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Stephen R. Spellman - One of the best experts on this subject based on the ideXlab platform.
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Allele-level HLA Matching for umbilical cord blood transplantation for non-malignant diseases in children: a retrospective analysis
The Lancet Haematology, 2017Co-Authors: Mary Eapen, Stephen R. Spellman, Tao Wang, Paul Veys, Jaap Jan Boelens, Andrew St. Martin, Carmem Sales Bonfim, Colleen Brady, Andrew J. Cant, Jean Hugues DalleAbstract:Summary Background The standard for selecting unrelated umbilical cord blood units for transplantation for non-malignant diseases relies on antigen-level (lower resolution) HLA typing for HLA-A and HLA-B, and allele-level for HLA-DRB1. We aimed to study the effects of allele-level Matching at a higher resolution—HLA-A, HLA-B, HLA-C, and HLA-DRB1, which is the standard used for adult unrelated volunteer donor transplantation for non-malignant diseases—for umbilical cord blood transplantation. Methods We retrospectively studied 1199 paediatric donor-recipient pairs with allele-level HLA Matching who received a single unit umbilical cord blood transplantation for non-malignant diseases reported to the Center for International Blood and Marrow Transplant Research or Eurocord and European Group for Blood and Marrow Transplant. Transplantations occurred between Jan 1, 2000, and Dec 31, 2012. The primary outcome was overall survival. The effect of HLA Matching on survival was studied using a Cox regression model. Findings Compared with HLA-matched transplantations, mortality was higher with transplantations mismatched at two (hazard ratio [HR] 1·55, 95% CI 1·08–2·21, p=0·018), three (2·04, 1·44–2·89, p=0·0001), and four or more alleles (3·15, 2·16–4·58, p 7 cells per kg compared with 21 × 10 7 cells per kg or less (HR 1·47, 1·11–1·95, p=0·0076), and transplantations done in 2000–05 compared with those done in 2006–12 (HR 1·64, 1·31–2·04, p Interpretation These data support a change from current practice in that selection of unrelated umbilical cord blood units for transplantation for non-malignant diseases should consider allele-level HLA Matching at HLA-A, HLA-B, HLA-C, and HLA-DRB1. Funding National Cancer Institute; National Heart, Lung, and Blood Institute; National Institute for Allergy and Infectious Diseases; US Department of Health and Human Services—Health Resources and Services Administration; and US Department of Navy.
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evaluation of HLA Matching in unrelated hematopoietic stem cell transplantation for nonmalignant disorders
Blood, 2012Co-Authors: John T Horan, Stephen R. Spellman, Michael Haagenson, Mary Eapen, Tao Wang, Jason Dehn, Haydar Frangoul, Vikas Gupta, Gregory A Hale, C K HurleyAbstract:The importance of human leukocyte antigen (HLA) Matching in unrelated donor transplantation for nonmalignant diseases (NMD) has yet to be defined. We analyzed data from 663 unrelated marrow and peripheral blood stem cell transplants performed from 1995 to 2007 for treatment of NMD. Transplantation from a donor mismatched at the HLA-A, -B, -C, or -DRB1, but not -DQB1 or -DPB1, loci was associated with higher mortality in multivariate analyses (P = .002). The hazard ratio for mortality for single (7/8) and double mismatched (6/8) transplants was 1.29 (0.97-1.72; P = .079) and 1.82 (1.30-2.55; P = .0004), respectively, compared with 8/8 matched transplants. HLA mismatches were not associated with acute or chronic GVHD, but were strongly associated with graft failure. After adjustment for other factors, the odds ratio for graft failure for 7/8 and 6/8 (allele and/or antigen) matched pairs compared with 8/8 matched transplants was 2.81 (1.74-4.54; P < .0001) and 2.22 (1.26-3.97; P = .006), respectively. Patients with NMD should receive transplants from allele matched (8/8) donors if possible. Unlike the case with malignancies, HLA misMatching in NMD is associated with graft failure rather than GVHD.
