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Originally published as JCO Early Release 10.1200/JCO.2006.08.0952 on November 20 2006 © 2006 American Society of Clinical Oncology. Allogeneic Marrow Stem-Cell Transplantation From Human Leukocyte Antigen–Identical Siblings Versus Human Leukocyte Antigen–Allelic–Matched Unrelated Donors (10/10) in Patients With Standard-Risk Hematologic Malignancy: A Prospective Study From the French Society of Bone Marrow Transplantation and Cell Therapy
From Lille; Agence de la biomédecine, St Denis; Créteil; Bordeaux; Angers; Nantes; Institute Gustave Roussy, Villejuif; Hospital St Louis, Paris; Hôpital Pitié-Salpetrieère, Paris; Hôpital Edouard Herriot, Lyon; Hôpital Necker, Paris; Nice; Besançon; Société Française de Greffe De Moelle et Thérapie Cellulaire, St Denis; register France Greffe de Moelle, St Denis; Unite de biostatistique, Université de Jussieu, Paris, France Address reprint requests to Jean-Pierre Jouet, MD, UAM allogreffes de CSH, Maladies du Sang, CHRU de Lille, F-59037, France; e-mail: jpjouet{at}chru-lille.fr
PURPOSE: To investigate the influence of donor type (human leukocyte antigen [HLA] -identical sibling donor versus HLA-A–, HLA-B–, HLA-Cw–, HLA-DRB1–, and HLA-DQB1–identical unrelated donors, or so-called 10/10) on the outcome of patients who underwent allogeneic stem-cell transplantation (alloSCT), adjusting for other prognostic factors, in patients with standard-risk hematologic malignancy. PATIENTS AND METHODS: Between March 2000 and January 2003, we prospectively investigated the outcome of 236 consecutive patients with standard-risk malignancy from 12 French centers. Fifty-five patients underwent alloSCT from an unrelated HLA-identical donor at the allelic level, whereas 181 patients received an alloSCT from an HLA-identical sibling. Diagnoses included acute leukemia (n = 175), chronic myeloid leukemia (n = 43), and myelodysplastic syndrome (MDS; n = 18). All patients received unmodified marrow graft following myeloablative conditioning with cyclophosphamide and total-body irradiation. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and short-course methotrexate in all patients.
RESULTS: In multivariable analysis, overall survival and transplantation-related mortality were adversely influenced by recipient cytomegalovirus (CMV) -positive serology, age of donor older than 37 years, and the occurrence of acute grade CONCLUSION: In patients with standard-risk malignancy, transplantation from unrelated HLA-allellically matched donors led to outcomes similar to those from HLA-identical sibling donors.
Allogeneic stem-cell transplantation (alloSCT) offers potential curative treatment for a wide range of otherwise fatal hematologic diseases.1-6 However, only one third of patients have a human leukocyte antigen (HLA) -identical sibling donor. Indeed, with the increase in the number of single-child families, stem-cell grafts from unrelated donors are being increasingly used. The success of unrelated alloSCT is influenced by the degree of HLA compatibility between donor and patient.7 In contrast, the presence of donor-recipient mismatching is associated with increased risk of post-transplantation complications, including graft rejection, acute and chronic graft-versus-host disease (GVHD), and mortality; these risks are increased by multiple HLA mismatches.8-12 This might explain why transplantation from unrelated or related mismatched donors has been restricted to patients with high-risk malignancy.13-18 Several studies have reported outcomes following alloSCT from an unrelated donor.8-10,14-16,19-21 However, to our knowledge, none of the studies prospectively investigated the effect of donor type on patient outcome. Furthermore, interpretation of data may be confounded both by the heterogeneity of transplantation modalities concerning the conditioning regimen, source of stem cells, use of antithymoglobulin (ATG) or GVHD prophylaxis, and by a disparity in the degree of HLA matching for unrelated transplantations. Although precise matching of the donor/recipient pair has been made easier by HLA typing at the allelic level,7 several issues with respect to unrelated transplantation remain to be addressed, including the impact of allelic HLA matching on patient outcome in terms of engraftment, graft rejection, overall survival (OS), event-free survival (EFS), relapse and transplantation-related mortality (TRM) rates, and whether this contributes to a lower incidence of GVHD. The main objective of this study was to prospectively estimate the influence of donor type (HLA-identical sibling donor versus HLA-A–, HLA-B–, HLA-Cw–, HLA-DRB1–and HLA-DQB1–identical unrelated donors, or so-called 10/10) on the outcome of patients who underwent alloSCT, adjusting for other prognostic factors, in patients with standard-risk hematologic malignancy. Taking into account the uncertainty concerning the most appropriate conditioning regimen and GVHD prophylaxis, and in order to avoid statistical bias due to transplantation modalities, all patients in this multicenter prospective study were required to receive the same pretransplantation preparative regimen, source of stem cells, and GVHD prophylaxis.
