The Outcome of the Combination of Tacrolimus, Sirolimus, and ATG for GvHD Prophylaxis on Allogeneic Stem Cell Transplantation From Matched Unrelated Donors

Graft-vs-Host Disease (GvHD) remains a significant complication of allogeneic stem cell transplantation from matched unrelated donors (MUD). Compared to MTX-based regimen, Tacrolimus/Sirolimus was found to decrease the incidence of acute GvHD (Keil et al, Biol Blood Marrow Transplant. 2009;16(2):S319, and Cutler et al, Blood. 2007;109:3108–14), whereas, the incorporation of Antithymocyte globulin (ATG) into MTX-based regimen decreases the incidence of chronic GvHD (Bacigalupo et al, Biol Blood Marrow Transplant. 2002;8(12):656–61). There are no reports of the outcome of the combination of Tacrolimus/Sirolimus and ATG. We compared the results of MUD using tacrolimus and sirolimus (day-3 to day +180) combined with ATG (2.5 mg/kg day −3,−2, and −1) (TSA) prophylaxis in consecutive patients treated at our institution from September 2006 to March 2009, with those using MTX-based prophylaxis without ATG in consecutive patients treated from January 2000 to August 2006. The primary endpoints were incidence of acute and chronic GvHD, lethal infectious complications, relapse, and survival.

Between 1/2000 and 3/2009, 71 MUD stem cell transplants were performed. 27 patients received TSA regimen as GvHD prophylaxis and 44 patients received traditional MTX-based prophylaxis without ATG. More patients in the TSA group received PBSC compared to the MTX group (63% vs. 36%; P=0.029), otherwise both groups were matched for age, sex, underline malignancies, disease risk per ASBMT criteria, degree of HLA-match, CMV serology, and conditioning regimens. The cumulative incidence of Grade II-IV classic acute GvHD at day +100 was significantly lower in the TSA group compared to control group (11.7% vs. 41.6%; Gray's test P =0.008). However, the cumulative incidence of aGvHD at day +365 was not statistically significant between both groups (33.1% vs. 44.4%; Gray's test P=0.154); this was due to an increase rate of delayed-onset aGvHD in TSA group (18.5%) compared to MTX group (2.3%). The rate of limited cGvHD was 7.1% vs. 30% in the TSA group and MTX group, respectively (Fisher's P= 0.12). 23% of patients surviving beyond day +100 in MTX group developed extensive/overlap cGvHD, whereas, there were no cases in the TSA group. The rate of CMV infection in patients not receiving corticosteroid treatment for GVHD was higher in the TSA group, although not statistically significant (36.8% vs. 16%, P=0.27). The rate of invasive fungal infections was similar (10.7% vs. 11.8%). The cumulative incidence of relapse at 2 years was 38.5% vs. 22.8% in the TSA and MTX groups, respectively (Gray's test P=0.18). Non-relapse mortality at 2 years was similar in both groups (42% vs. 48%; Grays's test P=0.8). Day +100 mortality was 14.4% and 27.3% in TSA and MTX group respectively. The median survivals were 251 days (95% CI, 170–332) vs. 349 days (95% CI, 236–462) for TSA and MTX groups, respectively. The 1- and 2-year overall survival were 42.3% and 31.7% for TSA group vs. 47.7% and 34.1% for MTX group, respectively (P=0.704). While the mortality rate from bacterial sepsis were equivalent, more patients in the TSA group who were not receiving corticosteroid treatment for aGvHD died from viral and fungal infection (14.3% vs. 0% at 12 months, Fisher's P=0.014).

This is the first report of the combination of TSA for GvHD prophylaxis in MUD transplants. This regimen resulted in a significant decrease in classic aGvHD as previously reported for combination of Tacrolimus/Sirolimus, and decrease in incidence of cGvHD as reported previously in the studies incorporated ATG in MTX-based regimens. Hence, this did not translate into benefit in overall survival due to an increased rate of relapse and lethal viral and fungal infections with TSA regimen. Our study does not demonstrate an appreciable benefit for the addition of ATG, at the dose used, to sirolimus and tacrolimus for GvHD prophylaxis. Further studies directed at optimizing the dose of ATG to lower the rate of lethal infections may result in an overall benefit.

No relevant conflicts of interest to declare.