Deutscher Konsensus 2013 zur immungenetischen Spenderauswahl für die allogene Stammzelltransplantation

Zusammenfassung

Der vorliegende 4. deutsche Konsensus zur immungenetischen Spenderauswahl für die allogene Stammzelltransplantation wurde von der Deutschen Gesellschaft für Immungenetik (DGI) und der Deutschen Arbeitsgemeinschaft für Knochenmark- und Blutstammzelltransplantation (DAG-KBT) gemeinsam erarbeitet und verabschiedet. Er stellt den gemeinsamen Nenner von mehr als 60 Transplantationseinheiten und fast 20 immungenetischen Sucheinheiten dar, die mehr als 3000 deutsche Patienten jährlich betreuen. Während der 1. Konsensus im Jahre 1996 den Anfang der Ablösung von zellulären und serologischen Methoden der HLA-Testung durch molekulargenetische Verfahren darstellte, wird nun die hochaufgelöste Bestimmung der Antigenbindungsstelle der HLA-Moleküle der 5 wichtigsten Genorte als Standard definiert. Das vorliegende Dokument behandelt die Suche nach verwandten und nicht-verwandten Spendern und alle infrage kommenden Stammzellquellen. Bei Sachverhalten, für die eine eindeutig wissenschaftliche Evidenz vorliegt, gibt dieser Konsensus eine klare Richtschnur vor, während es sonst, soweit möglich, die Handlungsoptionen beschreibt.

Abstract

This paper presents the fourth German consensus on the selection of donors for an allogeneic hematopoietic stem cell transplantation (HSCT) as agreed by the German Society for Immunogenetics (DGI) and the German Working Party for Bone Marrow and Blood StemCell Transplantation (DAG-KBT). It represents the common denominator of over 60 transplant teams and almost 20 immunogenetic search units taking care of over 3000 patients per year in Germany. While the first consensus marked the beginning of the transition from cellular and serological to DNA based methods, this consensus defines high resolution matching for the antigen recognition site of the five most relevant HLA loci as the “gold standard”. The document addresses the search for related and unrelated donors as well as the various sources of stem cells, depicts a clear guideline where evidence is mature and discusses options in areas of ongoing research.

Schlüsselwörter

HLA - Spendersuche - Spenderauswahl - Stammzelltransplantation - Knochenmarktransplantation

Key words

HLA - donor search - donor selection - stem cell transplantation - bone marrow transplantation

