Impact of Bridging Chemotherapy on Clinical Outcomes of CD19-Specific CAR T Cell Therapy in Children/Young Adults with Relapsed/Refractory B Cell Acute Lymphoblastic Leukemia

Abstract

Chimeric antigen receptor (CAR) T cells achieve response and durable remission in patients with relapsed/refractory (R/R) B cell malignancies. Following collection of patient T cells, chemotherapy ("bridging chemotherapy") is utilized during the manufacture of CAR T cells. However, the optimal bridging chemotherapy has yet to be defined. Our objective in this study was to report clinical outcomes following bridging chemotherapy in a cohort of pediatric/young adult patients with R/R B cell acute lymphoblastic leukemia (B-ALL) treated with CAR T cell therapy. This retrospective study included patients enrolled on clinical trial NCT01860937 or referred to Memorial Sloan Kettering Cancer Center for commercial CAR T cell therapy (tisagenlecleucel). Bridging chemotherapy (given after T cell collection and before CAR T cell infusion) was defined as high intensity if myelosuppression was expected for >7 days. Outcome comparison analyses were performed in high-intensity versus low-intensity bridging chemotherapy, 1 cycle versus ≥2 cycles of bridging chemotherapy, disease burden at the start of bridging chemotherapy, disease burden at the start of bridging chemotherapy with chemotherapy intensity, tumor debulking by bridging chemotherapy, and disease burden pre-lymphodepleting chemotherapy (LDC) for CAR T cell treatment. The outcomes of this analysis showed that the incidence of grade ≥3 infection was significantly higher (94% versus 56%; P = .019) and overall survival (OS) was significantly lower (hazard ratio, 3.73; 95% confidence interval, 1.39 to 9.97; P = .006) in patients who received ≥2 cycles versus 1 cycle of bridging chemotherapy. No difference in incidence was found for cytokine release syndrome (P > .99) or neurotoxicity/immune effector cell-associated neurotoxicity syndrome (P = .70). Disease burden at the start of bridging chemotherapy, disease burden prior to LDC, and tumor debulking by bridging chemotherapy also did not significantly affect outcomes after CAR T cell therapy in this cohort. In this study, patients receiving ≥2 cycles of bridging chemotherapy had higher rates of infection and lower OS but no difference in CAR-specific toxicity. Clinicians should carefully consider the use of additional cycles of chemotherapy during the bridging period as it delays treatment with CAR T cells and increases the risk of infectious complications. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Keywords: B cell acute lymphoblastic leukemia; Bridging chemotherapy; CAR T cell therapy; CD19 antigen; Immunotherapy; Tisagenlecleucel.

Figure 1.. Patient flow diagram for all patients screened for study.

Figure 2.. Overall survival curves.

A. Infused patients. Start time used is date of infusion. B. Infused patients stratified by D28 response. To assess the post-response survival, the OS time is defined as the time from 28 days post-infusion to the time of death. A landmark analysis is done in which patients who died before 28 days are excluded from the analysis (n=1 who did not achieve CR).

Figure 2.. Overall survival curves.

A. Infused patients. Start time used is date of infusion. B. Infused patients stratified by D28 response. To assess the post-response survival, the OS time is defined as the time from 28 days post-infusion to the time of death. A landmark analysis is done in which patients who died before 28 days are excluded from the analysis (n=1 who did not achieve CR).

Figure 3.. Flow diagram of all patients who received ≥ 2 cycles of bridging chemotherapy.