Acute Graft Versus Host Disease after Nonmyeloablative Allogeneic Stem Cell Transplantation with Low-Dose TBI, Fludarabine and Antithymocyte Globulin (ATG).

Abstract

Acute GvHD is a frequent complication of non-myeloablative transplantation although it is seen at a lower rate and severity than after myeloablative transplantation. The use of ATG in transplant conditioning produces substantial host immunosuppression. Furthermore, the persistence of ATG in the circulation after transplantation is thought to accomplish an in-vivo T-cell depletion of the stem cell inoculum. Non-myeloablative stem cell transplantation using low dose TBI (200cGy) and fludarabine results in a high rate of full donor chimerism. We previously showed that the addition of ATG to TBI 200 cGy and fludarabine can improve donor engraftment. Whether it also impacts on acute and chronic GvHD and on graft versus tumor effect is less known. Forty-seven patients, not eligible for conventional fully ablative allogeneic SCT by virtue of age or co-morbidities, underwent non-myeloablative allogeneic transplantation using ATG 15 mg/kg/day (equine) or 1.5mg/kg/day (rabbit) days −4 to −1, TBI 200 cGy on a single fraction on day −5, fludarabine 30 mg/kg/day on days −4 to −2. Oral immunosuppression with MMF and CSA were started on day −5. Allografts were unmanipulated peripheral blood progenitor cells collected on day 5 of mobilization with filgrastim 10 mcg/kg/day. Thirty-two patients (68%) had match related donors, 9 (19%) match unrelated (10/10), 1(2%) mismatch related (9/10) and 5 (10.6%) mismatch unrelated donors (9/10). Twenty-five patients had sex matched donors (53.2%). Full donor chimerism was documented in 85% and partial (>50%) in 11% of patients. At a median follow up of 309 days, graft versus host disease grade II–IV developed in 13 patients (27.6%). Fatal GvHD of liver and/or gut occurred in 8 patients (17%). The mean age of patients who developed GvHD was 54 years and 57 for those who did not (p=ns). The corresponding mean ages for their donors were 47 vs. 50 years (p=ns). Seven out of fourteen (50%) unrelated transplants recipients and 6/33 (18%) with related donors develop GVHD (p=0.023). Infectious complications were seen in 8 patients (17%) and were the cause of death in 6 (12%). Thirteen of the 47 patients (27.6%) underwent transplant for AML. Six patients had relapsed/refractory disease at the time of transplant, 3 were in CR2 and 4 in CR1. Eleven patients (84.6%) relapsed with AML after transplant. Previously reported data on non-myeloablative stem cell transplant using 200 cGy of TBI and fludarabine with no ATG showed an incidence of acute GvHD grade II–IV of 64% and 24% GvHD related mortality. Similar rates have been reported with fludarabine and melphalan reduced-intensity conditioning. In our cohort of 47 patients the addition of ATG resulted in decreased incidence of acute GvHD grade II–IV and GvHD related mortality without a high rate of infectious complications. A high incidence of disease relapse in patients with AML may reflect the high proportion of patients with advanced leukemia enrolled in the study. However, it also warrants further investigation to rule out that ATG may hinder graft versus leukemia effect.