21/05/2018. Continuing Education. Presentation Recording. learn.immucor.com

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1 Transplant Webinar Series: Ep. 6 Donor Selection for Haematopoietic Stem Cell Transplantation Future Webinars The Role of NGS in the Transplant Setting Featuring Dr Sujatha Krishnakumar Sirona Genomics, USA 21 June 2018 Link to register: Handouts Program-Handouts.aspx 1

2 Continuing Education ABHI, ASCLS/P.A.C.E., Florida and California Credits 1.0 Contact Hour or 0.15 continuing education credits (CECs) awarded Each attendee must register to receive CE credits at: Registration deadline is 15 June 2018 Certificates will be sent via only to those who have registered by 29 June 2018 Presentation Recording Session will be recorded and posted to Immucor s LEARN site. Access information will be sent to each registrant when the recording becomes available CE credits will be issued to anyone who listens to the recording within one year of the original presentation date (today). To access Learn go to: learn.immucor.com learn.immucor.com 2

3 Questions? You are all muted Q&A following session - Type in questions Course content is for information and illustration purposes only. Immucor makes no representation or warranties about the accuracy or reliability of the information presented and this information is not to be used for clinical or maintenance evaluations. The opinions contained in this presentation are those of the presenter and do not necessarily reflect those of Immucor. Donor Selection for Haematopoietic Stem Cell Transplantation Dr Deborah Sage 3

4 Introduction HLA genes remain the most important barrier to allogeneic haematopoietic stem cell transplantation (HSCT). Allorecognition of HLA alleles by T lymphocytes can lead to a high risk of acute Graft versus Host Disease (agvhd). For this reason a HLA genotypically identical sibling donor is the gold standard as a source of stem cells in HSCT. Only ~30% patients will have such a donor and therefore an alternative source of stem cells must be sought. Source of Donor for Transplant Related donor HLA matched Related donor HLA mismatched Related donor HLA Haploidentical donor Unrelated donor HLA Matched (10/10 or 12/12) HLA Matched Cord blood donation HLA Mismatched unrelated donor HLA Mismatched cord blood donation HSCT Activity in Europe : Donor origin: 1 st HSCT Baldomero: Transplant Activity Survey Dec 2016 The European Group for Blood and Marrow Transplantation 4

5 Patient factors influencing the donor search Clinical Diagnosis and the urgency to transplant Ethnic background HLA type Haplotype frequency Allele frequency Linkage (B-C; DRB1-DQB1) CMV status HLA antibody status ABO compatibility HLA Typing Performed by molecular typing technologies Should comply with European Federation for Immunogenetics (EFI) Standards Intermediate Resolution Typing PCR-SSO e.g. luminex based High Resolution typing Sequence based Typing Sanger sequencing Next generation sequencing Definition of HLA typing resolution Resolution Definition Example Low Allele group or first field A*02 High Allelic Encode same protein sequence in antigen binding site Unique nucleotide sequence for a gene, use of all digits in allele name A*02:01 A*02:01:01:01 5

6 HLA Typing Resolution Donor search strategy Factors Influencing Search Success Patient Factors Ethnicity HLA allele frequency HLA haplotype frequency HLA Linkage (B-C; DRB1- DQB1) CMV match ABO compatibility Sensitization status HLA, HPA, red cell antibodies Donor factors Resolution of HLA typing Improvements in UK registries Implementation of NGS by BBMR (NHSBT) CMV / ABO date Ethnicity Availability 6

7 Donor Search Strategy HLA type patient HLA type relatives Suitable related donor? no preliminary BMDW search Contact registry - start search yes Proceed to transplant Select potential Verification type HLA matched? no Select further or select mismatched yes Proceed to transplant Donor Search Strategy HLA type patient HLA type relatives Suitable related donor? no preliminary BMDW search Contact registry - start search yes Proceed to transplant Select potential Confirmatory type HLA matched? no Select further or select mismatched yes Proceed to transplant Unrelated Donor Registries 7

8 78 participating registries BMDW Activity Report million HLA typed ; 94% HLA-A, B, DR types BMDW Activity Report participating cord blood banks / registries BMDW Activity Report