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Sibling versus Unrelated Donor Allogeneic Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia: Refined HLA Matching Reveals More Graft-versus-Host Disease but not Less Relapse
Biology of Blood and Marrow Transplantation, 2009Co-Authors: Daniel J. Weisdorf, Stephen R. Spellman, Michael Haagenson, Stephanie J. Lee, Gene Nelson, Joseph H. Antin, Brian J. Bolwell, Jean Yves Cahn, Francisco Cervantes, Edward A. CopelanAbstract: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-versus-leukemia (GVL) effect. We previously reported similar, but not equivalent, outcomes of URD versus sibling donor HCT for CML using an older, less precise classification of HLA Matching. Here, we used our recently refined HLA-Matching classification, which is suitable for interpretation when complete allele-level typing is unavailable, to reanalyze outcomes of previous HCT for CML. We found that using our new Matching criteria identifies substantially more frequent misMatching than older, less precise "6 of 6 antigen-matched" URD-HCT. Under the new criteria, only 37% of those previously deemed "HLA- matched" were HLA well matched, and 44% were partially matched. Using our refined Matching criteria confirms the greater risk of graft failure in partially matched or mismatched URD-recipient pairs compared with either sibling or well-matched URD-recipient pairs. Acute and chronic graft-versus-host disease (aGVHD, cGVHD) are significantly more frequent with all levels of recategorized URD HLA Matching. Importantly, overall survival (OS) and leukemia-free survival (LFS) remain significantly worse after URD-HCT at any Matching level. No augmented GVL effect accompanied URD HLA mismatch. Compared with sibling donor transplants, we observed only marginally increased (not statistically significant) risks of relapse in well-matched, partially matched, and mismatched URD-HCT. These data confirm the applicability of revised HLA-Matching scheme in analyzing 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 remains the most closely matched donor.
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Classification of HLA-Matching for Retrospective Analysis of Unrelated Donor Transplantation: Revised Definitions To Predict Survival.
Blood, 2007Co-Authors: Daniel J. Weisdorf, Stephen R. Spellman, John P. Klein, Michael Haagenson, Mary M. Horowitz, Stephanie J. Lee, Claudio Anasetti, Michelle Setterholm, Rebecca J. Drexler, Martin MaiersAbstract:Unrelated donor (URD) hematopoietic cell transplantation (HCT) is best performed using a donor who is allele-matched with the recipient at HLA-A,B,C and DR. Earlier reports analyzing outcomes of HCT have been limited by incomplete or lower resolution typing at some HLA loci. Excluding these incompletely typed pairs from studies decreases the power of analyses because of smaller sample size. If adjustment for known and unknown HLA-Matching status could be accomplished, these patients could be retained in most analyses where HLA-Matching is not the primary research focus. To understand the impact of incompletely characterized major histocompatibility antigens on the success of HCT, we analyzed 15,867 URD HCT using multivariable regression modeling adjusting for HLA and non-HLA factors affecting 1 year and 5 year survival. Of 26 independent Matching groups defined by the completeness and resolution of donor:recipient pair Matching we identified 3 distinct groups with significantly different outcomes: well matched, partially matched, and mismatched. Well-matched cases had no identified HLA mismatch and informative, though not necessary high-resolution data at all 4 loci or allele Matching at HLA-A,B & DRB1 (n=7,753, 49% of the study population). Partially matched pairs had a defined, single locus mismatch at any of the 4 loci and/or missing HLA-C data [including 6/6 low/intermediate resolution A,B matched plus DRB1 allele matched] (n=5,396, 34%). Mismatched cases had 2 or more identified allele or antigen mismatches (n=2,692, 17%). Multiple-variable-adjusted one- and five-year survival estimates are shown in the Table. Using these HLA Matching categories, we identified independently significant, 7–8% better 5 year survival using a better matched donor (between these 3 categories) stratified across patient subgroups of recipient age, disease stage, and using either myeloablative or non-ablative conditioning. Notably, the common term “6/6 antigen matched” [6/6 low/intermediate resolution A,B matched plus DRB1 allele matched] had survival outcomes within the partial matched cohort. We suggest that these HLA subgroups should be used in analyses of URD HCT outcomes when complete HLA typing is not available. This improved categorization of HLA Matching status allows adequate adjustment for HLA donor-recipient HLA compatibility in retrospective studies and will help standardize interpretations of prior URD HCT experience.
