1
The Significance of the Direction of the HLA Mismatch in
Cord Blood Matching and the Implication of Graft-
Specific Anti...
2
Goals of Allogeneic HSCT
• Achieve Engraftment
• Absence of Graft versus Host Disease
• Prevent Relapse
• Effective Immu...
3
Search for Allogeneic
HSC
Nuclear family
Extended family
CBU and Unrelated Donors
44
Factors Influencing Decision to Transplant
 Quality of HLA match
 Recipient factors
 Diagnosis and stage of disease
...
5
Patient and Donor/CBU are Heterozygous in all HLA loci
Difference (mismatch) in One allele of HLA-A
• The HLA-A mismatch...
6
Patient is Homozygous in HLA-A and Donor/CBU is
Heterozygous in HLA-A
Mismatch Only in the HvG direction
• The HLA-A mis...
7
Patient is Heterozygous in HLA-A, Donor/CBU is
Homozygous in HLA-A for one allele present in the Patient
Mismatch Only i...
8
“HLA mismatch direction in cord blood transplantation: impact on
outcome and implications for cord blood unit selection”...
Cumulative probability of achieving ANC 500 during the first 77 days after transplantation.
Stevens C E et al. Blood 2011;...
Cumulative probability of TRM during the first 3 years after transplantation.
Stevens C E et al. Blood 2011;118:3969-3978
...
12
• “Evaluation of HLA matching in unrelated
hematopoietic stem cell transplantation for
nonmalignant disorders”
• John H...
13
14
BMT in Non-Malignant Diseases
CBU
• Similar to HSCT in non-Malignant
Diseases, absence of Engraftment may have
played a...
15
Goals of Allogeneic BMT
Achieve Engraftment:
• Patient’s immune system may cause
rejection
• Donor’s immune system may ...
16
Histocompatibility Factors
Affecting Engraftment
• HLA-mismatches in the Host versus graft
direction (HvG mismatch)
• P...
17
Homozygosity at a given locus vs
Heterozygosity
Major-Histocompatibility-Complex class I alleles and antigens in hemato...
18
Impact of High Resolution Mismatches (Allele Level) & Broad
Mismatches (Serologically Detectable) in Alleles of HLA Loci
20
The impact of HLA unidirectional mismatches on
the outcome of myeloablative hematopoietic stem
cell transplantation wit...
21
HvG and GvH mismatches
(Conclusions)
• The 7/8 groups differed only for grades 3-4 acute GVHD
where HVG MM had less GVH...
22
23
Causes of Death
• The 7/8 bi-directional and GVH MM
groups had slightly higher deaths attributed
to GVHD, compared to t...
24
Differences in the number of Mismatched Epitopes when the Patient
is Homozygous or Heterozygous at the Mismatched locus
25
Homozygosity at a given locus vs
Heterozygosity
• Patients homozygous at a given locus when presenting
humoral sensitiz...
26
Homozygosity at a given locus vs
Heterozygosity
• Patients homozygous at a given locus when presenting
humoral sensitiz...
DSA in TCD Haploidentical Stem Cell Transplantation
Ciurea SO, de Lima M, Cano P, Korbling M, Giralt S, Shpall EJ,
Wang X,...
Recently published work: Anti-HLA
Antibodies and Virtual Cross Match in MUDs
 Retrospective study - DSA found in 9/37 MUD...
Ciurea SO, Thall PF, Wang X, Wang SA, Hu Y, Cano P, Aung F, Rondon G,
Molldrem JJ, Korbling M, Shpall EJ, de Lima M, Champ...
Other Associations: Gender, Number of Pregnancies
and anti-HLA antibodies
Variable N
Coefficie
nt SE P-value OR 95% CI
Int...
31
Lower Expression of HLA in CBU-
CD34
Bone
Marrow
CD34
Cord Blood
CD34
Anti-HLA antibodies in CBU
transplantation
 DSA in Single Unit CBU TX
 Double CBU and DSA:
• DSA against both Units
• DS...
