Consolidative allogeneic hematopoietic stem cell transplantation after chimeric antigen receptor T-cell therapy for relapsed/refractory B-cell acute lymphoblastic leukemia: who? When? Why?

Huiwen Jiang,Yu Hu,Heng Mei

doi:10.1186/s40364-020-00247-8

Abstract

Although anti-CD19 chimeric antigen receptor (CAR) T-cell therapy shows good efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL), it fails to improve long-term leukemia-free survival (LFS). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CAR T-cell therapy has emerged as a promising strategy to prolong LFS. Nevertheless, which patients are likely to benefit from consolidative allo-HSCT, as well as the optimal therapeutic window, remain to be explored. Recent clinical data indicate that patients with complex karyotypes, adverse genes, and high pre-infusion minimal residual disease (MRD) by flow cytometry in the bone marrow, were at high risk of relapse after CAR T-cell therapy. High pre-lymphodepletion lactate dehydrogenase, low pre-lymphodepletion platelet count, absence of fludarabine in lymphodepletion, persistent leukemic sequence by high throughput sequencing in bone marrow after CAR T-cell infusion, and early loss of CAR T cells have also been linked to relapse after CAR T-cell therapy. In patients having these risk factors, consolidative allo-HSCT after CAR T-cell therapy may prolong LFS. Allo-HSCT provides optimal clinical benefit in patients with MRD-negative complete remission, typically within three months after CAR T-cell therapy. Herein, we summarize the clinical data on consolidative allo-HSCT after anti-CD19 CAR T-cell therapy, as well as the potential factors associated with allo-HSCT benefit. We also discuss the optimal therapeutic window and regimen of consolidative allo-HSCT. Finally, and most importantly, we provide recommendations for the assessment and management of r/r B-ALL patients undergoing anti-CD19 CAR T-cell therapy.

Highlights

Patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) often have clinicopathological characteristics associated with poor prognosis, such as high tumor burden and high-risk gene mutations
A certain benefit of consolidative allo-HSCT was observed in complete remission (CR) patients who were at high risk of relapse with an early loss of B-cell aplasia (BCA), regardless of allo-HSCT history. These findings suggest that patients should be considered for consolidative allo-HSCT during remission after chimeric antigen receptor (CAR) T-cell therapy if they have no history of allo-HSCT, or if they had a history of allo-HSCT but with a short persistence of functional CAR T cells
Factors associated with consolidative Allo-HSCT benefit By reviewing available data from the literature, we identified several risk factors associated with relapse after CAR T-cell therapy

Summary

Background

Patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) often have clinicopathological characteristics associated with poor prognosis, such as high tumor burden and high-risk gene mutations. Factors associated with consolidative Allo-HSCT benefit By reviewing available data from the literature, we identified several risk factors associated with relapse after CAR T-cell therapy These factors can be classified into the following categories: (1) pre-treatment (baseline) patient characteristics, such as complex karyotypes or adverse genes, high pre-infusion MRD by flow cytometry in the bone marrow, high pre-lymphodepletion LDH, and low pre-lymphodepletion platelet count; (2) lymphodepletion regimen without fludarabine; (3) post-CAR Tcell infusion parameters, such as persistent leukemic cells in the bone marrow and early loss of CAR T-cells. The relapse rate of MRD-negative CR patients was approximately 10% three months after CAR T-cell therapy [1, 21, 28] These findings support the usefulness of early transplantation discussion and HLA typing for suitable B-ALL patients before the administration of CAR T-cell therapy, and we recommend treatment with consolidative allo-HSCT within three months of CAR T-cell therapy to maximize its benefit and minimize the risk of toxicity-related death. In a humanized anti-CD19 CAR T-cell study, no survival benefit was observed in patients receiving consolidative allo-

50 Haploidentical

Findings

Conclusions