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Unrelated donor (URD) hematopoietic cell transplantation (HCT) can eradicate chronic myelogenous leukemia (CML). It has been postulated that greater donor:recipient-histoincompatibility can augment the graft vs. leukemia (GvL) effect. We previously reported similar, but not equivalent outcomes of URD vs. sibling donor HCT for CML using an older, less precise classification of HLA-matching.
Our recently refined HLA-matching classification, suitable for interpretation when complete allele-level typing is unavailable was used to reanalyze outcomes of previous HCT for CML.
We observed that new matching criteria identifies substantially more frequent mismatch than older, less precise “6 of 6 antigen” matched URD-HCT. Only 37% of those previously called “HLA-matched” were HLA-well-matched in new classification and 44% were partially-matched. The refined matching classification confirmed that partially matched or mismatched URD:recipient pairs have significantly greater risks of graft failure compared to either sibling or well-matched URD-HCT. Acute and chronic GVHD are significantly more frequent with all levels of recategorized URD HLA-matching. Importantly, survival and leukemia-free survival remain significantly worse following URD-HCT at any matching level. No augmented GvL effect accompanied URD HLA-mismatch. Compared to sibling donor transplants, we observed marginally increased, but not significantly different risks of relapse in either well-matched, partially-matched or mismatched URD-HCT.
These data confirm the utility of our revised HLA-matching schema as applicable for analysis of retrospective data sets when fully informative, allele level-typing is unavailable. In this analysis, greater histoincompatibility can augment GVHD but does not improve protection against relapse thus the best donor is still the most closely matched.
Allogeneic hematopoietic cell transplantation (HCT) can eradicate leukemia both by pretransplant conditioning and by a potent graft vs. leukemia (GvL) effect. It has been postulated that greater histoincompatibility between unrelated donors and their recipients may be associated with augmented GvL and hence lower risks of relapse. We previously reported similar, but not equivalent outcomes of 2,464 unrelated donor (URD) HCT compared to 450 sibling donor allotransplants for treatment of chronic myelogenous leukemia (CML) . We noted that HCT using an URD led to 7-10% poorer five year survival and slightly higher rates of graft-versus-host disease (GVHD) and transplant related mortality (TRM), but no greater protection against relapse. In that analysis , HLA-matching used an outdated definition; intermediate resolution matching at HLA-A and B (Class I) and allele level matching at HLA-DRB1 (Class II). While refined HLA-typing techniques have confirmed that allele typing at HLA-A, B, C, and DRB1 may all contribute to better posttransplant outcomes [2-4], it remains uncertain whether HLA mismatch between unrelated donors and their recipients can lead to better protection against relapse.
Data from the Center for International Blood and Marrow Transplant Research (CIBMTR) recently reported allele level typing of 3514 HLA-identical sibling compared to 1052 HLA-matched and partially-matched URD HCT recipients, all with chronic phase CML . Allele level mismatching at 4 HLA-loci (HLA-A, B, C and DR, but not DQ) identified greater risks of GVHD, TRM and overall mortality, but no greater protection against relapse accompanied even a single allele mismatch between donor and recipient.
In the observational databases at the National Marrow Donor Program (NMDP) and CIBMTR donors and recipient, matching is often incomplete and frequently is missing HLA-C typing data and class I allele-level typing. We recently described an HLA classification scheme able to categorize the quality of donor:recipient HLA-matching based upon the number of loci examined and the resolution of typing at each locus . We identified three levels of donor:recipient matching: well-matched with no defined mismatches and no untested HLA locus; partially-matched with only one untested or mismatched locus; and mismatched with two or more known or mismatched or untested HLA-loci. This new HLA matching schema allowed prediction of outcome even if donor:recipient pairs were incompletely typed; not at all for pertinent HLA-A, B, C, DR loci .
To assess the impact of mismatch on outcome and importantly on its association with any augmented Graft-versus Leukemia (GvL) effect, we reanalyzed our prior sibling and unrelated donor cohort  according to this HLA-new matching scheme . We now report our outcomes to contrast with recently published, complete allele level HLA-typing in a different validation cohort .
All patients had CML and received an allogeneic HCT from URD (n=2464) between 1988-1999. Data was reported to the NMDP using prospectively-designed data capture methods, auditing, centralized compilation and data error correction . Data from sibling donors (n=450) at 34 participating centers (1991-1999) used the same data capture methods. Adjusted probabilities of overall survival and leukemia-free survival were estimated by Cox’s proportional hazards regression model . Multivariate models were built using a stepwise forward selection technique, using a P-value of .05 or less as the criterion for inclusion in the final model. Transplant center was included as a fixed effect in the regression model.
