Unrelated Donor Search

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Unrelated Donor Search Selection Strategies
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National Marrow Donor Program HLA Matching
Guidelines for Unrelated Marrow Transplants
Biology Blood Marrow Transplantation 9610, 2003

• CK Hurley
• LA Baxter Lowe
• B Logan
• C Karanes

• C Anasetti
• D Weisdorf
• DL Confer
• S Davies

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Goals of Workshop

• How to search for the best unrelated donor
• When to turn to other options
• HLA matching (Weisdorf)
• Search strategies (Hurley)
• Non-HLA donor factors (Davies)
• Mismatched donor (Anasetti)
• Case discussion

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The Role of HLA Matching in Transplant Outcome
Using Unrelated Donors

• Daniel Weisdorf, MD
• University of Minnesota
• National Marrow Donor Program

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HLA Proteins Expressed on Cells
Class I A B C Class
II DR DQ DP Only on some cell types
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Serologic Types (Antigen Names)
B
62
(15)
Protein
(Broad specificity)
Serologic type in order discovered, broad or
split
Not required
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Allele (DNA) Names
0302
A
Gene followed by asterisk
Digits 1-2 Similarity and/or serology Digits
3-4 Order discovered
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(No Transcript)
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Questions

• How many loci should I type?
• How many loci should I match?
• What level of resolution should be used?
• Are some loci more important than others?
• How do I search for the best donor?
• How long should I search?

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The Minimum Acceptable Matchin the NMDP
A
C
B
DR
DQ
DP
6 Antigens (Loci) A, B and DR A and
B Intermediate level DR Allele level At least
5 of 6 antigens must match
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The Minimum Acceptable Matchin the NMDP
C
A
B
DR
DQ
DP
6 Antigens (Loci) A, B and DR A and
B Intermediate level DR Allele level At least
5 of 6 antigens must match
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How do we best use HLA to match unrelated donors
and recipients?
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Which Loci Impact Survival?
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Why are the results different?Because the
studies are different
Patients were predominantly Caucasian
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Impact of Mismatch on Survival
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Allele vs. Antigen Mismatch Survival
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DQ/DP Survival

• DQ/DP Mismatching Is Not a Risk Factor

Flomenberg, 2001
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Overall Survival by Matching Groups

• Matching Group N Survival
• Matched at 8 loci 16/16 108 39 9
• MM at DQ/DP only 683 39 4
• Allele MM at A,B,C or DR 631 29 4
• Serologic MM 452 23 4
• HLA-A, -B, -C, DRB1, DQA1, DQB1, DPA1 and DPB1

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HLA-A, -B -DR Serologically Matched
Pairsnumber of allele mismatches HLA-A, -B,
-C -DR
0 mismatched loci (n 791)
1 mismatched locus (n 394)
2 mismatched loci (n 172)
3 mismatched loci (n 65)
P-value lt 0.0001
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What Does This Mean?

• Mismatching is not contraindication to
  transplant, rather it is a risk factor for
  transplant
• Other risk factors include diagnosis, stage, age,
  CMV status, Transplant Center, donor age, etc.

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How many loci should I type?
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How many loci should I match?
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How do I search for the best donor?

• Strategy
• Search for an allele matched donor at HLA-A, -B,
  -C and DRB1 (8 of 8 allele match)
• Minimize the number of allele-level mismatches
• Try to avoid an antigen-level mismatch
• Implementation
• Ask an HLA expert to review the recipients
  typing results
• The experts opinion will determine whether to
  type a few donors (3-5) or many donors (gt 10)

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What if there is no perfect match?

• Assume that HLA-A, -B, -C and -DRB1 are equally
  important
• Accept one allele mismatch over one antigen
  mismatch
• Minimize the number of allele mismatches

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Matching Likelihood within NMDP Antigen Level
Match
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Length of Search

• Common haplotypes, 46 weeks
• More complex search takes longer
• Robust search strategy critical
• If no donors in 8M pool, unlikely newly
  recruited donors will be a match
• Reduce matching requirements
• Select another therapy (cord blood,
  non-transplant)

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Length of Search Clinical Status

• Clinical status influences search time degree
  mismatch acceptable
• Relatively stable disease 4 mo small clinical
  risk
• Acute leukemia short search
• Life expectancy, quality life with best available
  unrelated donor vs. alternative treatments

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References for Matching

• JMDP
• Morishima et al, Blood 994200, 2002
• Fred Hutchinson CRC
• Petersdorf et al, Blood 923515, 1998
• Petersdorf et al, NEJM 3451794, 2001
• NMDP
• Flomenberg et al, Blood 98813a, 2001

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Search Strategies Finding An HLA-Matched Donor

• Carolyn Katovich Hurley, PhD
• Georgetown University, Washington DC

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Submission of Unrelated Donor Search

• NMDP participating Transplant Center
• Via TRANS Link (immediate) or by fax (next day)
• Referring physician
• Contact NMDP Office of Patient Advocacy at
  888-999-6743 or opatriage_at_nmdp.org
• One-on-one help with submission interpreting
  search report
• Search and help are free until donor samples
  requested for further testing