9 Over 700 thousand cord blood units typed BMDW Activity Report 2016 Search and Match Service BMDW/WMDA Search and Match Service BMDW/WMDA 9

10 Differences in allele and haplotype frequencies in different populations Population Group Frequency HLA-B*46:01 allele frequency Afro-Caribbean 5 in 10,000 Caucasoid 4 in 10,000 Asian 567 in 10,000 Haplotype frequency A*01:01 B*08:01 DRB1*03:01 1 in 15 Caucasoid; 1 in 75 Afro- Caribbean A*30:01 B*42:01 DRB1*03:02 1 in 48 Afro-Caribbean; 0 in Caucasoid Hurley et al, Biology of Blood and Marrow Transplantation, 2006, NMDP data Likelihood of finding matched unrelated adult donor Range 66-97%: Available suitable match, by race/ethnic group, Be The Match Registry 100% 90% 80% Match likelihood 70% 60% 50% 40% 30% 20% 10% 0% Race or ethnic group of searching patient for hematopoietic cell transplantation 8/8 HLA match 7/8 HLA match Gragert L, et al. N Engl J Med. 2014; 371(4): Likelihood of finding unrelated donor or cord blood Range 91-99%: patients 20 years, when searching adult donor, then cord blood 100% 90% 80% Match likelihood 70% 60% 50% 40% 30% 20% 10% 0% Race or ethnic group of searching patient for hematopoietic cell transplantation 8/8 HLA adult donor 7/8 HLA adult donor 6/6 HLA cord blood 5/6 HLA cord blood 4/6 HLA cord blood Gragert L, et al. N Engl J Med. 2014; 371(4): New England Journal of Medicine

11 Using Bioinformatics to Aid the Chance of finding a donor NMDP Be the Match Haplogic algorithm BMDW (WMDA) Search and Match service Allows the opportunity to find a donor as quickly as possible by providing: probability matching for each donor/cord powered by OptiMatch; and additional information on each donor and cord blood unit (if provided by the listing organisation). Allele and haplotype frequencies Target different registries based on patient and donor ethnic background Target specific mm based on knowledge of HLA linkage disequilibrium (e.g. rare B-C association) Selecting a Mismatched / Alternative donor Antigen and Allele level mismatches A*01:01, A*02:01, B*07:02, B*08:01 patient A*01:01, A*02:06, B*07:02, B*08:01 donor 1 A*01:01, A*03:01, B*07:02, B*08:01 donor 2 Data indicates allele or antigen mismatches have similar influence on transplant outcome 11

12 HLA Matching (8/8) Results in Better Overall survival CIBMTR Study Overall survival early stage disease 8003 transplants Malignant disease Myeloablative conditioning BM (44%) / PBSC Confirmed results of Lee et al HLA mismatching associated with increased risk of: agvhd cgvhd TRM Overall mortality Pidala et al. Blood 2014; 124: Lee et al. Blood 2007; 110: No association with overall mortality Allele or Antigen mm Locus (HLA-A,-B,-C,-DRB1) Role of HLA-DP in transplantation HLA-DPB1 matched pairs have better rates of cgvhd HLA-DPB1 matched pairs have worse rates of relapse No overall effect on survival Shaw et al HLA-DPB1 T cell epitope (TCE) model 2004 Fleischhauer group Isolated two cell clones from a patient that received a HLA-DPB1 mismatched transplant Recipient = HLA-DPB1*02:01/*04:02 vs. donor = HLA-DPB1*02:01/*09:01 Two different cell clones showed differential reactivity against different groups of HLA-DPB1 alleles. Alleles in group 1 and 2 share a TCE that has a different conformation in group 2. HLA-DPB1 alleles separated according to immunogenicity. Group 1 High Immunogenicity Group 2 Intermediate Immunogenicity Group 3 Low Immunogenicity *09:01 *10:01 *17:01 *03:01 *14:01 *45:01 *01:01 *02:01 *02:02 *04:01 *04:02 *05:01 *06:01 *11:01 *13:01 *15:01 *16:01 *19:01 *20:01 *23:01 *46:01 12