Study Design The study was approved by the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) board and was begun after agreement by the Lille Hospital Ethics Committee. Participating centers were requested to prospectively register all patients who met inclusion criteria and had signed informed-consent sheets. We chose a prospective design with two groups of patients: one group who received alloSCT from an HLA-identical sibling donor (sibling group), and one who received alloSCT from an HLA-A–, HLA-B–, HLA-Cw–, HLA-DR–, and HLA-DQ–identical unrelated donor (unrelated group). Neither group was randomly constituted, but both groups were made as homogenous as possible using the following inclusion criteria. Patients included were younger than 55 years old and were referred for alloSCT with marrow from either a sibling or an HLA-identical unrelated donor. Patients had to have a standard-risk hematologic malignancy defined as acute leukemia (AL) in first or second complete remission (CR), chronic myeloid leukemia (CML) in a chronic or accelerated phase, or myelodysplastic syndrome (MDS) with marrow blasts  10%. Patients were required to have received the same myeloablative conditioning regimen and GVHD prophylaxis (see Transplantation Modalities). Patients who had received either T-cell–depleted marrow or peripheral stem-cell graft were excluded from the study, as were those patients who had received ATG with the conditioning regimen.
Patients
HLA Typing All donor/recipient pairs were typed at the allelic level. They were first typed at the two-digit level for HLA class I (HLA-A, HLA-B, and HLA-Cw) and class II (HLA-DRB1 and HLA-DQB1) using published HLA class I polymerase chain reaction sequence-specific oligonucleotide (PCR-SSO) and/or PCR–sequence-specific primers (PCR-SSP) typing protocols. For unrelated donors, HLA-A, HLA-B, HLA-Cw, HLA-DRB1, HLA-B3, HLA-B4, HLA-B5, and HLA-DQB1 subtyping was performed using different PCR-SSP kits. HLA typing was performed according to the current use of the European Federation for Immunogenetics (EFI) Histocompatibility Laboratory standards. Additional assays using sequence-specific amplification and direct DNA sequencing of amplified DNA were used as needed in specific cases to aid in allelic identification without ambiguities. Only donor/recipient unrelated pairs matched for both alleles were included in this study. Interpretation of typing results was based on alleles described in the WHO HLA nomenclature (four digits).22 Samples from donors and recipients with only a single allele identified by specific PCR or sequence analysis were assumed to be homozygous after review of transplantation center typing.
Transplantation Modalities
Statistical Analysis Survival analyses were performed with a follow-up end point on January 1, 2005. Five criteria were studied: OS, TRM, relapse, EFS, and acute GVHD. For OS, TRM, relapse, and EFS, grades II to IV acute GVHD was considered as a time-dependent risk factor. TRM was defined as death from any cause in the absence of relapse. EFS was defined as survival from alloSCT without relapse. TRM and relapse were treated as competing risk events. The time from transplantation to the onset of acute GVHD was considered for analysis in patients who had developed grades II to IV acute GVHD or grades III to IV acute GVHD. Death occurring within 100 days after transplantation was considered as a competing event for acute GVHD. For each criterion, all potential risk factors were first tested using univariate Cox models.24 For OS, TRM, relapse, and EFS, occurrence of grades II to IV acute GVHD was considered as a time-dependent risk factor. Overall survival and EFS rates were estimated using the Kaplan-Meier method.25 TRM, relapse, and acute GVHD rates were estimated using cumulative incidence functions.26 Thus, all potential risk factors were included in multivariable stepwise Cox regressions. In each final model, risk factors associated with a Wald test P value lower than 5% were retained and donor type was forced. All computations were performed using SAS Software (SAS Institute, Cary, NC).
The two groups were comparable in terms of initial patient characteristics. However, patients from the unrelated group were slightly younger and more often had MDS and male donors, whereas those patients receiving transplantations via a sibling donor more often had acute leukemia and favorable disease prognosis status (Table 1). Thirty-three (23%) of 141 patients with acute leukemia from the sibling group were in second CR compared with 14 (41%) of 34 patients from the unrelated group (P = .036). Time from diagnosis to alloSCT was longer for patients in the unrelated group than for patients in the sibling group (Table 1).
Engraftment and Transplantation Toxicity
Univariate Analysis
Acute GVHD. One hundred sixteen patients (49%) developed acute grades II to IV GVHD, including 83 patients (46%) from the sibling group and 33 (60%) from the unrelated group. Fifty patients (21%) developed acute grades III to IV GVHD; 34 patients (19%) from the sibling group and 16 (29%) from the unrelated group. The risk of developing acute grades III to IV GVHD was lower for patients with acute leukemia and for patients whose time from diagnosis to alloSCT was less than 5.5 months. The risk of acute grades II to IV GVHD was higher for patients with CML or for patients who had undergone alloSCT from an unrelated donor (Fig 1). The risk was lower for patients with acute leukemia or positive CMV serology.