Michael Haagenson - One of the best experts on this subject based on the ideXlab platform.
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evaluation of HLA Matching in unrelated hematopoietic stem cell transplantation for nonmalignant disorders
Blood, 2012Co-Authors: John T Horan, Stephen R. Spellman, Michael Haagenson, Mary Eapen, Tao Wang, Jason Dehn, Haydar Frangoul, Vikas Gupta, Gregory A Hale, C K HurleyAbstract:The importance of human leukocyte antigen (HLA) Matching in unrelated donor transplantation for nonmalignant diseases (NMD) has yet to be defined. We analyzed data from 663 unrelated marrow and peripheral blood stem cell transplants performed from 1995 to 2007 for treatment of NMD. Transplantation from a donor mismatched at the HLA-A, -B, -C, or -DRB1, but not -DQB1 or -DPB1, loci was associated with higher mortality in multivariate analyses (P = .002). The hazard ratio for mortality for single (7/8) and double mismatched (6/8) transplants was 1.29 (0.97-1.72; P = .079) and 1.82 (1.30-2.55; P = .0004), respectively, compared with 8/8 matched transplants. HLA mismatches were not associated with acute or chronic GVHD, but were strongly associated with graft failure. After adjustment for other factors, the odds ratio for graft failure for 7/8 and 6/8 (allele and/or antigen) matched pairs compared with 8/8 matched transplants was 2.81 (1.74-4.54; P < .0001) and 2.22 (1.26-3.97; P = .006), respectively. Patients with NMD should receive transplants from allele matched (8/8) donors if possible. Unlike the case with malignancies, HLA misMatching in NMD is associated with graft failure rather than GVHD.
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Sibling versus Unrelated Donor Allogeneic Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia: Refined HLA Matching Reveals More Graft-versus-Host Disease but not Less Relapse
Biology of Blood and Marrow Transplantation, 2009Co-Authors: Daniel J. Weisdorf, Stephen R. Spellman, Michael Haagenson, Stephanie J. Lee, Gene Nelson, Joseph H. Antin, Brian J. Bolwell, Jean Yves Cahn, Francisco Cervantes, Edward A. CopelanAbstract: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-versus-leukemia (GVL) effect. We previously reported similar, but not equivalent, outcomes of URD versus sibling donor HCT for CML using an older, less precise classification of HLA Matching. Here, we used our recently refined HLA-Matching classification, which is suitable for interpretation when complete allele-level typing is unavailable, to reanalyze outcomes of previous HCT for CML. We found that using our new Matching criteria identifies substantially more frequent misMatching than older, less precise "6 of 6 antigen-matched" URD-HCT. Under the new criteria, only 37% of those previously deemed "HLA- matched" were HLA well matched, and 44% were partially matched. Using our refined Matching criteria confirms the greater risk of graft failure in partially matched or mismatched URD-recipient pairs compared with either sibling or well-matched URD-recipient pairs. Acute and chronic graft-versus-host disease (aGVHD, cGVHD) are significantly more frequent with all levels of recategorized URD HLA Matching. Importantly, overall survival (OS) and leukemia-free survival (LFS) remain significantly worse after URD-HCT at any Matching level. No augmented GVL effect accompanied URD HLA mismatch. Compared with sibling donor transplants, we observed only marginally increased (not statistically significant) risks of relapse in well-matched, partially matched, and mismatched URD-HCT. These data confirm the applicability of revised HLA-Matching scheme in analyzing 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 remains the most closely matched donor.
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Classification of HLA-Matching for Retrospective Analysis of Unrelated Donor Transplantation: Revised Definitions To Predict Survival.
