Lower dose of ATG combined with post-transplant cyclophosphamide for HLA matched RIC alloHCT is associated with effective control of GVHD and less viral infections

Abstract

This study compares the outcomes before and after reducing the ATG dose from 4.5 to 2 mg/kg, in a combination of PTCy and CsA for GVHD prevention, in 250 patients treated with HLA matched RIC PB-alloHCT (70% received 4.5 mg/kg and 30% received 2 mg/kg). The incidences of grade II-IV and III-IV aGVHD at day +100, and moderate/severe cGVHD at 1-year were 12.6% vs. 20% (p = 0.431), 3.6% vs. 4.5% (p = 0.935), and 10.9% vs. 26.1% (p = 0.480), respectively. PTLD (9.1% vs. 1.3%, p = 0.026) and viral infections (30.3% vs. 12%; p = 0.001) were lower for those treated with 2 mg/kg of ATG. The reduction of the ATG dose resulted in a comparable OS (2-year: 64.7% vs. 64.7%), GRFS (2-year: 48.0% vs. 44.5%), RFS (2-year: 57.0% vs. 62.0%), and NRM (2-year: 17.8 vs. 14.9). The use of (2 mg/kg) ATG-PTCy-CsA for HLA matched RIC alloHCT results in lower viral infections, and incomparable GVHD preventive effect and survival rates.

Keywords:

• Anti-thymocyte globulin
• post-transplant cyclophosphamide
• peripheral blood stem cell
• matched related donor
• matched unrelated donor
• allogeneic stem cell transplantation

Supportive care and main definitions are described on the Supplementary Material

Statistical method

The main explanatory variable of interest was the dose of ATG provided for GVHD prophylaxis (4.5 vs. 2 mg/kg). Donor type (MRD vs. MUD) was considered a valuable endpoint variable in the study. The main outcome variables were: overall survival (OS), relapse-free survival (RFS), the cumulative incidence of acute and chronic GVHD, and GVHD-Free/RFS (GRFS). Other variables of interest were non-relapse mortality (NRM) and cumulative incidence of relapse (CIR). Categorical variables were presented as counts and percentages. Continuous variables were presented with medians and ranges. OS, RFS, and GRFS were calculated using the Kaplan–Meier product-limit method. NRM and CIR and the cumulative incidence of GVHD were estimated using the cumulative incidence method. Relapse was considered a competing event in the analysis of NRM, and death without relapse was considered a competing event for the analysis of CIR. Cumulative incidence of GHVD was estimated considering death and relapse as competing events. The impact of each explanatory variable and other risk factors on OS and RFS were analyzed using Cox Regression´s univariate and multivariable models; the impact on NRM and on the cumulative incidence of GVHD was analyzed using Fine–Gray test. Variables found to be significant in the univariate analysis and/or those considered clinically relevant for the study were included as explanatory in the multivariable model. The variables ATG dose and donor type were included as explanatory variables in all the multivariable analyses. All p-values were 2-sided and for the statistical analyses p < 0.05 was considered to indicate a statistically significant result. Statistical analysis was performed using version 9.4 of the SAS system for Windows (Copyright © 2002-2012 SAS Institute, Inc., Cary, NC).

Acknowledgments

We thank our patients and the nursing and support staff in the Hans Messner Allogeneic Blood and Marrow Transplant Program.

Author contributions

MQS and CC collected the data. MQS and AV designed the study, made the figures, and wrote the paper. EA did the statistical analysis of the data, made the figures, and reviewed the manuscript. AL, IP, WL, CC, AG, DK, FM, JL, RK, JM, and AV provided valuable input into the study design, analysis, and interpretation and reviewed the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).