Transplant Webinar Series: Ep. 6 Donor Selection for ... › en-us › Educational Program Handouts... · Donor Selection for Haematopoietic Stem Cell Transplantation. ... Source

Transplant Webinar Series: Ep. 6Donor Selection for Haematopoietic Stem Cell Transplantation

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


Handouts

http://www.immucor.com/en-us/Pages/Educational-Program-Handouts.aspx


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


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


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

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?


Select further donors

or

select mismatched donors

yes

no

Verification type

yes

no

Donor Search Strategy

HLA type patient

HLA type relatives






HLA matched?



or


yes

no

Confirmatory type

yes

no


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%

30%

40%

50%

60%

70%

80%

90%

100%

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%

40%

50%

60%

70%

80%

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.



(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.



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






HLA matched?



or


yes

no

Verification type

yes

no


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






HLA matched?



or


yes

no

Verification type

yes

no


HLA type & antibody screen patient

HLA type relatives

Suitable related haploidentical donor ?





HLA Compatible?

HLA antibody test



or

select mismatched or alternative cord blood donors

yes

no

Verification type

yes

no


Options for:• Haploidentical • Mismatched unrelated• Cord blood• HLA antibody testing to aid

selection of compatible donor

Our local experience of unrelated donor selection

0

50

100

150

200

250

300

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

0

10

20

30

40

50

60

2012 2013 2014 2015 2016

Year

Tran

spla

nts

Int

UK

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

0

5

10

15

20

25

30

35

40

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

86

36

4550

60

84 7 7 4

31

13 14 14 14

0

10

20

30

40

50

60

70

80

90

100

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


Questions?



We like you!

Like us on social media!


Questions?



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


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


Documents

Transplant Webinar Series: Ep. 6 Donor Selection for ... › en-us › Educational Program Handouts... · Donor Selection for Haematopoietic Stem Cell Transplantation. ... Source