Allogeneic-Hematopoietic Stem Cell Transplantation Is Effective and Safe for Relapsed/ Refractory B-ALL Patients Who Cannot Get Remission or MRD Negative after CART Treatment

Background: Chimeric antigen receptor T-cell (CART) Therapy has induced high rates of complete remission (CR) in the patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL), but a small portion of them still cannot obtain CR or minimal residual disease (MRD) negative. Salvaged allogeneic hematopoietic stem cell transplantation (allo-HSCT) could be the only curative treatment for this setting. According to previous reports, around 20% to 30% overall survival (OS) has been seen in the patients with r/r B-ALL treated with salvaged allo-HSCT. Aim: In current study, the efficacy and safety of allo-HSCT for the patients with r/r B-ALL who cannot achieve CR or MRD negative after CART therapy were evaluated. Methods: Between January 2018 and June 2021, 23 consecutive patients with r/r B-ALL who did not achieve CR or MRD negative after CART treatment and received allo-HSCT in our hospital were included. The median age was 10 (1-47) years old. The median disease course was 24 (8-89) months. Eight patients were in non-remission (NR) and 15 cases were MRD positive (10 detected by flow cytometry, and 5 detected by RT-PCR). The median blast in bone marrow (BM) in NR series was 39 (0.5-94)% in which two patients were only extramedullary leukemia, and the median flow cytometric MRD level in BM in MRD positive series was 0.11 (0-3)%. One patient had TP53 mutation, one had MLL-AF4 fusion gene and one had both TP53 mutation and MLL-AF4 fusion gene. Nineteen patients (82.6%) received at least two kinds of CART therapies (murinized CD19, humanized CD22, humanized CD19) and 4 patients (17.4%) received one kind of CART therapy (murinized CD19, humanized CD22 or humanized CD19). Three patents underwent second transplantation. Eighteen patients (78.3%) received allo-HSCT from haploidentical donors and 5 patients (21.7%) from unrelated donors (HLA 10/10 matched in 3 and 9/10 matched in 2). Myeloablative conditioning regimens with total body irradiation (fractionated, total 10 Gy) /etoposide (200mg/m 2 x 3) /fludarabine (30mg/m 2 x 5) or cyclophosphamide (1.8g/m 2 x 2) /rabbit anti-T-cell globulin were used. Cyclosporine, mycophenolate mofetil and short-term methotrexate were employed for graft-versus-host disease (GVHD) prophylaxis. Some patients received maintenance regimens with targeted medicine based on their fusion genes or gene mutations up to 2 years post-transplant. Results:All patients achieved durable engraftment. For the patients in NR (n=8) before transplantation, the median follow-up time was 336 (22-803) days. Four of them had been alive free of leukemia and MRD negative, and 4 patients died of relapse. One-year OS and leukemia-free survival (LFS) were 85.7% and 35.7%, respectively. No patient died of transplant-related events. Two patients developed grade III acute GVHD (aGVHD) and 1 patient had extensive chronic GVHD (cGVHD). All of them were resolved with immune-suppressants. CMV and EBV reactivation was detected in 6 and 1 patients, respectively. One patient had severe lung fungal infection and 1 case developed mild hemorrhagic cystitis. For the patients with MRD positive (n=15) before transplantation, the median follow-up time was 359 (42-872) days and one-year OS and LFS were 68.1% and 40.9%, respectively. Seven patients relapsed, three of them achieved MRD negative CR with donor-derived CART therapies, and 3 patients died of relapse. Six patients developed grade III~IV aGVHD and one patient had extensive cGVHD. All of them were resolved except one patient died from grade IV aGVHD. CMV and EBV reactivation was found in 6 and 1 patients, respectively. Three patients had mild hemorrhagic cystitis. No other severe infection occurred. C onclusion: Our results indicate that salvaged allo-HSCT has improved survival remarkably in r/r B-ALL patients who failed not only chemotherapy but also CART therapy.One-year OS and LFS can reach 85.7% and 35.7%, 68.1% and 40.9% in NR and MRD positive cohorts, respectively. Transplant-related mortality is quite low (1/23). The leading cause of death is disease recurrence (7/23). Under our protocol, allo-HSCT is a safe and effective salvaged modality for r/r B-ALL who cannot obtain CR or MRD negative with CART therapy. No relevant conflicts of interest to declare.