B-ALL relapses after blinatumomab as well as after CD19 CAR T-cells can escape the immune pressure of CD19-target therapy and manifest as a CD19-negative disease. The finding of CD19-negative relapse has crucial implications as it precludes the eligibility for treatment with another CD19-targeted therapy, and, therefore, the patient will be left with limited salvage therapeutic options.…”