13 Three group TCE model algorithm Group 1 High Immunogenicity Group 2 Intermediate Immunogenicity Group 3 Low Immunogenicity *09:01 *10:01 *17:01 *03:01 *14:01 *45:01 *01:01 *02:01 *02:02 *04:01 *04:02 *05:01 *06:01 *11:01 *13:01 *15:01 *16:01 *19:01 *20:01 *23:01 *46:01 Patient 1/1 1/2 1/3 2/2 2/3 3/3 Donor 1/1 1/2 1/3 2/2 Permissive Non permissive (HvG) Permissive 2/3 3/3 Non permissive (GvH) Permissive Donor and recipient share group 1 allele = permissive Donor and recipient share group 2 allele = permissive Donor and recipient do not share group 1 or 2 allele = non-permissive 8539 transplants Non-permissive HLA-DPB1 mismatches have poorer survival, non-relapse mortality and incidence of GvHD Permissive HLA-DPB1 mismatches had similar survival and non-relapse mortality outcomes to HLA- DPB1 matches Use of permissive mismatching as a targeted strategy for better donor selection. Fleischhauer et al HLA-DPB1 matching strategy Effect on incidence of agvhd and disease relapse Reduced incidence disease relapse (ALL, AML, CML) due to GvL effect May not always be considered in matching strategy Permissive vs non-permissive mismatches Patients with an increased risk of relapse may consider HLA-DPB1 mismatching to induce GvL 13

14 Cord Blood as a source of stem cells Cord Blood as a Source of Donor Stem Cells HLA matching based on a minimum of 4/6 matching for HLA-A, -B & -DRB1 Recommended HLA-A, B, C & DRB1 at high resolution Total nucleated cell count and CD34 dose important selection criteria 3x10 7 TNC/kg TNC dose may also be related to HLA matching Double cord unit transplants If individual units do not give sufficient TNC dose HLA antibodies in mismatched cords Avoid donor specific antibodies Viability, FACT accredited Cord blood unit selection Advisory Panel 14

15 Eurocord Recommendations Eurocord Recommendations Haploidentical 15

16 Trends in haploidentical HCT in Europe between EBMT data shows increase of 250% since 2010 Catherine J Lee et al. Haematologica 2017;102: by Ferrata Storti Foundation Commonly used platforms used in haploidentical-related transplantation. (A) University of Perugia: myeloablative conditioning and T celldepletion with megadose CD34+ cell allografts (B) Johns Hopkins: non-myeloablative conditioning with high-dose, posttransplantation cyclophosphamide. (C) Peking University: myeloablative conditioning and in vivo T cell modulation (GIAC protocol). Catherine J Lee et al. Haematologica 2017;102: by Ferrata Storti Foundation Haploidentical Transplants Differing protocols used Original protocols harnessed NK cell reactivity to induced GvL effect Reconstituted NK cells educated by KIR ligands of donor (i.e. HLA-C group 1 / group 2) If donor HLA type contains HLA-C ligand group not expressed by recipient, KIR ligand is missing and NK cell is not inhibited Alloreactivity (GvL) Protocols now used based on Strategy to modulate T cell alloreactivity post transplant Reduce agvhd e.g. High dose cyclophosphamide administered on d+3 & +4 16

17 Haploidentical transplant outcome Haploidentical transplants now have similar graft outcome as HLA identical and matched unrelated donor transplants Reference Tx. Disease Outcome HLA Id sib 10/10 MUD Haplo Bashey et al; 2016 Raiola et al; 2014 Di Stasi et al; various 2 yr DFS 56% 50% 54% 459 AML 4 yr DFS 32% 36% 43% 227 AML/MDS 3 yr PFS 36% 27% 36% Recommended donor choice algorithm for adults with intermediate or high-risk AML with an indication for allogeneic HCT. Catherine J Lee et al. Haematologica 2017;102: by Ferrata Storti Foundation HLA antibody testing 17

18 HLA Antibody Testing Should be undertaken at start of search process if unlikely to find a fully matched donor Aid selection of antigen mismatched to ensure HLA compatible donor MM unrelated donor Haploidentical donor Cord blood unit If patient receiving blood products important to monitor HLA antibody status At least one month prior to transplant The Donor Search Process Donor Search Strategy HLA type patient HLA type relatives Suitable related donor? no preliminary BMDW search Contact registry - start search yes Proceed to transplant Select potential Verification type HLA matched? no Select further or select mismatched yes Proceed to transplant 18