33
Evaluation of DSA by a Solid Phase Assay
with Single Antigen Beads
34
“The impact of anti-HLA antibodies on unrelated cord blood
transplantations”
Takanashi M, Atsuta Y, Fujiwara K, Kodo H,...
Cumulative incidence of neutrophil/platelet recovery and survival for 386 CBT cases. ab-
negative indicates patient does n...
36
“Donor-specific anti-HLA antibodies predict outcome in double umbilical
cord blood transplantation”
Cutler C, Kim HT, S...
Cumulative incidence of graft failure.
Cutler C et al. Blood 2011;118:6691-6697
©2011 by American Society of Hematology
no...
Cumulative incidence of neutrophil engraftment.
Cutler C et al. Blood 2011;118:6691-6697
©2011 by American Society of Hema...
Cumulative incidence of early death or relapse.
Cutler C et al. Blood 2011;118:6691-6697
©2011 by American Society of Hema...
DSA in the Study by Brunstein et al
• Lower cut-off for calling positve anti-HLA antibodies
• DSA against 1 Unit: n = 12; ...
Impact of donor specific anti-HLA antibodies on graft
failure and survival after reduced intensity conditioning-
unrelated...
43
Anti-HLA antibodies in CBU
transplantation
• HvG vector, Serologic Level mismatches (class I)
• Sensitivity, specificit...
“Complement (C1q) fixing solid-phase screening for HLA antibodies
increases the availability of compatible platelet compon...
0
5000
10000
15000
20000
25000
A*23:01
A*80:01
A*01:01
A*24:02
A*36:01
A*29:02
A*24:03
A*66:02
A*33:01
A*33:03
A*29:01
A*3...
46
Anti-HLA antibodies in CBU
transplantation
• Only 16-24 % PGF have DSA
• T-cell immunity
• Conditioning, Immunosuppress...
4747
Goals of Allogeneic BMT
• Absence of Graft versus Host Disease:
GvHD is mediated by donor’s T-cells
• Effective Immun...
Homozygosity at a given locus vs
Heterozygosity
• Patients homozygous at a given locus when presenting
humoral sensitizati...
49
Differences in the number of Mismatched Epitopes when the Patient
is Homozygous or Heterozygous at the Mismatched locus
50
Neutrophil Engraftment
(absence @ day+28)
Mismatch n RR L-R HR p
8/8 4779 1.00 - - 0.0009
C*03 PMM 134 0.84 0.33 2.16 0.72...
Histocompatibility Factors
Affecting Engraftment
• HLA-mismatches in the Host versus graft
direction (HvG mismatch)
• Sero...
Univariate Logistic Regression Model for Graft Failure in MUDT
Variable
Parameter
Estimate
Parameter
Standard Error
Univar...
Cumulative incidence of neutrophil and platelet recovery in subgroups of CD34 cell dose. ab-
negative indicates patient do...
Progression-free (A) and overall survival (B)
Cutler C et al. Blood 2011;118:6691-6697
©2011 by American Society of Hemato...
Anti-HLA antibodies in CBU
transplantation
 DSA in Single Unit CBU TX
 Double CBU and DSA
 DSA against both Units
 DSA...
The Significance of the Direction of the HLA Mismatch in Cord Blood Matching and the Implication of Graft-Specific Anti-HL...
The Significance of the Direction of the HLA Mismatch in Cord Blood Matching and the Implication of Graft-Specific Anti-HL...
