Reduced-Intensity Conditioning with Busulfan, Fludarabine, and Antithymocyte Globulin for Hematopoietic Cell Transplantation from Unrelated or Haploidentical Family Donors in Patients with Acute Myeloid Leukemia in Remission

Abstract

To investigate the role of antithymocyte globulin (ATG)-containing reduced-intensity conditioning (RIC) in hematopoietic cell transplantation (HCT) from unrelated (UD) or haploidentical family donors (HFD), we conducted a phase 2 trial of 237 patients (age range, 16 to 69 years) with acute myeloid leukemia (AML) in remission. Patients undergoing UD-HCT (n = 93) or HFD-HCT (n = 59) received RIC comprising busulfan, fludarabine, and ATG, 9 mg/kg, whereas those undergoing HCT from matched sibling donors (MSD, n = 85) received myeloablative busulfan and cyclophosphamide conditioning or aforementioned RIC with ATG, 4.5 mg/kg. For graft-versus-host disease (GVHD) prophylaxis, cyclosporine and methotrexate were administered. The median follow-up period was 44.7 months after HCT for 161 survivors. For UD-HCT versus HFD-HCT, there were no significant differences in leukemia recurrence, nonrelapse mortality, relapse-free survival, grades 2 to 4 acute GVHD, and moderate-to-severe chronic GVHD. Furthermore, when the outcomes of UD-HCT and HFD-HCT were combined and compared with those of MSD-HCT, there were no significant differences in leukemia recurrence (3-year cumulative incidence, 30% versus 29%), nonrelapse mortality (3-year cumulative incidence, 7% versus 8%), relapse-free survival (3-year estimate, 63% versus 63%), and grades 2 to 4 acute GVHD (120-day cumulative incidence, 16% versus 13%). Moderate-to-severe chronic GVHD, however, occurred less frequently in UD/HFD-HCT (2-year cumulative incidence, 22% versus 40%; P = .006). The addition of ATG to conditioning regimen was a significant predictor for less chronic GVHD (subdistribution hazard ratio, .59). In AML in remission, UD/HFD-HCT after ATG-containing RIC achieved leukemia control equivalent to that of MSD-HCT. Despite HLA disparity in UD/HFD-HCT, chronic GVHD occurred less frequently after ATG-containing RIC, suggesting a strong GVHD-modulating effect of ATG.

Reduced intensity allogeneic stem cell transplant with anti‐thymocyte globulin and post‐transplant cyclophosphamide in acute myeloid leukemia

“…5,9 The combination of fludarabine and busulfan with PTCy may potentiate the antineoplastic activity of the conditioning regimen to reduce relapse rates in high-risk AML patients. 16,21,27 In our cohort, the 2-year OS and RFS are comparable with published data from retrospective multicenter studies 28,29 and registry-based data studies from the EBMT 30 and CIBMTR. 31 RIC protocols reduce transplant-related mortality and allow older patients and those with co-morbidities to proceed with allo-HSCT.…”

Reduced-Intensity Conditioning and Dual T Lymphocyte Suppression with Antithymocyte Globulin and Post-Transplant Cyclophosphamide as Graft-versus-Host Disease Prophylaxis in Haploidentical Hematopoietic Stem Cell Transplants for Hematological Malignancies

“…RIC with low-dose busulfan and fludarabine and ATG + cyclosporineÀbased GVHD prophylaxis showed outcomes comparable with MUD with lower rates of cGVHD [18]. The inclusion of ATG in conditioning regimens results in faster achievement of donor chimerism, especially when using alternative donors [17,18]. However, the use of ATG is also associated with delayed immune reconstitution and increased infective complications, particularly viral reactivations with CMV or EBV [19À21].…”

Safety and Efficacy of Haploidentical Peripheral Blood Stem Cell Transplantation for Myeloid Malignancies Using Post-transplantation Cyclophosphamide and Anti-thymocyte Globulin as Graft-versus-Host Disease Prophylaxis

“…Furthermore, it spares regulatory T-cells (Tregs) and preserves quiescent hematopoietic stem and other progenitor cells [7][8][9][10]. The addition of ATG to standard conditioning has allowed better engraftment and rapid achievement of complete donor chimerism, particularly with alternative donors [11,12]. This benefit is somewhat offset by delayed immunological recovery and, thereby, an increased risk of infections, in particular those due to CMV and EBV [11,12].…”

“…The safety and efficacy of the use of post-transplant high dose PTCy combined with T-cell replete grafts in haploHSCT have been reported by several recent studies [7][8][9][10]. The use of anti-thymocyte globulin (ATG) as part of conditioning regimens leads to more rapid achievement of complete donor chimerism, in particular when using alternative donors [11,12].…”