19 Searching for a Matched Unrelated Donor Initially can search via BMDW website Search & Match service Gives info on numbers of available worldwide Request formal searches via the Anthony Nolan BBMR Welsh BMDR ANT Full international search Donor Selection If choice of A,B,C,DR, DQ identical select donor based on CMV status (CMV match) Age (younger donor associated with improved survival) Gender (male donor) Blood group If no matched, option to accept mismatches or continue to search HLA mismatch selection following hierarchy: HLA-DQB1>HLA-A>HLA-B or HLA-C> HLA-DRB1 HLA antibody status Verification Typing Obtain donor peripheral blood sample Registry HLA type often at low/medium resolution initially Confirm registry type CMV and ABO test HLA type HLA-A, B, Cw, DRB1 and DQB1 at high resolution May wish to look at HLA-DPB1 typing 19

20 Donor Search Strategy HLA type patient HLA type relatives Suitable related donor? no preliminary BMDW search Contact registry - start search yes Proceed to transplant Select potential Verification type HLA matched? no Select further or select mismatched yes Proceed to transplant Donor Search Strategy Suitable related haploidentical donor? yes Proceed to transplant HLA type & antibody screen patient no Options for: Haploidentical Mismatched unrelated Cord blood HLA antibody testing to aid selection of compatible donor HLA type relatives preliminary BMDW search Contact registry - start search Select potential Verification type HLA Compatible? HLA antibody test yes Proceed to transplant no Select further or select mismatched or alternative cord blood Our local experience of unrelated donor selection 20

21 Verification Typing Samples Tested CT requested CT tested Patients Reduction in VT samples tested per patient (4.2 to 3.4). Also see ~33% attrition rate Source of Final donor used UK and International 60 Transplants Year Int UK Increase use of UK donor from 40% to a peak of 62% in 2015 Final donor used for transplant UK Germany USA Other UK Germany USA Others

22 HLA and CMV matching; blood group compatibility HLA 10/10 match 24 (65%) 35 (80%) 28 (70%) 37 (66%) 36 (72%) HLA 9/10 match 13 (35%) 9 (20%) 11 (28%) 18 (32%) 13 (26%) CMV matched 31 (84%) 40 (91%) 37 (93%) 51 (93%) 46 (92%) ABO match /compatible 35 (95%) 35 (96%) 33 (83%) 49 (89%) 46 (92%) HLA and CMV matching; blood group compatibility /10 match 9/10 match CMV match ABO compatible % transplant undertaken with 10/10 matched and 91% transplants were CMV matched. Time taken to identify final donor 100 Days Year In 2012 the median time taken to identify the final donor for transplant was 31 days. This improved to 14 days across the audit period. (time between request and receipt of CT sample from donor selected for transplant) 22

23 Summary Summary - 1 HLA system highly polymorphic Matching for HLA has a profound effect on allograft outcome agvhd, cgvhd, TRM, relapse, rejection, overall mortality Many factors affect success search for stem cell donor Patient disease status / timing of transplant Related / unrelated HLA type / haplotype frequency CMV and ABO compatibility HLA antibodies Summary - 2 Recent data suggests strategy for selection alternative donor Adult mismatched Haploidentical Cord blood (single / double) Avoid HLA mismatches the patient may have HLA antibodies directed against 23

24 Questions? You are all muted Q&A following session - Type in questions We like you! Like us on social media! Questions? You are all muted Q&A following session - Type in questions 24

25 Continuing Education ABHI, ASCLS/P.A.C.E., Florida and California Credits 1.0 Contact Hour or 0.15 continuing education credits (CECs) awarded Each attendee must register to receive CE credits at: Registration deadline is 15 June 2018 Certificates will be sent via only to those who have registered by 29 June 2018 Future Webinars The Role of NGS in the Transplant Setting Featuring Dr Sujatha Krishnakumar Sirona Genomics, USA 21 June 2018 Link to register: Thank you! 25