Bone Marrow Transplantation (2009) 44, 571–577 & 2009 Macmillan Publishers Limited All rights reserved 0268-3369/09 $32.00 www.nature.com/bmt ORIGINAL ARTICLE HLA matching affects clinical outcome of adult patients undergoing haematopoietic SCT from unrelated donors: a study from the Gruppo Italiano Trapianto di Midollo Osseo and Italian Bone Marrow Donor Registry R Crocchiolo1,5, F Ciceri1, K Fleischhauer2, R Oneto3, B Bruno3, S Pollichieni4, N Sacchi4, MP Sormani5, R Fanin6, G Bandini7, F Bonifazi7, A Bosi8, A Rambaldi9, PE Alessandrino10, M Falda11 and A Bacigalupo3 1Department of Oncology, Hematology and Bone Marrow Transplantation Unit, S Raffaele Scientific Institute, Milano, Italy; 2Immunogenetics Laboratory, S Raffaele Scientific Institute, Milano, Italy; 3Department of Hemato-Oncology, Division of Hematology, Ospedale San Martino, Genova, Italy; 4Italian Bone Marrow Donor Registry, Ospedale Galliera, Genova, Italy; 5Biostatistics Unit, Department of Health Sciences (DISSAL), University of Genova, Genova, Italy; 6Division of Hematology and Bone Marrow Transplantation, University of Udine, Udine, Italy; 7Institute of Hematology and Clinical Oncology ‘LA Seragnoli’, Bologna, Italy; 8Department of Hematology, University of Florence, Florence, Italy; 9Department of Oncology and Hematology, Division of Hematology, Ospedali Riuniti, Bergamo, Italy; 10Division of Hematology, University of Pavia, Pavia, Italy and 11Division of Hematology, Ospedale San Giovanni Battista, Torino, Italy The importance of HLA donor–recipient matching in Keywords: haematopoietic SCT; haematological malig- unrelated haematopoietic SCT (HSCT) is the subject of nancy; unrelated donor; HLA matching. debate. In this retrospective study, we analyzed 805 adult patients from the Italian Registry receiving HSCT for a haematological malignancy from January 1999 to June 2006 and correlated the degree of HLA matching with Introduction transplant outcome. All patient–donor pairs had high- resolution typing at HLA-A, -B, -C, -DRB1 and -DQB1. Haematopoietic SCT (HSCT) represents a curative option There was a significantly higher risk of overall mortality, for many haematological malignancies.1 A HLA-identical non-relapse mortality, graft failure and acute GVHD sibling is considered the best HSC donor; however, the (aGVHD) for patients receiving HSCT from an unrelated search for an unrelated donor is currently performed when donor with one or more low- or high-resolution mismatch/ a patient lacks such an HLA-matched sibling. Searching es (Mm/s). When only a single HLA Mm is present (9/10 algorithms aim at finding the optimal match between the matched pairs), mortality risk is higher than among 10/10 patient and the potential donor.2 As the ‘10/10 matched’ matched pairs in patients transplanted with acute (that is, high-resolution identity at loci HLA-A, -B, -C, leukaemia in the first CR (‘early’ patients) but not in -DRB1 and -DQB1) donor is not always available, some the other patients (advanced patients): HR ¼ 1.69, 95% extent of HLA mismatch (Mm) can be accepted; however, CI ¼ 0.94–3.02, P ¼ 0.08; HR ¼ 1.03, 95% CI ¼ 0.80– there is still some controversy about the precise impact of 1.32, P ¼ 0.82, for early and advanced patients, respec- HLA mismatching on HSCT outcomes, because published tively. These results confirm that the advantage of a 10/10 reports indicate discordant results about the relative match has a greater effect in early patients, thus importance of loci involved.3–14 A recent study by Lee suggesting that a 9/10 matched donor can be chosen in et al.3 indicated that both class I and class II Mms affect patients with advanced disease lacking a rapidly available survival, suggesting that each HLA Mm is associated with 10/10 matched one. an additional unadjusted survival impairment of 9–10%. Bone Marrow Transplantation (2009) 44, 571–577; The same study did not find a significant role played by doi:10.1038/bmt.2009.67; published online 13 April 2009 HLA-DP or -DQ on survival. Other analyses reported a higher risk of graft failure correlated with class I Mms and a superior rate of mortality in the presence of two or more Mms (regardless of loci involved), whereas one Mm did not Correspondence: Dr R Crocchiolo, Hematology and Bone Marrow confer survival impairment.5,14 Single Mms at HLA-B or -C Transplantation Unit, San Raffaele Scientific Institute, Via Olgettina, 60, seem to be better tolerated than those at HLA-A or -DRB1 Milan 20132, Italy. 