How I use risk factors for success or failure of CD19 CAR T cells to guide management of children and AYA with B-cell ALL

Abstract

By overcoming chemotherapeutic resistance, chimeric antigen receptor (CAR) T cells facilitate deep, complete remissions and offer the potential for long-term cure in a substantial fraction of patients with chemotherapy refractory disease. However, that success is tempered with 10% to 30% of patients not achieving remission and over half of patients treated eventually experiencing relapse. With over a decade of experience using CAR T cells in children, adolescents, and young adults (AYA) to treat relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) and 5 years since the first US Food and Drug Administration approval, data defining the nuances of patient-specific risk factors are emerging. With the commercial availability of 2 unique CD19 CAR T-cell constructs for B-ALL, in this article, we review the current literature, outline our approach to patients, and discuss how individual factors inform strategies to optimize outcomes in children and AYA receiving CD19 CAR T cells. We include data from both prospective and recent large retrospective studies that offer insight into understanding when the risks of CAR T-cell therapy failure are high and offer perspectives suggesting when consolidative hematopoietic cell transplantation or experimental CAR T-cell and/or alternative immunotherapy should be considered. We also propose areas where prospective trials addressing the optimal use of CAR T-cell therapy are needed.

Graphical abstract

Figure 1.

Impact of previous blinatumomab treatment and disease burden on EFS following CD19 CAR T cells and OS following relapse. EFS, defined as the time from CD19 CAR T-cell infusion to one of the following events: no response, relapse, or death. (A) EFS stratified by blinatumomab-naïve patients (no blina—teal) vs blinatumomab-exposed patients who achieved a CR to blinatumomab (blina-CR—blue) vs blinatumomab-exposed patients who did not achieve a CR to blinatumomab (blina-no CR—red). P values for EFS curves: .59 (no blina vs blina-CR); .01 (blina-CR vs blina-no CR); .001 (no blina vs blina-no CR). (B) EFS stratified by high disease burden (≥5% bone marrow blasts—blue [high]) vs low disease burden (<5% bone marrow blasts—red (low). (C) OS following relapse, stratified by relapse immunophenotype. Median OS for CD19⁺ relapse was 18.9 months (95% CI, 11.2-27.0 months). Median OS for CD19⁻ relapse was 9.7 months (95% CI, 6.9-15.9 months). Median OS for LS was 3.7 months (95% CI, 1.2-7.0 months). Red: CD19⁺; blue: CD19⁻; green: LS. CI, confidence interval; LS, lineage switch. (A-B) Reproduced with permission from Wolters Kluwer Health, license number 5363041439390, from Myers et al; (C) reproduced with permission from Elsevier, license number 5363050768789, from Lamble et al.

Figure 2.

EFS and OS in patients in CR/CRi following tisagenlecleucel by Kaplan-Meier analyses with log-rank test P values. (A-B) EFS (A) and OS (B) of responding patients based on detection at 28 days after CAR infusion of BM NGS-MRD at any level (blue lines) compared with patients with BM NGS-MRD = 0 (green lines). (C-D) EFS (C) and OS (D) of responding patients based on detection at 3 months after CAR infusion of BM NGS-MRD at any level (blue lines) compared with patients with BM NGS-MRD = 0 (green lines). CRi, complete remission with incomplete count recovery. Reproduced with permission from CCC Marketplace, license number 1257504-1, from Pulsipher et al.

Figure 3.

Approach to peri-CAR T-cell risk stratification with monitoring and treatment options. This figure highlights various preinfusion risk factors that may affect long-term EFS, remission durability, and/or OS; and how these factors are further modulated by post–CAR T-cell outcomes, based primarily on NGS-MRD status and loss of BCA. Refer to Table 1 for specific information on risk factors. ASAP, as soon as possible; Blina, blinatumomab; CRi, complete remission with incomplete count recovery.