Blood, 2007Co-Authors: Daniel J. Weisdorf, Stephen R. Spellman, John P. Klein, Michael Haagenson, Mary M. Horowitz, Stephanie J. Lee, Claudio Anasetti, Michelle Setterholm, Rebecca J. Drexler, Martin MaiersAbstract:Unrelated donor (URD) hematopoietic cell transplantation (HCT) is best performed using a donor who is allele-matched with the recipient at HLA-A,B,C and DR. Earlier reports analyzing outcomes of HCT have been limited by incomplete or lower resolution typing at some HLA loci. Excluding these incompletely typed pairs from studies decreases the power of analyses because of smaller sample size. If adjustment for known and unknown HLA-Matching status could be accomplished, these patients could be retained in most analyses where HLA-Matching is not the primary research focus. To understand the impact of incompletely characterized major histocompatibility antigens on the success of HCT, we analyzed 15,867 URD HCT using multivariable regression modeling adjusting for HLA and non-HLA factors affecting 1 year and 5 year survival. Of 26 independent Matching groups defined by the completeness and resolution of donor:recipient pair Matching we identified 3 distinct groups with significantly different outcomes: well matched, partially matched, and mismatched. Well-matched cases had no identified HLA mismatch and informative, though not necessary high-resolution data at all 4 loci or allele Matching at HLA-A,B & DRB1 (n=7,753, 49% of the study population). Partially matched pairs had a defined, single locus mismatch at any of the 4 loci and/or missing HLA-C data [including 6/6 low/intermediate resolution A,B matched plus DRB1 allele matched] (n=5,396, 34%). Mismatched cases had 2 or more identified allele or antigen mismatches (n=2,692, 17%). Multiple-variable-adjusted one- and five-year survival estimates are shown in the Table. Using these HLA Matching categories, we identified independently significant, 7–8% better 5 year survival using a better matched donor (between these 3 categories) stratified across patient subgroups of recipient age, disease stage, and using either myeloablative or non-ablative conditioning. Notably, the common term “6/6 antigen matched” [6/6 low/intermediate resolution A,B matched plus DRB1 allele matched] had survival outcomes within the partial matched cohort. We suggest that these HLA subgroups should be used in analyses of URD HCT outcomes when complete HLA typing is not available. This improved categorization of HLA Matching status allows adequate adjustment for HLA donor-recipient HLA compatibility in retrospective studies and will help standardize interpretations of prior URD HCT experience.
Sergio Giralt - One of the best experts on this subject based on the ideXlab platform.
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Donor–recipient allele-level HLA Matching of unrelated cord blood units reveals high degrees of mismatch and alters graft selection
Bone Marrow Transplantation, 2014Co-Authors: Parastoo B. Dahi, Doris M. Ponce, Sean M. Devlin, Katherine L Evans, Marissa Lubin, Anne Marie Gonzales, Courtney Byam, Melissa Sideroff, Deborah Wells, Sergio GiraltAbstract:Donor–recipient allele-level HLA Matching of unrelated cord blood units reveals high degrees of mismatch and alters graft selection
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donor recipient allele level HLA Matching of unrelated cord blood units reveals high degrees of mismatch and alters graft selection
Bone Marrow Transplantation, 2014Co-Authors: Parastoo B. Dahi, Doris M. Ponce, Sean M. Devlin, Katherine L Evans, Marissa Lubin, Anne Marie Gonzales, Courtney Byam, Melissa Sideroff, Deborah Wells, Sergio GiraltAbstract:Donor–recipient allele-level HLA Matching of unrelated cord blood units reveals high degrees of mismatch and alters graft selection
C K Hurley - One of the best experts on this subject based on the ideXlab platform.
