Analysis benefits of a second Allo-HSCT after CAR-T cell therapy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia who relapsed after transplant

Abstract

Background: Chimeric antigen receptor (CAR) T-cell therapy has demonstrated high initial complete remission (CR) rates in B-cell acute lymphoblastic leukemia (B-ALL) patients, including those who relapsed after transplant. However, the duration of remission requires improvements. Whether bridging to a second allogeneic hematopoietic stem cell transplant (allo-HSCT) after CAR-T therapy can improve long-term survival remains controversial. We retrospectively analyzed long-term follow-up data of B-ALL patients who relapsed post-transplant and received CAR-T therapy followed by consolidation second allo-HSCT to investigate whether such a treatment sequence could improve long-term survival.

Methods: A single-center, retrospective study was performed between October 2017 and March 2022, involving 95 patients who received a consolidation second transplant after achieving CR from CAR-T therapy.

Results: The median age of patients was 22.8 years (range: 3.3-52.8) at the second transplant. After the first transplant, 71 patients (74.7%) experienced bone marrow relapse, 16 patients (16.8%) had extramedullary relapse, 5 patients (5.3%) had both bone marrow and extramedullary relapse and 3/95 patients (3.2%) had positive minimal residual disease (MRD) only. Patients received autologous (n=57, 60.0%) or allogeneic (n=28, 29.5%) CAR-T cells, while 10 patients (10.5%) were unknown. All patients achieved CR after CAR-T therapy. Before second HSCT, 86 patients (90.5%) were MRD-negative, and 9 (9.5%) were MRD-positive. All second transplant donors were different from the first transplant donors. The median follow-up time was 623 days (range: 33-1901) after the second HSCT. The 3-year overall survival (OS) and leukemia-free survival (LFS) were 55.3% (95%CI, 44.3-66.1%) and 49.8% (95%CI, 38.7-60.9%), respectively. The 3-year relapse incidence (RI) and non-relapse mortality (NRM) were 10.5% (95%CI, 5.6-19.6%) and 43.6% (95%CI, 33.9-56.2%), respectively. In multivariate analysis, the interval from CAR-T to second HSCT ≤90 days was associated with superior LFS(HR, 4.10, 95%CI,1.64-10.24; p=0.003) and OS(HR, 2.67, 95%CI, 1.24-5.74, p=0.012), as well as reduced NRM (HR, 2.45, 95%CI, 1.14-5.24, p=0.021).

Conclusions: Our study indicated that CAR-T therapy followed by consolidation second transplant could significantly improve long-term survival in B-ALL patients who relapsed post-transplant. The second transplant should be considered in suitable patients and is recommended to be performed within 90 days after CAR-T treatment.

Keywords: B-ALL; CAR-T; LFS; NRM; relapse; second transplant.

Figure 1

Cumulative incidence of aGVHD and cGVHD. (A) Cumulative incidence of grade 2-4 and grade 3-4 acute graft-versus-host disease (aGVHD) in 95 patients. The 100-day incidence of grade 2 to 4 aGVHD was 43.2% (95%CI, 34.3%-54.4%) and the incidence of grade 3 to 4 aGVHD was 8.4% (95%CI, 4.3%-16.3%). (B) Cumulative incidence of chronic graft-versus-host disease (cGVHD) in 95 patients. The incidence of any grade cGVHD at 180 days and at 2-year was 29.8% (95%CI, 21.8%-40.6%) and 44.2% (95CI, 35.1%-55.6%). The 180-day and 2-year cumulative incidence of extensive cGVHD was 24.5% (95%CI, 17.2%-34.9%) and 33.1% (95%CI, 24.9%-44.2%), respectively.

Figure 2

Long-term survival, including OS, LFS, RI and NRM. (A) Overall survival (OS) and leukemia-free survival (LFS) in 95 patients. After the second transplant, the 1-year OS and LFS were 69.3% (95%CI, 59.7%-78.2%) and 63.9% (95%CI, 54.0%-73.3%) respectively. The 3-year OS and LFS were 55.3% (95%CI, 44.3%-66.1%) and 49.8% (95%CI, 38.7%-60.9%), respectively. (B) Relapse incidence (RI) and non-relapse mortality (NRM) in 95 patients. The 3-year RI was 10.5% (95%CI, 5.6%-19.6%). The 3-year NRM was 43.6% (95%CI, 33.9%-56.2%).