Unmanipulated Haploidentical Reduced-Intensity Stem Cell Transplantation Using Fludarabine, Busulfan, Low-Dose Antithymocyte Globulin, and Steroids for Patients in Non–Complete Remission or at High Risk of Relapse: A Prospective Multicenter Phase I/II Study in Japan

Abstract

This prospective, multicenter phase I/II study of unmanipulated HLA-haploidentical reduced-intensity stem cell transplantation using a low dose of anti-T lymphocyte globulin (ATG) and steroid was conducted in 5 institutions in Japan. Thirty-four patients with hematologic malignancies who were in an advanced stage or at a high risk of relapse at the time of transplantation were enrolled. Among them, 7 patients underwent transplantation as a second transplantation because of relapse after the previous allogeneic stem cell transplantation. The conditioning regimen consisted of fludarabine, busulfan, and ATG (Fresenius, 8 mg/kg), and graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methylprednisolone (1 mg/kg). All patients except 1 (97.1%) achieved donor-type engraftment. Rapid hematopoietic engraftment was achieved, with neutrophils > .5 × 10(9)/L on day 11 and platelets > 20 × 10(9)/L on day 17.5. Treatment was started for ≥grade I GVHD, and the cumulative incidences of acute grade I and grade II to IV GVHD were 27.5% and 30.7%, respectively. The incidence of chronic GVHD (extensive type) was 20%. Fourteen patients (41.2%) had a relapse. The cumulative incidence of transplantation-related mortality at 1 year after transplantation was 26.5%. The survival rate at day 100 was 88.2%. The survival rates at 1 year for patients with complete remission (CR)/chronic phase (n = 8) and non-CR (n = 26) status before transplantation were 62.5% and 42.3%, respectively. In the multivariate analysis, non-CR status before transplantation was the only factor significant prognostic factor of increased relapse (P = .0424), which tended to be associated with a lower survival rate (P = .0524). This transplantation protocol is safe and feasible, if a suitable donor is not available in a timely manner. As the main cause of death was relapse and not GVHD, more intensified conditioning or attenuation of GVHD prophylaxis and/or donor lymphocyte infusion may be desirable for patients with non-CR status.

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

“…Between patients undergoing UD-HCT versus HFD-HCT, there were no significant differences in various HCT outcomes: 3-year leukemia recurrence (P = .45), 3-year NRM (P = .43), 3-year RFS (P = .25), 3-year OS (P = .40), neutrophil engraftment (100% in both groups), grades 2 to 4 acute GVHD (P = .20), moderate-to-severe chronic GVHD (P = .88), CMV reactivation (P = .27), and EBV reactivation (P = .88). These outcome values were consistent with previous reports of RIC containing busulfan, fludarabine, and ATG in UD-HCT [26,27,36,37] and HFD-HCT [32,34]. Furthermore, considering a wide range of donor-patient HLA disparities in these 152 patients, 55, 42, and 55 patients undergoing HCT with 0, 1 or 2, and 3 or 4 disparities of 8 HLA alleles, respectively, this observation was in agreement with the findings in UD-HCT, where the addition of ATG to conditioning regimens negated the adverse effects of donorpatient HLA disparity [24][25][26][27].…”

“…In both settings, we observed consistent donor cell engraftment (≥98%) and low rates of grades 2 to 4 acute GVHD (20%), chronic GVHD (<35%), and nonrelapse mortality (NRM, ≤18%). These findings corroborated the results observed by other investigators using similar RIC with ATG in UD-HCT [26,36,37] and HFD-HCT [34]. Although these outcomes appeared encouraging, leukemia recurrence remained a concern and could negatively impact patient survival in view of RIC and ATG, both of which were reportedly related to potential increases in disease progression [38,39].…”

“…In RIC regimens containing busulfan, fludarabine, and ATG, different preparations [34] and doses of ATG were studied. In studies using Thymoglobulin (Genzyme), the total dose ranged from 2.5 mg/kg to 12 mg/kg [17,27,31,32,57,58].…”

“…Furthermore, beneficial effects of ATG were shown in UD-HCT, where the detrimental effects of HLA disparity between donor and patient [7,23] were mitigated when ATG was added to the myeloablative conditioning [24][25][26] or RIC [25][26][27], which suggested that ATG may play a role in HLA-mismatched HCT. In fact, in HCT from family donors with an HLA-haplotype mismatch, several myeloablative [28][29][30] and RIC regimens [31][32][33][34] containing ATG were introduced. In a prospective study, patients with AML in remission undergoing HCT from haploidentical family donors (HFD) after a myeloablative conditioning regimen containing ATG showed similar incidence of leukemia recurrence and patient survival to those patients undergoing MSD-HCT [30].…”

Haploidentical related donor vs matched sibling donor allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndrome aged over 50 years: A single‐center retrospective study

“…In multivariate analysis, our result showed that disease status at transplant was independent risk factor for relapse. This result was consistent with other studies 40,46‐48 . Ogawa et al retrospectively analyzed the data of AML patients registered in the Japan Society of Hematopoietic Stem Cell transplantation who underwent allo‐SCT and were and confirmed that survival of patients with relapsed or refractory AML was poor due to the increased relapse 40 .…”