Integrating CAR T-Cell Therapy and Transplantation: Comparisons of Safety and Long-Term Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation After CAR T-Cell or Chemotherapy-Based Complete Remission in B-Cell Acute Lymphoblastic Leukemia

Abstract

Patients often undergo consolidation allogeneic hematopoietic stem cell transplantation (allo-HSCT) to maintain long-term remission following chimeric antigen receptor (CAR) T-cell therapy. Comparisons of safety and efficacy of allo-HSCT following complete remission (CR) achieved by CAR-T therapy versus by chemotherapy for B-cell acute lymphoblastic leukemia (B-ALL) has not been reported. We performed a parallel comparison of transplant outcomes in 105 consecutive B-ALL patients who received allo-HSCT after achieving CR with CAR-T therapy (n=27) or with chemotherapy (n=78). The CAR-T-allo-HSCT group had more patients in second CR compared to the chemotherapy-allo-HSCT group (78% vs. 37%; p<0.01) and more with complex cytogenetics (44% vs. 6%; p<0.001) but the proportion of patients with pre-transplant minimal residual disease (MRD) was similar. The median follow-up time was 49 months (range: 25-54 months). The CAR-T cohort had a higher incidence of Grade II-IV acute graft-versus-host disease (aGVHD 48.1% [95% CI: 46.1-50.1%] vs. 25.6% [95%CI: 25.2-26.0%]; p=0.016). The incidence of Grade III-IV aGVHD was similar in both groups (11.1% vs.11.5%, p=0.945). The overall incidence of chronic GVHD in the CAR-T group was higher compared to the chemotherapy group (73.3% [95%CI: 71.3-75.3%] vs. 55.0% [95%CI: 54.2-55.8%], p=0.107), but the rate of extensive chronic GVHD was similar (11.1% vs.11.9%, p=0.964). Efficacy measures 4 years following transplant were all similar in the CAR-T vs. the chemotherapy groups: cumulative incidences of relapse (CIR; 11.1% vs.12.8%; p=0.84), cumulative incidences of non-relapse mortality (NRM; 18.7% vs. 23.1%; p=0.641) leukemia-free survival (LFS; 70.2% vs. 64.1%; p=0.63) and overall survival (OS; 70.2% vs. 65.4%; p=0.681). We found that pre-transplant MRD-negative CR predicted a lower CIR and a higher LFS compared with MRD-positive CR. In conclusion, our data indicate that, in B-ALL patients, similar clinical safety outcomes could be achieved with either CD19 CAR T-cell therapy followed by allo-HSCT or chemotherapy followed by allo-HSCT. Despite the inclusion of more patients with advanced diseases in the CAR-T group, the 4-year LFS and OS achieved with CAR T-cells followed by allo-HSCT were as remarkable as those achieved with chemotherapy followed by allo-HSCT. Further confirmation of these results requires larger, randomized clinical trials.

Comparable outcomes in patients with B-cell acute lymphoblastic leukemia receiving haploidentical hematopoietic stem cell transplantation: Pretransplant minimal residual disease-negative complete remission following chimeric antigen receptor T-cell therapy versus chemotherapy

“…conducted a parallel comparison of outcomes among patients with B-ALL who received allo-HSCT after achieving CR with CAR-T therapy (n = 27) or chemotherapy (n = 78). The results demonstrated that there were no significant differences in clinical outcomes (OS, LFS, NRM, relapse, and extensive cGVHD) between the two groups, while a higher incidence of II–IV aGVHD (48.1%) and slower platelet engraftment (14 days) were observed in the CAR-T group ( 42 ). In a previous study, Shadman et al.…”

Chimeric Antigen Receptor T-Cell Therapy: What We Expect Soon

“…Combining allo-SCT and CAR-T cells therapy is an attractive area of research to improve the outcomes further. Allo-SCT has been used in several clinical trials after CAR-T cells treatment and showed efficacy and favorable prognosis in R/R B-ALL [ 40 , 41 ]. Considering the high heterogeneity among and within patients, different CAR-T cell products, and continuously improved treatment strategies, consolidative allo-SCT cannot be generalized; however, it is recommended for high-risk r/r B-ALL patients with no history of allo-SCT and achieved MRD-negative CR after anti-CD19 CAR-T therapy [ 41 ].…”

The Emerging Role of CAR T Cell Therapy in Relapsed/Refractory Hodgkin Lymphoma

“…This has yet to be explored in HL, though is being investigated in cases of B-cell acute lymphoblastic leukemia (B-ALL). In a study of B-ALL patients who had undergone allogeneic transplant, outcomes for those patients who had received CAR T cells as a bridge to transplant compared similarly to those receiving chemotherapy when looking at NRMrates, leukemia-free survival, and overall survival [83]. Patients receiving CAR T cells ahead of transplant did however have a higher incidence of acute graft versus host disease (grade II only) and chronic graft versus host disease, highlighting a potential negative effect of modulating the immune system ahead of transplant.…”