Low-Dose ATG-F Reduces Non-Relapse Mortality after Reduced-Intensity Bone Marrow Transplantation from an Unrelated Donor: A Single-Center Analysis of 65 Patients.
Authors: Fuji Shigeo , Fukuda Takahiro , Kim Sung-Won , Usui Eiji , Kurosawa Saiko , Yokoyama Hiroki , Saito Bungo , Takahashi Toshihiro , Mori Shin-ichiro , Heike Yuji , Tobinai Kensei , Tanosaki Ryuji , Takaue Yoichi 
Published: October 2019

Background: In Japan, peripheral blood stem cell transplantation from an unrelated donor has not been approved. Therefore, for unrelated bone marrow transplantation with a reduced-intensity conditioning regimen (u-RIST), low-dose TBI has been added to facilitate engraftment. However, non-relapse mortality (NRM), which was mostly related to GVHD, was extremely high (54% at 1 year) after u-RIST with cladribine/busulfan/TBI 4 Gy (Kim et al. ASH 2006). To overcome this problem, we introduced antithymocyte globulin (Fresenius: ATG-F) at a lower dosage of 5–10 mg/kg to replace TBI. This study evaluated the feasibility of this regimen.

Patients and Methods :From January 2000 to May 2007, 65 patients with hematological malignancies received u-RIST with a conditioning regimen including fludarabine (Flu 30 mg/m2 x 6 days) or cladribine (2CdA 0.11 mg/kg x 6 days) plus busulfan (oral Bu 4 mg/kg x 2 days, iv Bu 3.2 mg/kg x 2 days) with 4 Gy TBI (n=30), 2 Gy TBI (n=20) or low-dose ATG-F (n=15). The median age of the patients was 57 years (range, 20–65). Their diagnosis included AML/MDS (n=39), lymphoma (n=19) and others (n=7). There were no differences in pretransplant disease status or HLA-disparity among the 3 different groups.

Results: The median follow-up of surviving patients was 381 days (range, 64–1832). Although more patients in the ATG-F group experienced graft failure, all 3 patients were rescued with a second transplant or DLI. Compared to low-dose TBI group, the incidences of grade II–IV and III–IV acute GVHD were significantly lower in the ATG-F group, which resulted in significantly lower NRM, better overall survival (OS) and better progression-free survival (PFS) (Figure). However, the incidences of disease relapse and CMV reactivation were not different among the 3 groups. A Cox proportional hazard model showed that low-dose ATG-F was associated with a significantly better PFS.

Conclusions: Our study showed that very low-dose ATG-F (5–10 mg/kg) significantly reduced the incidence of acute GVHD without an increase in the relapse rate, which led to a significantly improved PFS rate. A slightly higher rate of graft failure was manageable. The optimal dose of ATG-F needs to be determined according to the source of stem cells and HLA-disparities, including ethnic differences, and our study should help to provide a model to pursue this.

TBI 4 Gy (n=30) TBI 2 Gy (n=20) LD ATG-F (n=15) P (TBI vs ATG-F) 2CdA/Flu 11/19 5/15 0/15 0.01 CSP/TAC 28/2 4/16 4/11 0.01 CR/non-CR, pretransplant 10/20 9/11 5/10 0.74 HLA match/mismatch 17/13 13/7 10/5 0.64 Graft failure 3% 0% 20% 0.04 Acute GVHD, grade II–IV 55% 74% 8% <0.01 Acute GVHD, grade III–IV 31% 16% 0% <0.01 1-year NRM 46% 15% 0% 0.01 1-year OS 47% 69% 100% <0.01 1-year Relapse 19% 40% 12% 0.43 1-year PFS 43% 51% 88% <0.01 Figure Figure