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Development of Search Strategy Selection of
Potential Donors

• Consult an HLA Expert !
• Local or NMDP HLA expert consultants
• NMDP search strategy workshops at annual council
  meeting spring meeting
• NMDP Search Strategy Manual
• Publications and other reference material

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NMDP Request for Search Consultation

• Form on web site (http//network.nmdp.org)
• Fax to Search Transplant Services department
• Report provided
• Urgent 3 days
• Standard 7 days
• Free
• Medical advice Dr. Karanes at NMDP,
  1-612-617-8354 or 1-800-627-5800

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Potential for Identifying Matched Donor Allele
Haplotype Frequencies

• Ag level haplotypes common in Cau A1,B7,DR2
  (21st), A30,B13,DR7 (13th)predict many potential
  matches
• Most of A,B,DRB1 alleles are commonly seen
  observed with haplotypes
• Associations (C, DQB1) are expected
• Serology typed donors likely correctly assigned

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Potential for Identifying Matched Donor Allele
Haplotype Frequencies

• The Problem A30,B13,DR7
• Haplotype is usually found with A3001, not
  A3002
• Conclude Check HLA typing
• Conclude Difficult to match A locus allele, most
  of potential matches will be mismatched

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Evaluation of Rare Allele

• Check HLA Typing
• Differences between alleles, method of testing
• Where can we find A3002 haplotype?
• A3002 is common in Afa, His, Nam
• Found with B5301 and B2705
• In Cau, found with B1801, DRB10301
• Conclude unlikely to find match in other
  population w/o other mismatches

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Robust Search with Alternate Treatment Strategy

• Patient may be assigned to treatment protocol
  with required match level (e.g., 10/10 allele
  level)
• If challenges in finding a match are anticipated,
  develop robust search strategy
• Be prepared to consider mismatch or move patient
  to another protocol or therapy

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Implications of Initiating Search with Low
Resolution Patient Types

• List of potential matches may be longer, chances
  of selecting mismatch greater
• Assume that many donors will match the patient
• May use the wrong typing strategy for donors,
  wasting time and money
• Conclude Type patients at allele resolution, key
  loci

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The NMDP Search Report
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Donor Summary Counts Report
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Matching Categories for DRB11501 Patient
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Donor Summary Counts Report
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Donor List Report 179 Potential Matches

• Demographics age, gender, weight, ethnicity/race
• Blood group, disease markers including CMV
• Availability temporarily unavailable due to
  pregnancy, etc.

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Number of Potential Donors to Select for Further
HLA Typing

• Select more than one potential donor to
  characterize
• No. depends on HLA types of patient
• 3 - gt 10 donors average is 4.5
• Not HLA matched
• Not allele matched following higher resolution
  testing
• A3002 patient estimate need to type 15-28 Cau
  donors to find 1 allele matched by chance
• Mistyped -- Serology gt DNA
• Unavailable -- Missing, unable or unwilling to
  donate
• 25-50 not available (NMDP)

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HLA Typing Strategy for Potential Donors
(patient allele)

• Conserve resources balanced by urgency of search
• Based on the HLA assignments, select loci
  resolution
• Type consecutively or in parallel
• Use local HLA laboratory or NMDP customized
  typing laboratory
• Type freshly drawn CT or repository samples

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International Searches

• Depends on patients HLA assignments
• Of 5000 unrelated transplants in 2001, 1/3 use
  HSC from donor in another country
• In US, 269 overseas donors for US patients out of
  2,205 transplants in yr
• NMDP will facilitate the international search
• Some registries including BMDW automatically
  searched
• Others at request
• NMDP web site lists registries

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Non-HLA Donor Attributes

• Stella Davies MBBS, Ph.D., MRCP Cincinnati
  Childrens HospitalBMT Program
  DirectorProfessor of Pediatrics

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NMDP Analysis Kollman, et al. Blood, 2001

• 6978 unrelated donor transplants analyzed
• Goal of the study was to investigate donor
  characteristics that might influence outcome of
  unrelated donor BMT

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Results

• Donor age and level of HLA-matching were the only
  donor factors significantly associated with
  overall or disease-free survival.

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The Impact of Donor Age on Outcome of Unrelated
Donor BMT
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Donor Age Impacts Survival After Matched or
Mismatched Unrelated Donor BMT
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Donor Gender Does Not Affect Survival
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Chronic GVHD is More Frequent With Multiparous
Female Donors
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Race / Ethnicity

• For equivalent degrees of match, transplantation
  between individuals of the same race/ethnicity
  does not improve survival.