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The Significance of the Direction of the HLA Mismatch in Cord Blood Matching and the Implication of Graft-Specific Anti-HLA Antibodies

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The Significance of the Direction of the HLA Mismatch in Cord Blood Matching and the Implication of Graft-Specific Anti-HLA Antibodies

  1. 1. 1 The Significance of the Direction of the HLA Mismatch in Cord Blood Matching and the Implication of Graft- Specific Anti-HLA Antibodies Marcelo A. Fernández Viña, Ph.D. Department of Pathology Medical School Stanford University
  2. 2. 2 Goals of Allogeneic HSCT • Achieve Engraftment • Absence of Graft versus Host Disease • Prevent Relapse • Effective Immune reconstitution
  3. 3. 3 Search for Allogeneic HSC Nuclear family Extended family CBU and Unrelated Donors
  4. 4. 44 Factors Influencing Decision to Transplant  Quality of HLA match  Recipient factors  Diagnosis and stage of disease  Age  Major organ function  CMV serology  Donor/CBU factors  Age – Period of collection  Body size - Cell Dose  CMV serology – Infectious Disease Markers  Pregnancy and transfusion history
  5. 5. 5 Patient and Donor/CBU are Heterozygous in all HLA loci Difference (mismatch) in One allele of HLA-A • The HLA-A mismatched antigen in the Donor/CBU can be recognized as foreign by the Patient’s Immune System (Host versus Graft; rejection) • The HLA-A mismatched antigen in the Patient can be recognized as foreign by the Donor/CBU’s Immune System (Graft versus Host; GvHD and GvL) 33 Molecules encoded in the HLA systemMolecules encoded in the HLA system Maternal origin PATIENT Encoded in HLA-DRB1 locus (Class II) Encoded in HLA-A locus (Class I) Paternal origin Encoded in HLA-B locus (Class I)
  6. 6. 6 Patient is Homozygous in HLA-A and Donor/CBU is Heterozygous in HLA-A Mismatch Only in the HvG direction • The HLA-A mismatched antigen in the Donor/CBU can be recognized as foreign by the Patient’s Immune System (Host versus Graft; rejection) • No mismatch in the Graft versus host direction (No Graft versus Host; No GvHD/ No GvL) 33 Molecules encoded in the HLA systemMolecules encoded in the HLA system Maternal origin DONOR/CBU Encoded in HLA-DRB1 locus (Class II) Encoded in HLA-A locus (Class I) Paternal origin Encoded in HLA-B locus (Class I)
  7. 7. 7 Patient is Heterozygous in HLA-A, Donor/CBU is Homozygous in HLA-A for one allele present in the Patient Mismatch Only in the HvG direction • The HLA-A mismatched antigen in the Patient can be recognized as foreign by the Donor/CBU ’s Immune System (Graft versus Host; GvHD and GvL) • No mismatch int Host versus Graft direction 33 Molecules encoded in the HLA systemMolecules encoded in the HLA system Maternal origin PATIENT Encoded in HLA-DRB1 locus (Class II) Encoded in HLA-A locus (Class I) Paternal origin Encoded in HLA-B locus (Class I)
  8. 8. 8 “HLA mismatch direction in cord blood transplantation: impact on outcome and implications for cord blood unit selection” Stevens CE, Carrier C, Carpenter C, Sung D, Scaradavou A Blood. 2011 Oct 6;118(14):3969-78. • 1202 single CBU TX • 1993-2006 (57% before 2000) • Engraftment at day 77 • 75 % <16 y/o • 67% Malignancies • Early (23%), Intermediate (46%), Advanced 30%) • 6/6 – 6% • 5/6 – 38% • 364 1 bidirectional MM • 58 GvH-only MM • 40 HvG-Only MM • 76% Neutrophil engraftment • 51 % Platelet engraftment • Match grade (p<0.001) and cell dose (p<0.006) changed over time • Engraftment Faster in the GvH- only (HR = 1.6, P = .003) • GvH-only had Less TRM, Mortality, Treatment Failure in patients with Maligancy • Comparable to Matched transplants
  9. 9. Cumulative probability of achieving ANC 500 during the first 77 days after transplantation. Stevens C E et al. Blood 2011;118:3969-3978 ©2011 by American Society of Hematology
  10. 10. Cumulative probability of TRM during the first 3 years after transplantation. Stevens C E et al. Blood 2011;118:3969-3978 ©2011 by American Society of Hematology Patients with malignancies HLA-matched or GVH-only mismatched CB grafts Patients with other diseases 1 bidirectional mismatch
  11. 11. 12 • “Evaluation of HLA matching in unrelated hematopoietic stem cell transplantation for nonmalignant disorders” • John Horan, Tao Wang, Michael Haagenson, Stephen R. Spellman, Jason Dehn, Mary Eapen, Haydar Frangoul, Vikas Gupta, Gregory A. Hale, Carolyn K. Hurley, Susana Marino, Machteld Oudshoorn, Vijay Reddy, Peter Shaw, Stephanie J. Lee and Ann Woolfrey • Blood. 2012 Oct 4;120(14):2918-24.