The study population has been described previously . Most sibling donor (63%) and URD recipients (59%) were male; their median age was 39 and 36, respectively. Most recipients were in first chronic phase (sibling 82%; URD 67%) and were a median of 7 and 17 months from diagnosis; 86 and 83% had pre-HCT performance scores 90-100. Myeloablative pre-transplant conditioning included total body irradiation along with cyclophosphamide in 2340 cases (287 sibling and 2053 URD HCT). Others received chemotherapy-only conditioning (without radiation), most often busulfan + cyclophosphamide. As shown in Table 1, 450 HLA-genotypically identical sibling donors were contrasted with 2,464 URD HCT originally categorized as HLA- matched (reflecting “6 antigen matching” meaning; intermediate resolution matching at HLA-A and B and allele matching at DRB1) or HLA-partially matched ; only 805 (32.8%) were included in the allele-level matching GvL report . These URD are all now recategorized into well-matched, partially-matched, and mismatched. As indicated (Table 1), 667 of the 1,797 (37%) originally considered HLA-matched were HLA well-matched in the new classification scheme. However, of the pairs originally called matched, 783 (44%) are now classified as partially matched and 347 (19%) as mismatched. Of the prior 667 mismatched URD:recipient pairs, only 14 (2%) are now classified as well-matched, 109 (16%) as partially-matched, and 544 (82%) as mismatched.
The refined matching classification modified the conclusions of our prior report. In the original analysis, graft failure was significantly more frequent following both matched and partially matched URD transplants compared to HLA-identical sibling HCT (Table 2). After reclassification only partially-matched or mismatched URD:recipient pairs have significantly greater risks of graft failure. Acute GVHD Grade II-IV, originally reported as significantly more frequent in both matched and partially-matched URD HCT remain significantly more frequent in all 3 URD groups. Chronic GVHD, remains significantly more frequent in all 3 groups and the hazard ratios are close to those originally reported. Importantly, survival and disease-free survival remain significantly worse in URD transplants at any matching level using either the older, imprecise or the newer, more refined HLA classification.
We originally reported that hematologic relapse was unaffected by the histoincompatibility between donor and recipient. We could not detect more GvL associated with decreasing HLA-compatibility, despite more frequent acute and chronic GVHD. In the present analysis, compared to matched sibling donor HCT, we observe marginally increased, but not significantly different risks of leukemia relapse between the HLA-matching cohorts. In the multivariate analysis, not surprisingly, advanced phase disease, older recipient age, and transplants from male donors are associated with more frequent relapse (not shown).
These findings confirm the clinical utility of the revised HLA classification scheme even when incomplete or only intermediate resolution HLA-typing is available. These findings identify substantial mis-classification in the less precise and outdated “6 of 6 matched” terminology and confirms the validity of this revised HLA classification in predicting graft failure, GVHD, survival, disease-free survival, and leukemia relapse. Using this schema, we observe findings similar to those reported using fully informative allele level typing: even modest HLA allele-level differences adversely impact survival. While we emphasize that complete allele level typing at HLA-A, B, C, and DR is most useful for URD selection prior to HCT, retrospective analyses can rely on this refined HLA classification scheme to predict outcome and assess the clinical importance of histoincompatibility, even if complete HLA-typing is unavailable. We also note that despite hopes or assertions to the contrary, incomplete HLA matching does not augment GvL, at least for patients with CML. We can speculate about differences that we might find if we analyzed HCT using reduced intensity conditioning, or only imatinib resistant patients or even whether the immunosuppression required to control mismatch-associated GVHD may limit the impact of the observed GvL. However, available data suggest that even in an era when HCT is reserved for patients failing tyrosine kinase inhibitor therapy , the best donor is still the most closely HLA matched in order to provide limited peri-transplant morbidity and potent GvL.
Support The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from AABB; Aetna; American Society for Blood and Marrow Transplantation; Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Association of Medical Microbiology and Infectious Disease Canada; Astellas Pharma US, Inc.; Baxter International, Inc.; Bayer HealthCare Pharmaceuticals; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Canadian Blood and Marrow Transplant Group; Celgene Corporation; CellGenix, GmbH; Centers for Disease Control and Prevention; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Cubist Pharmaceuticals; Cylex Inc.; CytoTherm; DOR BioPharma, Inc.; Dynal Biotech, an Invitrogen Company; Enzon Pharmaceuticals, Inc.; European Group for Blood and Marrow Transplantation; Gambro BCT, Inc.; Gamida Cell, Ltd.; Genzyme Corporation; Histogenetics, Inc.; HKS Medical Information Systems; Hospira, Inc.; Infectious Diseases Society of America; Kiadis Pharma; Kirin Brewery Co., Ltd.; Merck & Company; The Medical College of Wisconsin; MGI Pharma, Inc.; Michigan Community Blood Centers; Millennium Pharmaceuticals, Inc.; Miller Pharmacal Group; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Nature Publishing Group; New York Blood Center; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics, Inc.; Otsuka Pharmaceutical Development & Commercialization, Inc.; Pall Life Sciences; PDL BioPharma, Inc; Pfizer Inc; Pharmion Corporation; Saladax Biomedical, Inc.; Schering Plough Corporation; Society for Healthcare Epidemiology of America; StemCyte, Inc.; StemSoft Software, Inc.; Sysmex; Teva Pharmaceutical Industries; The Marrow Foundation; THERAKOS, Inc.; Vidacare Corporation; Vion Pharmaceuticals, Inc.; ViraCor Laboratories; ViroPharma, Inc.; and Wellpoint, Inc. 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. This project has also been supported by funding from the National Marrow Donor Program and the Department of the Navy, Office of Naval Research Grant #N00014-05-1-0859 to the NMDP. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the Office of Naval Research or the National Marrow Donor Program.
For the Chronic Leukemia Working Committee of the CIBMTR
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