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evaluation of HLA Matching in unrelated hematopoietic stem cell transplantation for nonmalignant disorders
Blood, 2012Co-Authors: John T Horan, Stephen R. Spellman, Michael Haagenson, Mary Eapen, Tao Wang, Jason Dehn, Haydar Frangoul, Vikas Gupta, Gregory A Hale, C K HurleyAbstract:The importance of human leukocyte antigen (HLA) Matching in unrelated donor transplantation for nonmalignant diseases (NMD) has yet to be defined. We analyzed data from 663 unrelated marrow and peripheral blood stem cell transplants performed from 1995 to 2007 for treatment of NMD. Transplantation from a donor mismatched at the HLA-A, -B, -C, or -DRB1, but not -DQB1 or -DPB1, loci was associated with higher mortality in multivariate analyses (P = .002). The hazard ratio for mortality for single (7/8) and double mismatched (6/8) transplants was 1.29 (0.97-1.72; P = .079) and 1.82 (1.30-2.55; P = .0004), respectively, compared with 8/8 matched transplants. HLA mismatches were not associated with acute or chronic GVHD, but were strongly associated with graft failure. After adjustment for other factors, the odds ratio for graft failure for 7/8 and 6/8 (allele and/or antigen) matched pairs compared with 8/8 matched transplants was 2.81 (1.74-4.54; P < .0001) and 2.22 (1.26-3.97; P = .006), respectively. Patients with NMD should receive transplants from allele matched (8/8) donors if possible. Unlike the case with malignancies, HLA misMatching in NMD is associated with graft failure rather than GVHD.
S Kahraman - One of the best experts on this subject based on the ideXlab platform.
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successful haematopoietic stem cell transplantation in 44 children from healthy siblings conceived after preimplantation HLA Matching
Reproductive Biomedicine Online, 2014Co-Authors: S Kahraman, C Beyazyurek, Mehmet Akif Yesilipek, Gulyuz Ozturk, Mehmet Ertem, Sema Anak, Savas Kansoy, Serap Aksoylar, Baris Kuskonmaz, Haldun OnizAbstract:Abstract Haematopoietic stem cell transplantation (HSCT) remains the best therapeutic option for many acquired and inherited paediatric haematological disorders. Unfortunately, the probability of finding an HLA matched donor is limited. An alternative technique is PGD combined with HLA Matching, which offers the possibility of selecting unaffected embryos that are HLA compatible with the sick child, with the aim of possible use of stem cells from the resulting baby in future. Since the first successful report for Fanconi anaemia a decade ago, the therapeutic success of this technique was reported in a few cases and for a limited number of disorders. Here, we report full recovery of 44 sick children who received HSCT from healthy infants conceived after pre-implantation HLA Matching for the following 10 indications; beta-thalassaemia, Wiskott–Aldrich syndrome, Fanconi anaemia, sickle cell anaemia, acute myeloid leukaemia, acute lymphoblastic leukaemia, Glanzmann's thrombasthaenia, Diamond–Blackfan anaemia, X-linked adrenoleukodystrophy and mucopolysaccharidosis type I. No serious complications were observed among recipients and donors. Graft failure occurred in four children with beta-thalassaemia where a second HSCT was planned. Preimplantation HLA Matching is a reliable technique and provides a realistic option for couples seeking treatment for an affected child when no HLA-matched donor is available.
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short tandem repeats haplotyping of the HLA region in preimplantation HLA Matching
European Journal of Human Genetics, 2005Co-Authors: Francesco Fiorentino, A. Biricik, H. Karadayi, S Kahraman, S Sertyel, G Karlikaya, Y Saglam, Daniele Podini, Andrea Nuccitelli, Marina BaldiAbstract:Recently, preimplantation genetic diagnosis (PGD) has been considered for several indications beyond its original purpose, not only to test embryos for genetic disease but also to select embryos for a nondisease trait, such as specific human leukocyte antigen (HLA) genotypes, related to immune compatibility with an existing affected child in need of a haematopoetic stem cell (HSC) transplant. We have optimized an indirect single-cell HLA typing protocol based on a multiplex fluorescent polymerase chain reaction (PCR) of short tandem repeat (STR) markers scattered throughout the HLA complex. The assay was clinically applied in 60 cycles from 45 couples. A conclusive HLA-Matching diagnosis was achieved in 483/530 (91.1%) of the embryos tested. In total, 74 (15.3%) embryos revealed an HLA match with the affected siblings, 55 (11.4%) of which resulted unaffected and 46 (9.5%) have been transferred to the patients. Nine pregnancies were achieved, five healthy HLA-matched children have already been delivered and cord blood HSCs, were transplanted to three affected siblings, resulting in a successful haematopoietic reconstruction.