Reduced Incidence of Acute and Chronic Graft-versus-Host Disease (GvHD) without Increased Relapse in Patients with High-Risk Myeloid Disorders Given Thymoglobulin (THY) as Part of the Transplant Conditioning Regimen: A Dose-Finding Study.
Authors: Deeg H. Joachim , Appelbaum F. R. , Storer B. , Cassarella M. , Scott B. , McDonald G. , Storb R. 
Published: October 2019

Abstract
GvHD is a major cause of morbidity and mortality after allogeneic hemopoietic cell transplantation (HCT). Recent data suggest that rabbit anti-thymocyte globulin (THY) given pre-transplant is effective in reducing the incidence of GvHD. We transplanted 54 patients, 9-65 (median 49) years of age, with advanced myelodysplastic syndrome (MDS, beyond Refractory Anemia[RA], n=29), myelofibrosis (n=12), or other myeloid disorders (n=13), after conditioning with a regimen of targeted busulfan (BU; steady state level 800-900ng/ml), cyclophosphamide (CY) and THY (Thymoglobulin, Sangstat) which was given on days -3,-2 and -1. The starting dose was 4.5 mg/kg (total), to be escalated (in cohorts of 15 patients) to 6.0 and 7.5 mg/kg, dependent upon GvHD incidence and EBV reactivation ≥1000 copies). Patients also received methotrexate (MTX) + cyclosporine (CSP). Seventeen ( patients were accrued in the first cohort (2 did not receive the prescribed dose of THY), and none activated EBV; among 20 patients in the second cohort (5 with incomplete THY dose) one re-activated EBV, and, thus, the third cohort was to receive the same dose, 6 mg/kg, (n=17; two with incomplete THY dose). Donors were HLA-identical siblings in 28, and HLA matched unrelated volunteers in 26 patients. All but two patients had sustained engraftment; 32 (59%) developed acute, and 24 of 46 patients at risk (52%) developed chronic GvHD. The incidence of acute/chronic GvHD was 41%/45% for related, and 60%/36% for unrelated patients given the prescribed doses of THY (80%/85% for the 9 patients in both groups with incomplete THY dose). Relapse incidence for patients given the prescribed dose of THY was 16% for related, and 2% for unrelated recipients; it was 44% among the 9 patients who did not receive the full dose of THY. There was a suggestion that greater ‘area under the curve’ for the CY metabolite CEPM was correlated with non-relapse mortality. Overall, 38 patients (70%) are surviving with a follow-up of 3-20 (median 13) months. Concurrently, 27 patients, 11-64 (median 51) years of age, with low-risk MDS (RA) were conditioned with the identical targeted BUCY regimen (and MTX+CSP) but without THY, and transplanted from HLA-identical related (n=14) or unrelated donors(n=13). All patients engrafted, and none relapsed; 24 (89%) developed acute, and 24 of 25 patients at-risk (96%) developed chronic GvHD. Overall 18 patients (67%) are surviving at 9-39 (median 23) months; there was no difference between related and unrelated transplants. These data suggest that THY, added to targeted BUCY, reduced the incidence of acute and chronic GvHD. With EBV monitoring it may be possible to further escalate the dose of THY and further reduce the incidence of GvHD. However, because of actual or presumed toxicity, 16% of patients did not receive the prescribed dose of THY. There was no evidence for an increase in infections or relapse compared to historical data. The projected survival of patients with advanced disease is encouraging, but longer follow-up is needed.