Multivariable Analysis
The effect of donor type was nonsignificant for overall survival, EFS, relapse, TRM, or acute GVHD. Overall survival and TRM were adversely influenced by a recipient CMV-positive serology, donor age older than 37 years, and the occurrence of acute grades II to IV GVHD. EFS rates were higher for patients with recipient CMV-positive serology. Acute grades II to IV GVHD rates were higher for patients with CML, but unexpectedly lower for patients with recipient CMV-positive serology. No factor was found to influence either relapse or acute grades III to IV GVHD.
To our knowledge, this is the first study which prospectively compares results of sibling transplantation to HLA-allellically matched (10/10) unrelated transplantation. We observed 2-year overall survival, EFS, relapse, and TRM rates of 62.9%, 55.6%, 19.4%, and 25%, respectively. Our results are similar to those reported in studies following alloSCT for standard-risk hematologic malignacies.5,14,15,27-32 Graft failure rates were comparable in both groups and were similar to those reported for patients undergoing HLA-matched transplantation.33 None of the patients included in this study had advanced disease, which might explain why disease status at transplantation did not significantly influence relapse or EFS rates. As expected, acute GVHD turned out to be the most significant factor adversely influencing OS and TRM.34 However, in our analysis, donor type, adjusted for other prognostic factors, was not found to be significantly associated with grades II to IV acute GVHD. This suggests that use of a 10/10 molecularly HLA-matched graft led to a risk of acute GVHD comparable with that of sibling transplant. However, the limited number of such patients included here does not enable confirmation of this statement. Indeed, as shown in Figure 1 and Table 3, a 15% difference in the incidence of grades II to IV acute GVHD rate persisted despite molecular HLA matching. Whether extending molecular matching to DPB1 (so called 12/12) would further decrease the risk of acute GVHD is currently unknown, but seems to be associated with an increased risk of relapse in recipients of T-cell–depleted unrelated transplantation.35 Factors associated with grades II to IV acute GVHD include diagnosis of CML, which may be due in part to more advanced disease in those patients, since an advanced stage has been linked to increased risk of acute GVHD.15 Unexpectedly, acute GVHD was associated with recipient CMV-negative serology. While recipient CMV-positive serology is known to be associated with worse OS,6,36,37 we do not have an explanation for the association between acute GVHD and recipient CMV-negative serology finding. Of note, OS was not influenced by donor origin. Although a prospective assessment of chronic GVHD (cGVHD) was not planned in the study design, we have retrospectively investigated this parameter in order to assess its probable impact on patients' outcome. Therefore, of the 201 assessable patients who survived more than 100 days after transplantation, 51 of 157 patients from the sibling group and 15 of 44 patients from the unrelated group had developed cGVHD. As for acute GVHD, occurrence of cGVHD was considered as a time-dependent factor and estimated using the Kaplan-Meier method.25 There was no significant difference between the two groups regarding the incidence of cGVHD. Patients receiving transplantations from an unrelated donor more often developed extensive cGVHD than did those patients receiving transplantations from a sibling donor (11 of 44 v 17 of 157, respectively; P = .025). However, there was no negative impact of extensive grades on TRM. Given that the occurrence of cGVHD was observed within the first year after transplantation (median, 176 days post-transplantation;interquartile range, 121 to 247 days), and taking into consideration the median follow-up of this study (34.6 months), a significant negative impact of cGVHD on patients' outcome would have been detected. Nevertheless, the small number of patients who developed extensive cGVHD does not allow any firm conclusions. Despite the prospective nature of this study, the younger ages observed in the unrelated-group patients and the lower proportion of patients with AL in first CR highlight the fact that physicians continue to be wary of alloCST from unrelated donors, even in a molecularly HLA-matched setting (10/10). Given the estimates found in this study for the effect of donor type, the number of case subjects needed to obtain a significant effect has been computed at 10,312 for overall survival; 5,425 for TRM; 6,648 for EFS; and 2,210 for relapse. Therefore, we suggest that if there were an effect of donor type on alloSCT outcome, it would have no effect on OS, TRM, or EFS. For patients with standard-risk malignancy undergoing alloSCT with CY and TBI as conditioning treatment, unmodified marrow as a source of graft, and Cs-A plus short-course MTX as GVHD prophylaxis, no significant difference was observed between the sibling group and the unrelated group in terms of patient outcome. However, no conclusions can be drawn with certainty concerning patients with more advanced disease, those who received a peripheral blood graft, or those with a nonmyeloablative conditioning regimen. Further studies are warranted in order to evaluate the impact of donor type in these settings. In conclusion, this study strongly suggests that 10/10 HLA-matched unrelated donor transplantation provides a chance of cure similar to that of HLA-matched sibling alloSCT.
The authors indicated no potential conflicts of interest.
published online ahead of print at www.jco.org on November 20, 2006. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
II GVHD. Event-free survival rates were lower for patients with recipient CMV-positive serology. Acute grades II to IV GVHD rates were higher for patients with chronic myeloid leukemia (CML). No factor was found to influence either relapse or acute grades III to IV GVHD. The effect of donor type was nonsignificant for all criteria. 
2 test. 
