Work

283: The use of Sirolimus Combined with Tacrolimus and Low-Dose Methotrexate to Prevent Graft-Versus-Host Disease following Unrelated Donor Hematopoietic Stem Cell Transplantation

Year: 2008

Type: article

Abstract: The use of sirolimus (siro) combined with tacrolimus (tacro) and low-dose methotrexate (MTX) recently showed a promising result in preventing acute GVHD after unrelated donor hematopoietic stem cell transplantation (MUD-HCT) (Antin et al. Blood 2003). We studied this approach in 77 patients (female = 30, male = 47) who received a MUD-HCT after full-intensity conditioning (TBI-VP16: 17, TBI-Cy: 10, BuCy: 3, BEAM: 2) or reduced intensity conditioning (FluMel: 45) from April 2005 to March 2007. Patient age ranged from 19 to 67 (median 46). The cohort consisted of 20 patients with AML, 19 with ALL, 15 with NHL, 8 with MDS, 5 with MPD, 4 with HD, 3 with CML, and 2 with CLL. Twenty-seven of 77 patients had low-risk disease (1st/2nd CR, CML-CP, or MDS-RA). Patients received a bone marrow (n = 15) or peripheral blood stem cell graft (n = 62). GVHD prophylaxis consisted of tacro, siro, and MTX 5 mg/m2 for 3–4 days. High-resolution (HR) molecular HLA typing was performed for class I and II. Forty-two pairs were in HR molecular match in all 10 antigens (HLA-A, B, C, DR, and DQ). Lack of iKIRL was found in 50 pairs. After a median follow up of 13 months, 50 are alive. The 1-year probabilities of overall survival (OS), disease-free survival, relapse, and non-relapse mortality were 60.6% (95%CI: 52.6–67.6), 55.9% (95%CI: 48.8–62.5), 15.0% (95%CI: 8.5–25.7), and 25.4% (95%CI: 17.9–35.3), respectively. Severe thrombotic microangiopathy was observed in two patients and was reversible. Acute GVHD grade II-IV and III-IV occurred in 46 (60%) and 17 (22%), respectively. Of 46 patients evaluable, 26 (56.5%) developed chronic GVHD (22=extensive, 4=limited). Multivariate analysis for acute GVHD (II-IV) demonstrated a significantly increased risk with older age (≥ median) (HR 1.9[1.0–3.5], p = 0.05) and a trend for patients without lack of iKIRL (HR 1.9[0.9–3.8], p = 0.08). Degree of HLA match, conditioning regimen, disease risk, gender mismatch, stem cell source, or CMV serostatus had no significant impact on acute GVHD. Reduced intensity conditioning was associated with better OS (76%) compared with full-intensity conditioning (38%, p = 0.01), which remained significant in multivariate analysis (HR: 0.4[0.2–0.8], p = 0.02). In summary, our results show the combination of siro, tacro, and low-dose MTX is associated with an acute GVHD rate comparable to our historic data after MUD-HCT, and associated with a promising OS when combined with FluMel reduced-intensity conditioning.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2007.12.293