Chimeric antigen receptors T cells as second line therapy for acute leukemia relapsed after allogeneic hematopoietic stem cell transplantation: high remission rate without causing graft versus host disease

Abstract

Objective To analyze the efficiency and safety of chimeric antigen receptors T cells for acute B lymphoblastic leukemia (B-ALL) patients who relapsed after allogeneic hematopoietic stem cell transplantation (allo HSCT) andshowednoresponseforchemotherapy followed by donor lymphocyte infusion (DLI). Methods We conducted a clinical trial of allogeneic T cells engineered to express a chimericantigen receptor (CAR) for patients with B-ALL that had progressed after allo HSCT and DLI. Chemotherapies were administered for most cases. The T cells were obtained from each recipient's allo-HSCT donor. The clinical data of 10 patients between 2015.1.1 and 2016.3.31 were collected and analyzed. Results Ten patients have been treated to date. Morphology relapses occurred in 7 cases, and 3 patients had minimal residual disease.The median age was 35 years (8-52 years). They received the first course of CAT-T cells at a median of 24 months (range 6.0-66 months) after the allo-HSCT, and the median dose of CAR-T cells was 2.53×106/kg [(0.44-5.5)×106/kg]. Eightout of 10 treated patients obtained remission, including complete remissions (CR) in 5 casesand partial remissions (PR) in 3 cases. The overall response rate was 80%. All the responded patients achieved the best effect after the first course. The median days to reach the best response in patients with morphology relapses were 24 days (14-37days) and the maintaining time of the curative effect was 1.3 to 6.3 months (mean 4.75 months after CAR-T cells infusion. The response was associated with the blast cells in bone marrow (response group vs. non-response group, 28.5% vs. 90.0%, P=0.010), and not with the dose of CAR-T cells (13.1×106/kg vs. 20.0×106/kg, P=0.538). The side effects of treatment could be evaluated in 22 courses. Fever occurred in 13 courses, and the median time for the onset of fever was 6 days (range 0-8 days) after infusion. Twelve of them were clinically diagnosed with cytokine release syndrome (CSR), including 1 moderate case and the others were mild. Only 1 case had rash and diagnosed with grade Ⅰgraft-versus-host disease (GVHD), and the rash regressed spontaneously. To the end of 2016.3.31, the overall survival of all patients was 49.4% at 15th month after CAR-T cells therapy. Conclusion Our study demonstrates that immunotherapy with CAR-T cells is feasible in patients with B-ALL relapsed and heavily treated by DLI after allo HSCT without causing GVHD. The response rate is related to the percentage of morphological blasts. Key words: Chimeric antigen receptor; Adoptive cell therapy; B-cell acute lymphoblastic leukemia; Cytokinereleasesyndrome