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Transplant Webinar Series: Ep. 6Donor Selection for Haematopoietic Stem Cell Transplantation
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The Role of NGS in the Transplant Setting
Featuring
Dr Sujatha KrishnakumarSirona Genomics, USA
21 June 2018
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Donor Selection for Haematopoietic Stem Cell Transplantation
Dr Deborah Sage
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 TransplantRelated 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
The European Group for Blood and Marrow TransplantationThe European Group for Blood and Marrow TransplantationBaldomero: Transplant ActivitySurvey Dec 2016
HSCT Activity in Europe 1990-2015:Donor origin: 1st HSCT
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
Resolution Definition Example
Low Allele group or first field A*02
High Encode same protein sequence in antigen binding site
A*02:01
Allelic Unique nucleotide sequence for a gene, use of all digits in allele name
A*02:01:01:01
Definition of HLA typing resolution
HLA Typing Resolution
Donor search strategy
Factors Influencing Search Success
Donor factors•Resolution of HLA typing
– Improvements in UK registries– Implementation of NGS by
BBMR (NHSBT)
•CMV / ABO date
•Ethnicity
•Availability
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
HLA type patient
HLA type relatives
Suitable related donor ?
Proceed to transplant
preliminary BMDW search
Contact registry -start search
Select potential donors
HLA matched?
Proceed to transplant
Select further donors
or
select mismatched donors
yes
no
Verification type
yes
no
Donor Search Strategy
HLA type patient
HLA type relatives
Suitable related donor ?
Proceed to transplant
preliminary BMDW search
Contact registry -start search
Select potential donors
HLA matched?
Proceed to transplant
Select further donors
or
select mismatched donors
yes
no
Confirmatory type
yes
no
Donor Search Strategy
Unrelated Donor Registries
78 participating registriesBMDW Activity Report 2016
30 million HLA typed donors; 94% HLA-A, B, DR typesBMDW Activity Report 2016
54 participating cord blood banks / registriesBMDW Activity Report 2016
Over 700 thousand cord blood units typedBMDW Activity Report 2016
Search and Match Service BMDW/WMDA
Search and Match Service BMDW/WMDA
Differences in allele and haplotype frequencies in different populations
Population Group FrequencyHLA-B*46:01 allele frequencyAfro-Caribbean 5 in 10,000Caucasoid 4 in 10,000Asian 567 in 10,000Haplotype frequencyA*01:01 – B*08:01 – DRB1*03:01 1 in 15 Caucasoid; 1 in 75 Afro-
CaribbeanA*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
0%
10%
20%
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Mat
ch li
kelih
ood
Race or ethnic group of searching patient for hematopoietic cell transplantation
8/8 HLA match ≥7/8 HLA match
Likelihood of finding matched unrelated adult donorRange 66-97%: Available suitable match, by race/ethnic group, Be The Match Registry®
Gragert L, et al. N Engl J Med. 2014; 371(4): 339-348.
Likelihood of finding unrelated donor or cord bloodRange 91-99%: patients ≥20 years, when searching adult donor, then cord blood
Gragert L, et al. N Engl J Med. 2014; 371(4): 339-348.New England Journal of Medicine © 2014
0%
10%
20%
30%
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50%
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90%
100%
Mat
ch li
kelih
ood
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
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– www.allelefrequencies.net
• 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
8003 transplants• Malignant disease• Myeloablative conditioning• BM (44%) / PBSC• Confirmed results of Lee et
al. 2007
HLA mismatching associated with increased risk of:• aGvHD• cGvHD• TRM• Overall mortality
No association with overall mortality• Allele or Antigen mm• Locus (HLA-A,-B,-C,-DRB1)
Overall survivalearly stage disease
HLA Matching (8/8) Results in Better Overall survival
Pidala et al. Blood 2014; 124: 2596-2606Lee et al. Blood 2007; 110: 4576-4583
CIBMTR Study
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. 2010
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
*09:01*10:01*17:01
Group 2 Intermediate
Immunogenicity
*03:01*14:01*45:01
Group 3Low Immunogenicity
*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
Three group TCE model algorithm Patient
1/1 1/2 1/3 2/2 2/3 3/3
Donor 1/1
Permissive
Non‐permissive (HvG) 1/2
1/3
2/2
Non‐permissive (GvH)
Permissive
2/3
3/3 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
Group 1 High Immunogenicity
*09:01*10:01*17:01
Group 2 Intermediate Immunogenicity
*03:01*14:01*45:01
Group 3Low Immunogenicity
*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
Fleischhauer et al. 2012
• 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.
