Impatto clinico nel trapianto allogenico da donatori non familiari dei mismatch al locus HLA-DPB1

Transcription

1 Impatto clinico nel trapianto allogenico da donatori non familiari dei mismatch al locus HLA-DPB1 Gruppo Italiano Trapianto Midollo Osseo Italian Bone Marrow Donor Registry Immunogenetics and HSCT Units International Working Group in HSCT KatharinaFleischhauer Unità Molecolare e Funzionale di Immunogene8ca Is8tuto Scien8fico San Raffaele Milano XII Congresso Nazionale SIES Simposio GITMO O=obre Roma

2 Probability of finding a MUD MUD Activations in 2010 (EBMT) Sucessful (37%) Unsuccessful (63%) 1 2 CMV KIR 40% (16% of all pt; 6743) > one 10/10 or 9/10 matched MUD HLA-DP Sex ABO

3 HLA Class II DP Antigens α-β chain Heterodimers 2 DPA1 and 33 DPB1 alleles in >95% of Caucasians Hollenbach et al., Immunogenetics 2012 DPA1 23 (2) Alleles DPB1 134 (33) Alleles Low Linkage DR-DP: 80% DP mismatched MUD-HSCT Petersdorf et al., B J Hematol DP mismatches elicit T cell alloreactivity in vivo and in vitro Shaw et al., J Exp Med 1980 Gashet et al., BBMT 1998

4 HLA-DPB1 Allele Mismatches in MUD-HSCT Survival HR 1.08; p=0.1 Relapse HR 0.68; p= HLA-DPB1 allele mismatches do not impact Survival after MUD-HSCT However they are important targets of Graft versus Leukemia Shaw et al., Blood 2007

5 HLA-DPB1 Allele Mismatches mediate GvL 10/10 MUD-HSCT for chronic B cell leukemia; Relapse post-hsct DLI Relapse Remission after CD4 + DLI from HLA-DP mismatched MUD-HSCT correlates with DP-specific alloreactive T cells ex-vivo Rutten et al., Leukemia 2008

6 Graft Rejection targeted to HLA-DPB1: TCE Groups HLA-DP4 Acute HSCT Rejection 10/10 MRD HLA-DP9 Permissive DP Mismatch: same TCE Group - 50% Non-Permissive DP Mismatch: different TCE Groups - 30% Fleischhauer et al., 2001 DP Allele Match 20% TCE Group 1+2 T Cell Crossreactivity DPB1* TCE Group Immunogenicity TCE Group 1 09:01, 10:01, 17:01 03:01, 14:01, 45:01 01:01, 02:01, 04:01 + others Zino et al., Blood 2004

7 Alloreactive CD4+ T cell responses to HLA-DP Responder AUTO Stimulator ALLO ,12% ,34% 0.12% 4.33% 10 4 CD CD CD CD137 DPB1* / CD137 DPB1*0901 DPB1 0901/ ,93% ,43% % % CD CD CD CD137 CD137 Non-permissive TCE Group DP mismatches elicit significantly higher alloreactive T cell respones compared to permissive mismatches Sizzano et al., Blood 2010

8 HLA-DPB1 TCE Group Mismatches in MUD-HSCT 496 MUD-HSCT; onco-hematologic; BM; >50% ATG; no DP Allele matches Survival in 10/10 N=201 Survival in 9/10 N=195 Non-Permissive DP Mismatches reduce survival in 10/10 and 9/10 MUD-HSCT Crocchiolo et al., Blood 2009

9 HLA-DPB1 TCE Group Mismatches in MUD-HSCT 8539 MUD-HSCT; oncohematologic; BM; 20% TCD; 20% DP Allele Matched Survival in 10/10 N=5428 Survival in 9/10 N=3111 P=0.002 P=0.06 Non-Permissive DP Mismatches reduce survival in 10/10 and 9/10 MUD-HSCT Similar survival in 9/10 permissive or 10/10 non-permissive! 15th IHWS Fleischhauer et al., Lancet Oncol 2012

10 HLA-DPB1 TCE Group Mismatches and Relapse A: DP Allele Matched; P: Permissive; HvG/GvH: Non-permissive agvhd n.s. 1 ** 1.36 * 1.24 Relapse *** 1 *** *** 0.96 * A P HvG GvH A P HvG GvH Permissive DP mismatches: Bias for GvL over GvHD 15th IHWS Fleischhauer et al., Lancet Oncol 2012

11 HLA-DPB1 TCE Webtool Patient TCE 3/3 Donor 1 TCE 2/3 Non-Permissive HvG Donor 2 TCE 3/3 Permissive

12 HLA-DPB1 TCE Matching Strategy Patient Search MUD No 60% MUD Yes 40% Several 10/10 and 9/10 16 (40)% Only 1 MUD 24 (60)% Ask Upfront for HLA-DP DP Non-Permissive DPB1 Matched DP Permissive 5 (12)% 3 (8)% 8 (20)% 11 (28)%

13 Conclusions HLA-DP mismatches are clinically relevant in unrelated HSCT because they are frequent (80%) they are targets of GvL (reduced relapse risk) they can impair Survival (non-permissive DPB1 TCE Group mismatches) Webtool for non-permissive DPB1 TCE Group mismatches available at can reduce the risk of Mortality for patients with several MUD Prospective Study is needed GITMO-IBMDR?

14 Acknowledgements Elisabetta Zino Roberto Crocchiolo Gruppo Italiano Trapianto Midollo Osseo Italian Bone Marrow Donor Registry Immunogenetics and HSCT Units International Working Group in HSCT Rosi Oneto Alessandro Rambaldi Andrea Bacigalupo Nicoletta Sacchi Federico Sizzano Pietro Crivello Laura Zito Fabio Ciceri Bronwen Shaw Ted Gooley Mari Malkki Effie Petersdorf