Long-Term Follow-Up of CD19-CAR T-Cell Therapy in Children and Young Adults With B-ALL

Abstract

PURPOSE CD19 chimeric antigen receptor (CD19-CAR) T cells induce high response rates in children and young adults (CAYAs) with B-cell acute lymphoblastic leukemia (B-ALL), but relapse rates are high. The role for allogeneic hematopoietic stem-cell transplant (alloHSCT) following CD19-CAR T-cell therapy to improve long-term outcomes in CAYAs has not been examined. METHODS We conducted a phase I trial of autologous CD19.28ζ-CAR T cells in CAYAs with relapsed or refractory B-ALL. Response and long-term clinical outcomes were assessed in relation to disease and treatment variables. RESULTS Fifty CAYAs with B-ALL were treated (median age, 13.5 years; range, 4.3-30.4). Thirty-one (62.0%) patients achieved a complete remission (CR), 28 (90.3%) of whom were minimal residual disease−negative by flow cytometry. Utilization of fludarabine/cyclophosphamide–based lymphodepletion was associated with improved CR rates (29/42, 69%) compared with non–fludarabine/cyclophosphamide–based lymphodepletion (2/8, 25%; P = .041). With median follow-up of 4.8 years, median overall survival was 10.5 months (95% CI, 6.3 to 29.2 months). Twenty-one of 28 (75.0%) patients achieving a minimal residual disease−negative CR proceeded to alloHSCT. For those proceeding to alloHSCT, median overall survival was 70.2 months (95% CI, 10.4 months to not estimable). The cumulative incidence of relapse after alloHSCT was 9.5% (95% CI, 1.5 to 26.8) at 24 months; 5-year EFS following alloHSCT was 61.9% (95% CI, 38.1 to 78.8). CONCLUSION We provide the longest follow-up in CAYAs with B-ALL after CD19-CAR T-cell therapy reported to date and demonstrate that sequential therapy with CD19.28ζ-CAR T cells followed by alloHSCT can mediate durable disease control in a sizable fraction of CAYAs with relapsed or refractory B-ALL (ClinicalTrials.gov identifier: NCT01593696 ).

Acute Lymphoblastic Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology

“…197 In contrast, data in children and young adults treated on another clinical trial at the National Institutes of Health/National Cancer Institute with a similar CAR construct suggested consolidative allogeneic HCT post-CAR T-cell therapy might be associated with superior outcomes (2-year cumulative incidence of relapse posttransplant, 9.5%; 5year event-free survival posttransplant, 62%). 198 The ZUMA-3 clinical trial phase II results using the CAR Tcell product KTE-X19 (brexucabtagene autoleucel) also showed promising efficacy in adults with R/R ALL, by demonstrating MRD-negative CR in 76% of patients, with a median duration of remission of 12.8 months, a median relapse-free survival of 11.6 months, and a median overall survival of 18.2 months. 199 KTE-X19 is currently being evaluated in children and young adults with R/R ALL.…”

The Role of Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Leukemia

“…Anti-CD19 CAR T-cell therapy has produced impressive MRD-negative CR rates, ranging from 56% to 93%. However, durability of response after CAR T is variable and influenced by CAR T-cell expansion, persistence and characteristics of co-stimulatory domains [11,143,144]. Studies with CD28-based anti-CD19 CAR T cells, which are characterized by short persistence after infusion, have a higher tendency of referral to HSCT compared to studies with 41BB-based CAR T cells.…”

“…In the long-term follow-up study of 50 children and young adults (CAYA) treated with a CD28-based anti-CD19 CAR T, 62.0% patients achieved a CR, which was FCM-MRD negative in 90.3% of cases. Noteworthy, MRD-negative patients proceeding to allo-HSCT had a 5-year EFS of 61.9%, while all MRDnegative subjects who did not proceed to a consolidative HSCT experienced leukemia relapse [143]. In the global phase II trial of tisagenlecleucel in 75 CAYA with R/R B-ALL, only eight patients among those who obtained disease remission underwent allo-HSCT.…”

Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. II: CAR-T cell therapy for patients with CD19+ acute lymphoblastic leukemia

“…not) 76.9% vs . 11.6%; 23/110 7/23 75/102 16/110 previous HSCT Significant improvement in survival with allogeneic HSCT Shah BD 17 , Lancet 2021 ZUMA-3 Adult 55 Flu Cy 39 (71%) 38/39 (99%) 12 months SG - 71% 6 months SLD - 58% 12/39 12/39 42% previous HSCT Shah N 57 , JCO 2021 Fase I Pediatric and Adult 28ζ 50 Flu-Cy and others 62% 90.3% 4.8 years SG – 10.5 months 9.5% after HSCT 75% SLE 5 years after HSCT - 62% ⁎ Reported in Turtle et al JCI 2016. CTI: Car T cell infusion; AYA: adolescents and young adults: Flu: fludarabine; Cy: cyclophosphamide; LD: disease-free survival; SG: overall survival; SLE: event-free survival.…”