• Literatur

• 1 Ottinger HD, Albert E, Arnold R et al. German consensus on immunogenetic donor search for transplantation of allogeneic bone marrow and peripheral blood stem cells. Bone Marrow Transpl 1997; 20: 101-105
• 2 Ottinger HD, Müller CR, Goldmann SF et al. Second German Consensus on immunogenetic donor search for allotransplantation of hematopoietic stem cells. Ann Hematol 2001; 80: 706-714
• 3 Ottinger HD, Müller CR, Riebschläger S et al. Dritter Deutscher Konsensus zur immungenetischen Spenderauswahl für die allogene Stammzelltransplantation. Im Internet: http://www.immungenetik.de/data/Konsensus_Version_AugustFinal_2005.pdf Stand: 30.09.2014
• 4 Spellman SR, Eapen M, Logan BR et al. A perspective on the selection of unrelated donors and cord blood units for transplantation. Blood 2012; 120: 259-265
• 5 European Federation for Immunogenetics (EFI). EFI Standards for Histocompatibility & Immunogenetics Testing Version 5.7. Im Internet: http://www.efiweb.eu/fileadmin/user_upload/members/pdf/2012-08-07_Standards_version_5.7.pdf Stand: 30.09.2014
• 6 Zentrales Knochenmarkspender-Register für die Bundesrepublik Deutschland gemeinnützige GmbH. Deutsche Standards für die nicht verwandte Blutstammzellspende. Version 8. Im Internet: http://www.zkrd.de/de/_pdf/ZKRD-Standards-V8_deutsch.pdf Stand: 30.09.2014
• 7 Marsh SGE, Albert ED, Bodmer WF et al. Nomenclature for factors of the HLA system, 2010. Tissue Antigens 2010; 75: 291-455
• 8 The European Bioinformatics Institute, Part of the European Molecular Biology Laboratory (EMBL-EBI). HLA Nomenclature. Im Internet: http://www.ebi.ac.uk/ipd/imgt/hla/nomenclature/index.html Stand: 30.09.2014
• 9 The European Bioinformatics Institute, Part of the European Molecular Biology Laboratory (EMBL-EBI). Ambiguous Allele Combinations. Im Internet: http://www.ebi.ac.uk/ipd/imgt/hla/ambig.html Stand: 30.09.2014
• 10 Bochtler W, Maiers M, Oudshoorn M et al. World Marrow Donor Association guidelines for use of HLA nomenclature and its validation in the data exchange among hematopoietic stem cell donor registries and cord blood banks. Bone Marrow Transplant 2007; 39: 737-741
• 11 Nuñes E, Heslop H, Fernandez-Viña M et al. Definitions of histocompatibility typing terms. Blood 2011; 118: e180-e183
• 12 Elsner HA, Blasczyk R. Immunogenetics of HLA null alleles: implications for blood stem cell transplantation. Tissue Antigens 2004; 64: 687-695
• 13 Oudshoorn M, Horn PA, Tilanus M et al. Typing of potential and selected donors for transplant: methodology and resolution. Tissue Antigens 2007; 69: 10-12
• 14 National Marrow Donor Program (NMDP). NMDP Policy for Confirmatory Typing Requirements. Effective May 1, 2009. Im Internet: https://bioinformatics.bethematchclinical.org/WorkArea/DownloadAsset.aspx?id=6634 Stand: 30.09.2014
• 15 DGHO Deutsche Gesellschaft für Hämatologie und Onkologie e. V. et al. Kodierleitfaden Hämatologie, Onkologie und Stammzelltransplantation Version 2011. Im Internet: http://www.dgho.de/informationen/dokumente-der-arbeitskreise/arbeitskreis-drg-dokumentation-kodierung/Kodierleitfaden%25202011.pdf Stand: 30.09.2014
• 16 Ottinger HD, Ferencik S, Beelen DW et al. Hematopoietic stem cell transplantation: contrasting the outcome of transplantations from HLA-identical siblings, partially HLA-mismatched related donors, and HLA-matched unrelated donors. Blood 2003; 102: 1131-1137
• 17 Ottinger HD, Beelen DW, Massenkeil G et al. Allotransplantation of haematopoietic stem cells for early stage leukaemia in patients aged 40 years or more: overall survival improves significantly if a younger unrelated donor is preferred over an older sibling donor. Bone Marrow Transpl 2005; 35 (Suppl. 02) S86 O406
• 18 Ottinger HD, Rebmann V, Pfeiffer KA et al. Positive serum cross-match as predictor for graft-failure in HLA mismatched allogeneic blood stem cell transplantations. Transplantation 2002; 73: 1280-1285
• 19 Holdsworth R, Hurley CK, Marsh SG et al. The HLA dictionary 2008: a summary of HLA-A, -B, -C, -DRB1/3/4/5, and -DQB1 alleles and their association with serologically defined HLA-A, -B, -C, -DR, and -DQ antigens. Tissue Antigens 2009; 73: 95-170
• 20 Middleton D. The Allele Frequency Net Database. Im Internet: http://www.allelefrequencies.net Stand: 30.09.2014
• 21 Bochtler W, Beth M, Eberhard HP et al. OptiMatch® – a universally configurable HLA matching framework. Tissue Antigens 2008; 71: 321
• 22 Petersdorf EW, Hansen JA, Martin PJ et al. Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation. N Engl J Med 2001; 345: 1794-1800
• 23 Petersdorf EW, Anasetti C, Martin PJ et al. Limits of HLA mismatching in unrelated HSCT. Blood 2004; 104: 2976-2980
• 24 Ottinger HD, Ferencik S, Beelen DW et al. Impact of high resolution HLA-A,B,C donor-recipient matching on outcome of unrelated hematopoietic stem cell transplantation. Transplantation 2004; 78: 1077-1080
• 25 Tiercy JM, Passweg J, van Biezen A et al. Isolated HLA-C mismatches in unrelated donor transplantation for CML. Bone Marrow Transpl 2004; 34: 249-255
• 26 Kröger N, Zabelina T, Binder T et al. HLA-mismatched unrelated donors as an alternative graft source for allogeneic stem cell transplantation after antithymocyte globulin-containing conditioning regimen. Biol Blood Marrow Transplant 2009; 15: 454-462
