The use of sirolimus combined with tacrolimus and low-dose methotrexate recently showed a promising result in preventing GVHD after unrelated donor hematopoietic stem cell transplantation (

Antin et al. Blood 2003; 102: 1601
). We studied this approach in 33 patients who received an unrelated donor transplant after full-intensity conditioning or reduced intensity conditioning from April 2005 to March 2006. All patients gave written informed consent for City of Hope protocols approved by the local institutional review board. Patient age ranged from 21 to 65 (median 46). Ten were female and 23 were male. The cohort consisted of 12 patients with AML, 9 with NHL, 6 with ALL, and the remaining 6 with other diagnosis (MDS=2, MPD=2, CML=1, HD=1). Patients were conditioned with either full-intensity regimen (FTBI-VP16=8, FTBI-Cy=6, BuCy=2) or reduced-intensity regimen using fludarabine (125mg/m2) plus melphalan (140mg/m2) (n=17) and received either a bone marrow graft (n=8) or peripheral blood stem cell graft (PBSC: n=25). GVHD prophylaxis consisted of tacrolimus (target serum level 5–10 ng/ml) and sirolimus (target serum level 3–12 ng/ml) started on day -4, and methotrexate 5mg/m2 for 3–4 days (days 1, 3, 6, +/− 11). High-resolution (HR) molecular HLA typing was performed for class I and II. Twenty pairs were in HR molecular match in all 10 antigens (HLA-A, B, C, DR, and DQ), five were in HR molecular 6/6 match (mismatch in C and/or DQ), and the remaining 8 pairs had a molecular mismatch in HLA-A (n=4), B (n=3), and DR (n=1). Eight transplants were from female donors to male recipients. After a median follow up of 7 months (range: 3–15), 26 patients are alive. Causes of death include relapse (3), VOD (2), and sepsis with multiorgan failure associated with grade 4 GVHD (1). The probabilities of 1-year overall survival, disease-free survival, and relapse were 74% (95%CI: 59–85%), 59% (95%CI: 41–75%) and 28% (95%CI: 16–45%), respectively. The probability of transplant-related mortality was 9% (95%CI: 5–18%) at 100 days and 19% (95%CI: 10–32%) at 1 year. Thrombotic microangiopathy was observed in two patients and were reversible. The probability of grade 2–4 acute GVHD was 44+9% (grade 3–4: 24+8%). Of 26 patients evaluable, 12 developed chronic GVHD (7=extensive, 5=limited). There was no difference in GVHD between full-intensity transplants and reduced-intensity transplants. There was a trend for reduced grade 2–4 acute GVHD in HR 10/10 match transplants (n=20: 31%) compared with the others (n=13: 62%, p=0.08). The current data compare favorably to our historic control (n=181: reduced intensity=98, full-intensity=83) using tacrolimus plus methotrexate or cyclosporine plus MMF with the incidence of grade 2–4 acute GVHD at 64% (p=0.02). In summary, our result show the combination of sirolimus, tacrolimus and low-dose methotrexate is associated with improved GVHD prophylaxis and acceptable toxicity. However, transplants others than 10/10 HR molecular match require further improvement.

Topics:
donors, graft-versus-host disease, hematopoietic stem cell transplantation, methotrexate, rapamycin, tacrolimus, graft-versus-host disease, acute, hla-a antigens, hla-a2 antigen, transplantation

Disclosure: No relevant conflicts of interest to declare.

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2006, The American Society of Hematology
2006
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