1.
Low Non-Relapse Mortality after HLA Matched Related Two-Step Hematopoietic Stem Cell Transplantation using Cyclophosphamide (CY) for Graft versus Host Disease Prophylaxis and the Potential Impact of Non-CY-Exposed T Cells on Outcomes
Grosso, D., Carabasi, M., Filicko-O'Hara, J., Wagner, J. L., O'Hara, W., Sun, M., Colombe, B., Shi, W., Werner-Wasik, M., Rudolph, S., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
The use of cyclophosphamide (CY) for bidirectional tolerization of recipient and donor T cells is associated with reduced rates of graft versus host disease (GVHD) and non-relapse mortality (NRM) after human leukocyte antigen (HLA) matched hematopoietic stem cell transplantation (HSCT). However, recurrent disease remains the primary barrier to long term survival. We extended our two-step approach to HLA matched related HSCT using a radiation-based myeloablative conditioning regimen combined with a high dose of T cells in an attempt to reduce relapse rates while maintaining the beneficial effects of CY tolerization. After conditioning, patients received their grafts in two components. First, a fixed dose of 2x10(8)/kg T cells was infused, followed 2 days later by CY. Second, a CD34-selected graft containing a small residual amount of non-CY exposed T cells, median dose of 2.98x10(3)/kg, was administered. Forty-six patients with hematological malignancies were treated. Despite the myeloablative conditioning regimen and use of high doses of T cells, at 1 and 5 years, the cumulative incidences (CI) of grades 2-4 acute and chronic GVHD, and NRM were very low at 13%, 9% and 4.3% respectively. This contributed to a high overall survival (OS) rate of 89.1% at 1 year and 65.8% at 5 years. Relapse was the primary cause of mortality with a CI of 23.9% at 1 year and 45.7% at 5 years. In a post hoc analysis, relapse rates were significantly lower in patients receiving greater than versus less than the group median of non-CY exposed, residual T cells in the CD34 product, 19.3% versus 58.1% (p=0.009) without concomitant increase in NRM. In its current form, this two-step regimen was highly tolerable but strategies to reduce relapse, potentially the addition of T cells not exposed to CY, are needed.
2.
Anti-CD19 CAR-T Therapy Bridging to Allo-HSCT for Relapsed/refractory B-cell Acute Lymphoblastic Leukemia: An Open-Label Pragmatic Clinical Trial
Jiang, H., Li, C., Yin, P., Guo, T., Liu, L., Xia, L., Wu, Y., Zhou, F., Ai, L., Shi, W., et al
American journal of hematology. 2019
Abstract
Chimeric antigen receptor-modified T-cell (CAR-T) therapy is effective and safe for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL), but its value has been limited in terms of long-term leukemia-free survival. New strategies that can help CAR-T therapy achieve lasting effect are urgently warranted. This non-randomized interventional pragmatic clinical trial aimed to explore whether consolidative allogeneic hematopoietic stem cell transplantation (allo-HSCT) could improve the long-term prognosis of the minimal residual disease-negative complete remission (MRD(-) CR) patients after CAR-T therapy. In the first stage, 58 r/r B-ALL patients received split doses of CAR-T cells after lymphodepleting chemotherapy, and 51 (87.9%) achieved CR. In the second stage, 21/47 MRD(-) CR patients without previous allo-HSCT and contraindications or other restrictions, on their own accord, received consolidative allo-HSCT within three months after CAR-T therapy. There was no difference in overall survival (OS) between the MRD(-) CR patients who received allo-HSCT and those who didn't, but event-free survival (EFS) and relapse-free survival (RFS) were significantly prolonged by allo-HSCT in the subgroups with either high (≥ 5%) pre-infusion bone marrow MRD assessed by flow cytometry (BM-FCM-MRD) or poor prognostic markers (P < 0.05). However, no difference was found in EFS and RFS for patients with pre-infusion BM-FCM-MRD < 5% and without poor prognostic markers (P > 0.05). To conclude, CAR-T therapy bridging to allo-HSCT is a safe and effective therapeutic strategy for r/r B-ALL patients, and may prolong their EFS and RFS, especially when they have high pre-infusion BM-FCM-MRD or poor prognostic markers. This article is protected by copyright. All rights reserved.