  12. 12. 13
  13. 13. 14 BMT in Non-Malignant Diseases CBU • Similar to HSCT in non-Malignant Diseases, absence of Engraftment may have played a major role in causing morbidity and mortality
  14. 14. 15 Goals of Allogeneic BMT Achieve Engraftment: • Patient’s immune system may cause rejection • Donor’s immune system may enhance the engraftment through the destruction of patient’s immune cells that cause rejection
  15. 15. 16 Histocompatibility Factors Affecting Engraftment • HLA-mismatches in the Host versus graft direction (HvG mismatch) • Patient’s Homozygosity (HvG mismatch) • Donor-specific anti-HLA Antibodies • ABO Major Mismatch
  16. 16. 17 Homozygosity at a given locus vs Heterozygosity Major-Histocompatibility-Complex class I alleles and antigens in hematopoietic- cell transplantation. Petersdorf EW, Hansen JA, Martin PJ, Woolfrey A, Malkki M, Gooley T, Storer B, Mickelson E, Smith A, Anasetti C. N Engl J Med. 2001 Dec 20;345(25):1794-800 • CML, No ATG • RESULTS: A single HLA allele mismatch did not increase the risk of graft failure, whereas a single antigen mismatch significantly increased the risk • The risk was also increased if the recipient was HLA homozygous at the mismatched class I locus or if the donor had two or more class I mismatches • CONCLUSIONS: HLA class I antigen mismatches that are serologically detectable confer an enhanced risk of graft failure after hematopoietic-cell transplantation. Transplants from donors with a single class I allele mismatch that is not serologically detectable may be used without an increased risk of graft failure
  17. 17. 18
  18. 18. Impact of High Resolution Mismatches (Allele Level) & Broad Mismatches (Serologically Detectable) in Alleles of HLA Loci
  19. 19. 20 The impact of HLA unidirectional mismatches on the outcome of myeloablative hematopoietic stem cell transplantation with unrelated donors • Hurley CK, Woolfrey A, Wang T, Haagenson M, Umejiego J, Aljurf M, Askar M, Battiwalla M, Dehn J, Horan J, Oudshoorn M, Pidala J, Saber W, Turner V, Lee SJ, Spellman S • Blood. 2013 May 1. [Epub ahead of print] PubMed PMID: 23637130 • 2,687 myeloablative MUD; malignant disease • 7/8 bidirectional MM transplants, n=1393 • 7/8 host vs. graft (HVG) vector MM , n=112 • 7/8 graft vs. host (GVH) vector MM, n=119 • 8/8 matches, n=1063
  20. 20. 21 HvG and GvH mismatches (Conclusions) • The 7/8 groups differed only for grades 3-4 acute GVHD where HVG MM had less GVHD than the 7/8 bidirectional MM (HR 0.52, p=0.0016) and GVH MM (HR 0.43, p=0.0009) but not the 8/8 group (HR 0.83, p=0.39) • There were no differences between the 7/8 groups for relapse, chronic GVHD, neutrophil engraftment or graft failure • Unidirectional GVH vector mismatches have the same risk as 7/8 bidirectional mismatches • Recipients with a 7/8 HVG MM have a reduced risk of acute GVHD without an increased risk of disease relapse or graft failure compared to a 7/8 bi-directional MM at a heterozygous locus
  21. 21. 22
  22. 22. 23 Causes of Death • The 7/8 bi-directional and GVH MM groups had slightly higher deaths attributed to GVHD, compared to the 8/8 and 7/8 HVG MM groups, 18.2% and 18.0% vs. 14.9% and 14.3%, respectively • The 7/8 HVG MM group had more deaths attributed to graft rejection than the 8/8, 7/8 GVH MM and 7/8 bidirectional groups, 9.5% vs. 0.6%, 1.1% and 1.6%, respectively
