Sirolimus, Tacrolimus, And Rabbit ATG (rATG) As Graft-Versus-Host Prophylaxis In Patients Undergoing Unrelated Donor Hematopoietic Stem Cell Transplant (HCT)

The use of sirolimus combined with tacrolimus +/- low-dose methotrexate (MTX) recently showed a promising result in preventing acute GVHD after unrelated donor HCT (Antin et al. Blood 2003) although a significant number of patients still experienced chronic GVHD. In an attempt to further improve the outcome, we have developed a novel combination of tacrolimus (FK), sirolimus (SIR) and r-ATG +/- MTX (MTX given for patients with a mismatch donor) and studied in a total of 51 patients who underwent unrelated donor HCT from 7/5/2006 to 7/31/2009. The median age at transplant was 56 (range: 16 -71). Twenty were female and 31 were male. Indications for transplant were as follows: ALL (n=12, CR1/2=11, Induction Failure=1), AML (n=19: CR1/2=12: relapse/induction failure=7), CML (n=4: CP1/2=2, AP/BC=2), non-Hodgkin Lymphoma (n=5); CLL (n=1), MDS (n=8), MPD (n=2). Thirty one patients received reduced-intensity conditioning (fludarbine/melphalan [Flu/Mel]) and 20 received full-intensity conditioning (FTBI/VP-16: n=13, FTBI/Cytoxan: n=7). All received PBSC graft except for two patients who received bone marrow graft. Twenty-nine of 51 patients had a 10/10-match donor by high resolution HLA typing. Engraftment rate was 92.2% (n=47) with the median neutrophil engaftment at 15 days (range: 10-39). Eighteen patients (38% of 47 engrafted) developed grade II-IV acute GVHD (grade III=3, grade IV=0). Chronic GVHD developed in 21 of 37 evaluable patients (57%, limited n=7, extensive n=14). We observed TTP/HUS in 10 patients (20%) and one case of VOD. Eighteen (42%) of 43 patients at risk (R+ or D+) developed CMV reactivation, while 10 patients developed EBV reactivation (19.6%). After a median follow up of 11 months (range: 2-35) 38 patients were alive. The 1-year probabilities of overall survival, disease-free survival (DFS), and relapse rate were 74.7% (63-83%), 73.2% (62-82%), and 11% (5-25%), respectively. Non-relapse mortality was 14.7% (8-26%) at 100 day and 17.5% (10-29%) at 1 year. There were no significant differences in the outcomes according to conditioning regimens, although there was a trend for lower NRM with Flu/Mel (11% vs. 27% at 1 year, p=0.1). In summary FK/SIR combined with r-ATG +/- MTX is associated with a promising early result in GVHD prevention and survival in this high-risk population. However, the rate of graft failure (n=4) appeared greater than our historic data, which is being further investigated at our institution.