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Donor CMV Serologic Status Did Not Affect
Survival in CMV Positive or Negative Recipients
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EBMT Analysis Better Survival of CMV Positive
Recipients with CMV Positive Donors (N1108)
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EBMT Analysis

• Improved survival due to reduced TRM
• Effect NOT seen in subset with acute leukemia
• Effect abrogated by T-cell depletion so may be
  due to transfer of donor immunity

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Does KIR Ligand Incompatibility Impact Outcome of
Unrelated Donor BMT?
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From Farag et al, Blood 2002100 1935-47
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Haploidentical TCD BMTRuggeri et al, Science,
2002
Survival in AML 5 vs. 60 at 5 years plt0.0005
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Disease-Free Survival
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KIR Ligand Incompatibility in Unrelated Donor BMT

• The data regarding KIR and unrelated donor BMT
  are currently unclear
• There are NO data to support preference for a
  mismatched donor over a matched donor
• NMDP is participating in a P01 with clinical and
  biological components to investigate KIR biology
  and BMT

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Donor Socio-Economic Status (SES) Impacts
Availability an NMDP Study
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Background

• Objective To evaluate whether or not there is an
  association between SES (Socio Economic Score)
  and donor availability
• Methodology SES index methodology derivation
  is well understood and described in ACS
  publication
• SES Index A continuous numerical scale obtained
  from a statistical formula based on the status of
  an individuals educational, occupational, and
  income backgrounds

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Analysis Highlights

• There was a highly statistically significant
  difference in socio economic index scores for
  donors available at the time of CT vs.
  unavailable at time of CT (plt0.0001 by the
  Wilcoxon rank sum test)
• Donors of lower SES are more likely to be
  unavailable

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Socio Economic Status (SES) ComparisonDonors
Unavailable at CT (N18,130)
Racial Proportions across SES Classes are highly
statistically significantly different (plt0.0001,
chi-square test)
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Conclusions

• Younger donors are preferable
• CMV positive donors may be preferable for some
  CMV positive recipients further studies are
  needed
• Donors of lower SES are less likely to be
  available

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The HLA-Mismatched Donor

• Claudio Anasetti, M.D.
• Fred Hutchinson Cancer Research Center

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What is the risk of donor HLA mismatching?

• Graft failure
• Acute GVHD
• Chronic GVHD incidence and duration
• Mortality

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How to assess the risk/benefitof a mismatched
transplant?

• Compare against alternative therapies
• Not against an ideal donor

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Which mismatch is preferable?

• HLA-A, B, C and DRB1 mismatches are associated
  with similar mortality

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Are there permissible mismatches?

• Low resolution (antigen) mismatchesA01 vs.
  02
• are more risky than
• High resolution (alleles) mismatchesA0101
  vs. 0102

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What is the implication?
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Can donor have more than one allele mismatch?

• Multiple mismatches compound the risk

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Can T cell depletion offset the risk of
mismatching?

• Randomised trials showed no survival benefit of
  marrow T-depletion or ATG treatment in unrelated
  donor transplants

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What about KIR epitope mismatching?

• Data from JMDP showed that KIR epitope
  mismatching is a risk factor for GVHD and
  mortality in T-replete grafts
• The proposed beneficial role of KIR epitope
  mismatching on outcome of T-depleted grafts has
  to be confirmed

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How can I minimize graft failure?

• Avoid mismatches at HLA-A, B, or C
• Avoid donors with a positive crossmatch test

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Additional Cases
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Case 1 6 mo child with inherited metabolic
disorder

• Summary of search
• 179 A,B,DR potential matches
• Predicted most will be A3001 15-28 to find 1
  match
• 3 donors unavailable
• 6 donors typed at A locus 5 were 3001, 1 A19 was
  A74
• 2 donors with A3001 allele identical at other
  loci

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Case 1 6 mo child with inherited metabolic
disorder

• What would you do?
• Test more? Select those with repository samples?
• Test potentially matched non-Caucasian donors?
• Select mismatched donor? Select A mismatch with
  3001?
• Test potentially use cord unit
  A01XX,3001,B07XX, 13XX,DRB11501,0701 with
  87x107 nucleated cells?

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Case 2 6 yr old child with ALL

• A six-year old child presents B-lineage ALL that
  has relapsed in the marrow 12 months into
  therapy. The child has good organ function, no
  active infection and has completed re-induction
  therapy, being in remission at day 28.
• The child is adopted, of Korean descent and no
  information is available, nor will be available
  regarding her family.

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Case 2 6 yr old child with ALL

• 2 potential unrelated donors
• 54-year old parous female,
• allele matched at HLA-A,B and DRB1
• single allele mismatch at C
• 19 year old male,
• allele level matched at HLA-A,B and C,
• single antigen mismatch at DRB1

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Case 2 6 yr old child with ALL

• Search of the cord blood registries reveals
  numerous 4/6 (A,B DR) allele level matches
• The largest UCB cell dose is 4 x 106/kg
• No CD34 count is available for this unit
• A second 4/6 allele level matched unit
• total cell dose 3 x 106/kg
• CD34 count 3 x 105/kg

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Case 2 6 yr old child with ALL

• How would donor preference change if the
  recipient is a 38 year old man with AML?