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
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– 3x107 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
Eurocord Recommendations
Eurocord Recommendations
Haploidentical donors
Trends in haploidentical HCT in Europe between 1990–2015.
Catherine J Lee et al. Haematologica 2017;102:1810-1822
©2017 by Ferrata Storti Foundation
EBMT data shows increase of 250% since 2010
Commonly used platforms used in haploidentical-related transplantation.
Catherine J Lee et al. Haematologica 2017;102:1810-1822
©2017 by Ferrata Storti Foundation
(A) University of Perugia: myeloablative conditioning and T cell-depletion with “megadose” CD34+ cell allografts
(B) Johns Hopkins: non-myeloablative conditioning with high-dose, post-transplantation cyclophosphamide.
(C) Peking University: myeloablative conditioning and in vivo T cell modulation (GIAC protocol).
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
Haploidentical transplant outcome
Reference Tx. Disease Outcome HLA Id sib
10/10 MUD
Haplo
Bashey et al; 2016
475 various 2 yr DFS 56% 50% 54%
Raiola et al; 2014
459 AML 4 yr DFS 32% 36% 43%
Di Stasi et al; 2014
227 AML/MDS 3 yr PFS 36% 27% 36%
Haploidentical transplants now have similar graft outcome as HLA identical and matched unrelated donor transplants
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;102:1810-1822
©2017 by Ferrata Storti Foundation
HLA antibody testing
HLA Antibody Testing
• Should be undertaken at start of search process if unlikely to find a fully matched donor
• Aid selection of antigen mismatched donors 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
HLA type patient
HLA type relatives
Suitable related donor ?
Proceed to transplant
preliminary BMDW search
Contact registry -start search
Select potential donors
HLA matched?
Proceed to transplant
Select further donors
or
select mismatched donors
yes
no
Verification type
yes
no
Donor Search Strategy
Searching for a Matched Unrelated Donor
• Initially can search via BMDW website Search & Match service– Gives info on numbers of donors 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 donors select donor
based on– CMV status (CMV match)– Age (younger donor associated with improved survival)– Gender (male donor)– Blood group
• If no matched donors, 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
HLA type patient
HLA type relatives
Suitable related donor ?
Proceed to transplant
preliminary BMDW search
Contact registry -start search
Select potential donors
HLA matched?
Proceed to transplant
Select further donors
or
select mismatched donors
yes
no
Verification type
yes
no
Donor Search Strategy
HLA type & antibody screen patient
HLA type relatives
Suitable related haploidentical donor ?
Proceed to transplant
preliminary BMDW search
Contact registry -start search
Select potential donors
HLA Compatible?
HLA antibody test
Proceed to transplant
Select further donors
or
select mismatched or alternative cord blood donors
yes
no
Verification type
yes
no
Donor Search Strategy
Options for:• Haploidentical • Mismatched unrelated• Cord blood• HLA antibody testing to aid
selection of compatible donor
Our local experience of unrelated donor selection
0
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200
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350
2012 2013 2014 2015 2016
CT requested CT tested Patients
Verification Typing Samples Tested
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 donors
1523 24
3427
22
21 16
2123
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Year
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Increase use of UK donor from 40% to a peak of 62% in 2015
Final donor used for transplant
UK Germany USA Others123 66 19 18
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UK Germany USA Other
20122013201420152016
2012 2013 2014 2015 2016HLA 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
HLA and CMV matching; blood group compatibility
0102030405060708090
100
10/10 match 9/10 match CMV match ABO compatible
2012
2013
2014
2015
2016
71% transplant undertaken with 10/10 matched donors and 91% transplants were CMV matched.
Time taken to identify final donor
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36
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60
84 7 7 4
31
13 14 14 14
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2012 2013 2014 2015 2016
Year
Day
s
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)
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
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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:
https://www.surveymonkey.co.uk/r/ImmucorTransplantEp6
• Registration deadline is 15 June 2018• Certificates will be sent via email only to those who
have registered by 29 June 2018
All Content © 2015 Immucor, Inc.
Future Webinars
Link to register: https://immucor.webinato.com/register
The Role of NGS in the Transplant Setting
Featuring
Dr Sujatha KrishnakumarSirona Genomics, USA
21 June 2018
All Content © 2015 Immucor, Inc.