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.

Keywords: CD19 CAR T-cell therapy; allogeneic hematopoietic cell transplantation; relapse; relapse/refractory B cell acute lymphoblastic leukemia; survival.

Figure 1

Enrollment, and parallel comparison. Between November 2015 and August 2016, 105 consecutive B-ALL patients who underwent allo-HSCT after achieving CR either from CAR-T therapy (n=27) or chemotherapy (n=78) were enrolled for parallel comparison.

Figure 2

Cumulative incidences of Grade II-IV and Grade III-IV acute GVHD. (A) Cumulative incidences of Grade II-IV acute GVHD: CAR-T group: 48.1% (95% CI:46.1, 50.1%) vs. chemotherapy group: 25.6% (95% CI: 25.2, 26.0%); p=0.016. (B) Cumulative incidences of Grade III-IV acute GVHD: CAR T-cell group: 11.1% (95% CI: 10.3, 11.9%) vs. chemotherapy group: 11.5% (95% CI: 11.3, 11.7%); p=0.945. (C) Cumulative incidences of Grade II-IV acute GVHD: CRS Grade 0-I 47.4% (95% CI: 44.7, 50.1%) vs. CRS Grade II-IV: 50.0% (95% CI:42.6, 57.4%); p=0.95. (D) Cumulative incidences of Grade III-IV aGVHD: CRS Grade 0-I: 10.5% (95% CI: 9.5, 11.5%) vs. CRS Grade II-IV: 12.5% (95% CI: 9.4, 15.6%); p=0.92.

Figure 3

Cumulative incidences of chronic and extensive chronic GVHD. (A) Cumulative incidences of chronic GVHD: CAR T-cell group: 73.3% (95% CI: 71.3, 75.3%) vs. chemotherapy group: 55.0% (95% CI: 54.2, 55.8%); p=0.107. (B) Cumulative incidences of extensive chronic GVHD: CAR T-cell group: 11.1% (95% CI:10.3, 11.9%) vs. the chemotherapy group: 11.9% (95% CI: 11.7, 12.1%); p=0.964.

Figure 4

Cumulative incidences of relapse (CIR) and NRM. (A) Cumulative incidence of relapse: CAR T-cell group: 4-year CIR of 11.1% (95% CI: 10.3, 11.9%) vs. chemotherapy group: 12.8% (95% CI:12.6, 13.0%) (p=0.84). (B) Cumulative incidence of NRM: CAR T-cell group: 4-year NRM of 18.7% (95% CI:17.5, 19.9%) vs. chemotherapy group: 4-year NRM of 23.1% (95% CI:22.7, 23.5%); p=0.64.

Figure 5

LFS and OS. (A) LFS and OS in the CAR-T and chemotherapy groups. The 4-year LFS for the CAR-T group was 70.2% (95% CI:53.0, 87.4%) vs. 64.1% (95% CI:53.5, 74.7%) for the chemotherapy group (p=0.63). The 4-year OS for the CAR-T group was 70.2% (95% CI:53.0, 87.4%) vs. 65.4% (95% CI:54.8, 76.0%) for the chemotherapy group (p=0.681) (B) LFS and OS according to MRD. The 4-year LFS for patients who achieved MRD- CR was 72.2% (95% CI:61.8, 82.6%) and 51.5% (95% CI:34.4, 68.6%) for those that had an MRD+ CR (p=0.024). The 4-year OS for the MRD- CR group was 73.6% (95% CI:63.4, 83.8%) and 51.5% (95% CI:34.4, 68.6%) for the MRD+CR group (p=0.02). (C) LFS and OS according to cGVHD. 4-year LFS for patients without cGVHD was 62.2% (95% CI:46.5, 77.9%), 85.6% (95% CI:75.8,95.4%) for those with limited cGVHD and 36.4% (95% CI:8.0, 64.8%) for those with extensive cGVHD (no vs. limited cGVHD, p=0.009; limited vs. extensive cGVHD, p<0.001; no vs. extensive cGVHD, p=0.20). 4-year OS for the no cGVHD group was 64.9% (95% CI:49.6, 80.2%), 85.6% for the limited cGVHD group (95% CI:75.8, 95.4%) and 36.4% for the extensive cGVHD group (95% CI:8.0, 64.8%) (no vs. limited cGVHD, p=0.019; limited vs. extensive cGVHD, p<0.001; no vs. extensive cGVHD, p=0.123).