• 27 Fürst D, Müller C, Vucinic V et al. High-resolution HLA matching in hematopoietic stem cell transplantation: a retrospective collaborative analysis. Blood 2013; 112: 3220-3229
• 28 Flomenberg N, Baxter-Lowe LA, Confer D et al. Impact of HLA class I and class II high resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplant outcome. Blood 2004; 104: 1923-1930
• 29 Lee SJ, Klein J, Haagenson M et al. High resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 2007; 110: 4576-4583
• 30 Woolfrey A, Klein JP, Haagenson M et al. HLA-C antigen mismatch is associated with worse outcome in unrelated donor peripheral blood stem cell transplantation. Biol Blood Marrow Transplant 2011; 17: 885-892
• 31 Fleischhauer K, Shaw BE, Gooley T et al. Effect of T-cell epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study. Lancet Oncol 2012; 13: 366-374
• 32 Shaw BE, Gooley TA, Malkki M et al. The importance of HLA-DPB1 in unrelated donor hematopoietic cell transplantation. Blood 2007; 110: 4560-4566
• 33 Zino E, Frumento G, Marktel S et al. A T-cell epitope encoded by a subset of HLA-DPB1 alleles determines nonpermissive mismatches for hematologic stem cell transplantation. Blood 2004; 103: 1417-1424
• 34 Fernandez-Viña M, Klein J, Haagenson M et al. The clinical significance of matching for alleles at the low expression HLA loci DP, DQ and DRB3/4/5 in unrelated hematopoietic stem cell transplantation. ASH Annual Meeting 2008; Abstract 561.
• 35 Zwaan FE, Hermans J, Gratwohl A. EBMT Leukaemia Party (EBMT-LWP). The influence of donor-recipient sex mismatching on the outcome of allogeneic BMT in leukemia. Bone Marrow Transplant 1989; 4 (Suppl. 02) S8 (abstract)
• 36 Gratwohl A, Hermans J, Goldman JM et al. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Lancet 1998; 352: 1087-1092
• 37 Spierings E, Vermeulen CJ, Vogt MH et al. Identification of HLA class II-restricted H-Y-specific T-helper epitope evoking CD4+ T-helper cells in H-Y-mismatched transplantation. Lancet 2003; 362: 610-615
• 38 Gratwohl A. Major questions after “minor” answers. Blood 2004; 103: 8-9
• 39 Kollman C, Howe CWS, Anasetti C et al. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: The effect of donor age. Blood 2001; 98: 2043-2051
• 40 Finke J, Schmoor C, Bethge WA et al. ATG-Fresenius Trial Group. Prognostic factors affecting outcome after allogeneic transplantation for hematological malignancies from unrelated donors: results from a randomized trial. Biol Blood Marrow Transplant 2012; 18: 1716-1726
• 41 Ljungman P, Brand R, Einsele H et al. Donor CMV serological status and outcome of CMV seropositive recipients after unrelated donor stem cell transplantation; an EBMT megafile analysis. Blood 2003; 102: 4255-4260
• 42 Boeckh M, Nichols WG. The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy. Blood 2004; 103: 2003-2008
• 43 Davies SM, Ruggieri L, DeFor T et al. Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants. Blood 2002; 100: 3825-3827
• 44 Giebel S, Locatelli F, Lamparelli T et al. Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors. Blood 2003; 102: 814-819
• 45 Cook MA, Milligan DW, Fegan CD et al. The impact of donor KIR and patient HLA-C genotypes on outcome following HLA-identical sibling hematopoietic stem cell transplantation for myeloid leukaemia. Blood 2004; 103: 1521-1526
• 46 Bornhäuser M, Schwerdtfeger R, Martin H et al. Role of KIR ligand incompatibility in hematopoietic stem cell transplantation using unrelated donors. Blood 2004; 103: 2860-2861
• 47 Beelen DW, Ottinger HD, Ferencik S et al. Genotypic inhibitory killer immunoglobulin-like receptor ligand incompatibility enhances the long-term antileukemic effect of unmodified allogeneic hematopoietic stem cell transplantation in patients with myeloid leukemias. Blood 2004; 105: 2594-2600
• 48 Witt CS. The influence of NK alloreactivity on matched unrelated donor and HLA identical sibling haematopoietic stem cell transplantation. Curr Opin Immunol 2009; 21: 531-537
• 49 Cooley S, Weisdorf DJ, Guethlein LA et al. Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood 2010; 116: 2411-2419
• 50 Heinemann FM, Ferencik S, Ottinger HD et al. Impact of disparity of minor histocompatibility antigens HA-1, CD 31, and CD49B in hematopoietic stem cell transplantation of patients with chronic myeloid leukemia with siblings and unrelated donors. Transplantation 2004; 77: 1103-1106
• 51 Eapen M, Klein JP, Sanz GF et al. Effect of donor-recipient HLA matching at HLA A, B, C, and DRB1 on outcomes after umbilical-cord blood transplantation for leukaemia and myelodysplastic syndrome: a retrospective analysis. Lancet Oncol 2011; 13: 1214-1221
• 52 Rocha V, Spellman S, Zhang MJ et al. Eurocord-European Blood and Marrow Transplant Group and the Center for International Blood and Marrow Transplant Research. Effect of HLA-matching recipients to donor non-inherited maternal antigens on outcomes after mismatched umbilical cord blood transplantation for hematologic malignancy. Biol Blood Marrow Transplant 2012; 18: 1890-1896
• 53 van Rood JJ, Stevens CE, Smits J et al. Re-exposure of cord blood to non-inherited maternal HLA antigens improves transplant outcome in hematological malignancies. Proc Natl Acad Sci U S A 2009; 106: 19952-19957