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We examined the effect of donor characteristics on graft failure (<5% donor chimerism within 3 months after transplantation), acute and chronic graft-versus-host disease (GVHD) and survival after unrelated donor reduced intensity conditioning (RIC)transplantation in 709 patients with hematologic malignancies. Donor-recipient pairs were HLA typed at HLA-A, -B, -C, -DRB1 (allele-level). Five hundred and one patients were >95% donor chimerism, 145 patients, 5–95% and 63 patients <5%. The only donor characteristic associated with transplant-outcome was donor-recipient HLA matching. One or two-loci mismatched transplants led to higher grade 2–4 (RR 1.27, p=0.035) and grade 3–4 (RR 1.85, p<0.001) acute GVHD and two-loci mismatched transplants, higher mortality (RR 2.22, p<0.001). Graft failure was higher after transplantation of bone marrow (RR 2.33, p=0.002). Donor age, parity and donor sex match were not associated with transplant-outcome. Donor-recipient HLA-matching is the only donor characteristic predictive for survival after RIC regimens for hematologic malignancies.
Hematopoietic stem cell transplantation (HSCT) is a curative option for malignant and nonmalignant diseases.1 The last decade has seen an expansion of HSCT in part due to use of reduced intensity conditioning (RIC) regimens making this treatment option available to the elderly and patients with co-morbidities who are unlikely to tolerate myeloablative conditioning regimens.2,3,4 RIC regimens now account for approximately 40% of allogeneic transplantations in adults with hematologic malignancies. The characteristics of donors that influence HSCT-outcomes after myeloablative conditioning regimens are described.5,6 However, little is known about the effect of unrelated adult donor (URD) characteristics on the outcomes of RIC HSCT. Therefore, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) we examined the association between donor characteristics and outcomes after URD HSCT with RIC regimens for hematologic malignancies.
Included are 709 patients with haematological malignancies (Table 1) who received a RIC regimen for their first URD transplantation in 1999 – 2006 in the U.S., and facilitated by the National Marrow Donor Program. The preparative regimen was considered RIC when patients received busulfan<9 mg/kg, melphalan<150 mg/m2, total body irradiation (TBI) 200 cGy single dose or >200 – 450 cGy (single or fractionated dose).7 Patients received either bone marrow (BM) or peripheral blood progenitor cells (PBPC). The decision to offer RIC regimen and choice of graft type was at the discretion of the transplant centre. Allele-level HLA typing at -A, -B, -C and -DRB1 were available for all donor-recipient pairs; donor-recipient HLA typing was performed at a centrallaboratory. Mismatches at intermediate (antigen) or high (allele) resolution were considered equivalent and described as allele-mismatches.5 Excluded were patients aged <18 years, those who had received a prior autologous or allogeneic transplantation, T-cell depleted BM and CD34 selected PBPC and recipients of cord blood grafts. The study was approved by the Institutional Review Boards of the Medical College of Wisconsin and the National Marrow Donor Program.
Primary endpoints were graft failure defined as absence of absolute neutrophil count ≥0.5 × 109/L or donor chimerism<5% within 3 months post-transplant without clinical relapse for patients with absolute neutrophil count ≥0.5 × 109/L andoverall survival. For patients with chimersim assay <95% and >5%(mixed donor chimerism), subsequent assay confirmed <5% (graft failure)or >95%(full donor chimerism). Chimerism assays were performed on bone marrow or whole bloodwithout taking cellular subsets into account; the timing and method of assay was at the discretion of the transplant center. The median time to chimerism assay was 1.5 months (range 0.9–3.0). In 79 patients (11%), the method employed was fluorescent in-situ hybridization and for the remaining patients, molecular methods. Secondary endpoints were acute grade 2–4, grade 3–4 graft-versus-host disease (GVHD) and chronic GVHD.8,9
Patient, disease, donor and transplant characteristics are shown in Table 1. The probability of overall survival was calculated using the Kaplan-Meier estimator.10 Death from any cause was an event and surviving patients were censored at last follow-up. Logistic regression model was constructed to identify risk factors for graft failure at 3-months and the Cox model, for acute and chronic GVHD and overall mortality.11 Models were built using forward step-wise selection and variables shown in Table 1 that attained a significance level of ≤0.05 retained in the final model. All p-values are two-sided. The effect of transplant center on overall survival was tested using the frailty method.12 All analysis were done using SAS version 9.1 (SAS Institute, Cary, NC).
Our primary objective was to identify the effect of donor characteristics on graft failure, acute and chronic GVHD and survival to allow selection of the optimal URD for RIC-HSCT in patients with hematologic malignancies. The median follow-up of surviving patients is 2.5 years. Donor-recipient matching considered matching at HLA-A, -B, -C, -DRB1 (allele-level typing). Five hundred and one patients were >95% donor chimerism, 145 patients (5–95%; mixed chimerism) and 63 patients <5%(graft failure). Graft failure rates were higher after transplantation of BM compared to PBPC (OR 2.33, 95% CI 1.35–4.01, p=0.002). No other characteristic was associated with graft failure. Transplantation of BM was not associated with higher mortality risks despite the higher risk of graft failure. In the 145 patients with mixed donor chimerism, 101 had recurrent disease, which ultimately resulted in graft failure; the median time to recurrent disease was 57 days from transplantation. Eighteen patients with mixed donor chimerism died from transplant-related complications. Only 26 patients are alive and disease-free at last follow-up. Forty-five of 63 patients with graft failure(<5% donor chimerism) are dead (recurrent disease or organ failure) and 18 are alive; 10 of these patients are in remission. Despite higher graft failure rates associated with transplantation of BM, graft type was not associated with overall survival; 28 of 39 (72%) PBPC recipients and 17 of 24 (71%) are dead. Patients with graft failure receive alternative therapies and our data suggest salvage rates do not differ by graft type for first transplantation. Consequently, in the current analysis, graft type was not associated with overall survival.