3 E-mail: [email protected] in American patients, whereas in Japanese patients the Received 21 January 2009; revised 20 February 2009; accepted 21 presence of HLA-A and -B Mm significantly reduced February 2009; published online 13 April 2009 survival and Mm at HLA-C or -DRB1/DQB1 did not.12 Donor–patient HLA matching and outcome of UD HSCT R Crocchiolo et al 572 The relative importance of antigenic (detected by serological Table 1 Patients’ and donors’ characteristics or low-resolution typing) or allelic (high resolution) Mms Characteristics N % Median has also been studied, and the results are controversial (range) because the studies report both an equivalent3,11 and a different7 effect on outcome. Finally, a recent analysis Number of transplants 805 100 provided by Kawase et al.4 identified 16 significant high- Median patients’age at HSCT 41 (18–65) Patients’ gender: (M/F) 452/353 56/44 risk HLA Mm combinations for severe acute GVHD Disease: (aGVHD), whereas the selection of a cross-reactive group- ALL 154 19 compatible donor does not seem to improve transplant AML 234 29 outcome.9 MDS 70 8 secAL 24 39 This study was designed to assess the role of patient– MPS other than CML 22 3 donor HLA matching on the outcomes of unrelated HSCTs MM 63 8 performed for haematological malignancies in 805 adult NHL 76 9 patients in Italy. HL 52 6 CLL 14 2 CML 96 13 Disease status at HSCT: Patients and methods CML-CP1 40 5 Early 157 20 Patients and treatments Advanced 608 75 A total of 805 patients aged 18 years or more who received HSCTs from unrelated donors in Italy from 1 January 1999 ATG as GVHD prophylaxis: Yes 549 68 to 30 June 2006 were included in the analysis (Table 1). No 216 27 Eligible diagnoses were ALL, AML, CML, myelodysplastic NK 40 5 syndrome, myeloproliferative syndromes other than CML, secondary acute leukaemia, multiple myeloma, Hodgkin’s HSCT conditioning: RIC 230 28 lymphoma, non-Hodgkin’s lymphoma and CLL. Informed MAC 538 67 consent was obtained from each transplantation centre. NK 37 5 All clinical data were obtained from the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) registry, and all Source of stem cells: patient–donor typing results were collected from the Italian BM 455 57 15 PBSC 348 43 Bone Marrow Donor Registry (IBMDR). According to NK 2 0 disease status at HSCT, patients were categorized into three groups: CML in first chronic phase (‘CML-CP1’), acute Total body irradiation: leukaemia in first complete remission (‘early’) and all other Yes 457 57 No 336 42 diseases (‘advanced’). HSCT conditioning regimens were NK 12 1 both myeloablative and reduced intensity, according to local or cooperative protocols. Induction therapy and HSCT Patients’ CMV status: indication was decided by treating physicians in each centre, Positive 501 62 according to the risk/benefit profile based on the most Negative 112 14 NK 192 24 updated knowledge at the time of therapy. Information on in vivo T-cell depletion was collected; aGVHD prophylaxis was Median donors’ age 35 (19–61) mostly performed with CYA and MTX. Donors’ gender: (M/F) 561/244 69/31 Donors’ CMV status: Positive 386 48 HLA typing and HSCT Negative 411 51 All Mms were classified according to the loci involved and NK 8 1 according to whether they were detected at low- or high- Abbreviations: BM ¼ bone marrow; HL ¼ Hodgkin’s lymphoma; resolution level. MAC ¼ myeloablative conditioning; MDS ¼ myelodysplastic syndrome; Originally, only low-resolution typing of loci A, B and MM ¼ multiple myeloma; MPS ¼ myeloproliferative syndrome; NK ¼ not high-resolution at locus DRB1 were used to screen known; NHL ¼ non-Hodgkin’s lymphoma; RIC ¼ reduced-intensity con- potential donors, and the matching at these three loci was ditioning; secAL ¼ secondary acute leukaemia; PBSC ¼ peripheral blood 16 stem cells. the minimum requested for performing HSCT; in the Characteristics of patients, donors and HSCT are here shown. absence of such a ‘6/6 matched’ donor, some exceptions were allowed; therefore, transplants using a ‘5/6 matched’ donor were performed. Clinical end point definitions As the degree of typing was heterogeneous among Overall survival (OS), non-relapse mortality, aGVHD and patient–donor pairs, this analysis includes only 10/10 engraftment were defined according to European Group high-resolution typed pairs, to exclude any confoun- for Blood and Marrow Transplantation (EBMT) criteria;17 ding effect eventually played by the match at loci not relapse-related death is defined as death because of relapse fully typed. after HSCT, irrespective of further treatment performed for Bone Marrow Transplantation Donor–patient HLA matching and outcome of UD HSCT R Crocchiolo et al 573 relapse. All outcomes were evaluated from the day of stem Results cell infusion. Grading of aGVHD was performed according to current criteria.18 Patient–donor pairs A total of 805 pairs typed at high resolution for HLA-A, -B, -C, DRB1 and -DQB1 were included in the analysis. Statistical analysis Overall, three quarters of patients (611 out of 805, 75%) Continuous variables were expressed as median (range), received HSCT for an advanced-stage haematological whereas categorical ones were expressed as proportions and malignancy; of these, 205 were lymphoid malignancies percentages. Probabilities of OS were calculated using the other than ALL: 76 non-Hodgkin’s lymphoma, 63 multiple Kaplan–Meier estimator19 and survival curves were com- myeloma, 52 Hodgkin’s lymphoma and 14 CLL.