Consistent with reports after myeloablative conditioning regimens for hematologic malignancies5, risks of acute grade 2–4 and grade 3–4 acute GVHD were higher after transplantations mismatched at 1 or 2-loci(Table 2). Risks of acute 2–4 and grade 3–4 GVHD were lower with in vivo T-cell depletion. Grade 3–4 acute GVHD was lower with tacrolimus-containing GVHD prophylaxis regimens. Chronic GVHD was not associated with HLA mismatch and consistent with reports after myeloablative transplant conditioning.5 Chronic GVHD was lower with in vivo T-cell depletion regimens (Table 2). We examined for an effect of in-vivo T-cell depletion on survival and found none. Our findings differ from a recent CIBMTR report15; use of ATG was associated with significantly lower survival in recipients of non-TBI conditioning regimens. That report had almost 800 patients who received in vivo T-cell depletion compared to the 419 patients in the current analysis and differences in sample size likely account for the observed difference between the two reports.
The only donor characteristic affecting overall survival was donor-recipient HLA mismatch (Table 2, Figure 1). Compared to matched transplants mortality risks were higher after transplants mismatched at 2-loci but not for transplantations mismatched at one-locus. Only 170 donor-recipient pairs were mismatched at 1-locus and the relatively small sample size may explain our inability to detect a significant difference. Mortality risks were also higher after 2-loci mismatched transplants compared to 1-locus mismatched transplants (RR 1.88 95% CI 1.27 – 2.78, p=0.002). We considered donor-recipient matching at HLA-A, -B, -C and –DRB1. Though we did not consider matching at HLA-DQ, typing was available for 90% of donor-recipient pairs (N=641) and most pairs (N=577; 90%) were matched at this locus. Death from infection, interstitial pneumonitis and organ failure were more likely after one and two-loci mismatched transplantations compared to matched transplantations. Disease status at transplantation is a predictor of mortality and a modifiable factor for many patients through early referral for HSCT. Mortality rates were higher when patients were not in remission at transplantation (RR 1.42, 95% CI 1.16–1.74, p<0.001). This effect is independent of donor-recipient HLA mismatch. Patients aged >60 years (RR 1.41, 95% CI 1.13–1.76, p=0.002) and those with performance score <90 at transplantation (RR 1.39, 95% CI 1.12–1.71, p=0.003) experienced higher mortality.
We specifically explored for an effect of donor age, donor-recipient sex match, cytomegalovirus serostatus and ABO compatibility and did not find an association between these characteristics and graft failure, GVHD or survival. Our findings are consistent with a recent report that considered donor-recipient matching at allele-level for HLA-A, -B, -C, -DRB1 after URD HSCT with myeloablative conditioning for hematologic malignancies.5 A likely explanation for our inability to detect differences in HSCT outcomes by donor age could be due to the fact that only 5% of donors were older than 50 years. Though the National Donor Marrow Program guideline limit donor age to 18–60 years, the current study population suggest approximately 70% of adult donors called to donate are aged 18–40 years. The selection of younger donors by transplant physicians effectively prevents us from further exploring the effect of donor age on transplantation outcomes. Others have shown GVHD and mortality risks are higher in male recipients of female donors when the donor is a matched sibling13 and more recently, these findings were confirmed in another report.14 In that report,14 75% of transplantations used were matched sibling donors, most received myeloablative conditioning regimens and the observed effect of donor-recipient sex match was most pronounced for chronic myeloid leukemia (CML) and myeloma. Our inability to observe an effect of donor-recipient sex match on HSCT-outcomes may be explained by differences in study population. Ours is limited to recipients of URD HSCT with RIC regimens, donor-recipient matching considered allele-level HLA typing at HLA-A, -B, -C and –DRB1, only 10% of patients in the current analysis had CML and there were no patients with myeloma. Patients with myeloma were excluded, as URD HSCT is not considered first-line treatment. Importantly, our observations are consistent with a large series on URD HSCT with myeloablative conditioning regimens.5
Our findings have important implications for selecting adult unrelated donors when considering RIC regimens for patients with hematologic malignancies. Survival rates are highest with donor-recipient pairs matched at HLA-A, -B, -C, and -DRB1. Avoiding transplantation of bone marrow grafts and transplantation of PBPCs will lower graft failure rates.
Funding: Public Health Service Grant (U24-CA76518) from the National Cancer Institute, the National Heart, Lung and Blood Institute and the National Institute of Allergy and Infectious Diseases; the Office of Naval Research (N00014-06-1-0704 and N00014-08-1-0058) and Health Resources and Services Administration (HHSH234200637015C). The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, or any other agency of the U.S. Government.
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