  23. 23. 24 Differences in the number of Mismatched Epitopes when the Patient is Homozygous or Heterozygous at the Mismatched locus
  24. 24. 25 Homozygosity at a given locus vs Heterozygosity • Patients homozygous at a given locus when presenting humoral sensitization tend to make anti-HLA antibodies reactive with many (in some instances all but self antigens) HLA antigens of the same locus • Novel anti-HLA antibody screening techniques allow to precisely identify anti-HLA antibodies defining unacceptable or high risk mismatches. Therefore, donors can be excluded or given lower priority on the basis of their HLA mismatch and the patient’s antibody reactivity. • Current conditioning/immunosupression (ATG) this risk for primary graft loss mediated by T-cells may be greatly reduced
  25. 25. 26 Homozygosity at a given locus vs Heterozygosity • Patients homozygous at a given locus when presenting humoral sensitization tend to make anti-HLA antibodies reactive with many (in some instances all but self antigens) HLA antigens of the same locus • Novel anti-HLA antibody screening techniques allow to precisely identify anti-HLA antibodies defining unacceptable or high risk mismatches. Therefore, donors can be excluded or given lower priority on the basis of their HLA mismatch and the patient’s antibody reactivity. • Current conditioning/immunosupression (ATG) this risk for primary graft loss mediated by T-cells may be greatly reduced
  26. 26. DSA in TCD Haploidentical Stem Cell Transplantation Ciurea SO, de Lima M, Cano P, Korbling M, Giralt S, Shpall EJ, Wang X, Thall PF, Champlin RE, Fernandez-Vina M  DSA were detected in 5 of 24 consecutive patients (21%)  4/24 patients had primary graft failure (PGF)  3/4 (75%) patients with DSA failed to engraft as compared with 1/20 (5%) without DSA (P=0.008) DSAEngraftment YES NO YES 1 3 NO 19 1 “High risk of graft failure in patients with anti-HLA antibodies undergoing haploidentical stem-cell transplantation” Transplantation. 2009 Oct 27;88(8):1019-24
  27. 27. Recently published work: Anti-HLA Antibodies and Virtual Cross Match in MUDs  Retrospective study - DSA found in 9/37 MUDT patients with graft failure  1/78 had DSA in the matched control group of patients who engrafted (TCR grafts, 85% mismatched at DP locus) Spellman S, Bray R, Rosen-Bronson S, Haagenson M, Klein J, Flesch S, Vierra-Green C, Anasetti C. The detection of donor-directed, HLA-specific alloantibodies in recipients of unrelated hematopoietic cell transplantation is predictive of graft failure. Blood. 2010 Apr 1;115(13):2704-8 PGF Control DSA 9/37 (24%) 1/78 (1%) Class I +/- Anti-DP 5 1 Anti-DP alone 4 0 DSA and PGF RR = 24.8 – 28.1
  28. 28. Ciurea SO, Thall PF, Wang X, Wang SA, Hu Y, Cano P, Aung F, Rondon G, Molldrem JJ, Korbling M, Shpall EJ, de Lima M, Champlin RE, Fernandez-Vina M. Donor-specific anti-HLA Abs and graft failure in matched unrelated donor hematopoietic stem cell transplantation. Blood. 2011 Nov 24;118(22):5957-64 592 MUD TX 75 % of the 8/8 transplants present at least one mismatch in DP, DQ, DRB3/4/5 in the HvG vector  20 % of HSC patients are immunized against HLA HLA Immunization in FEMALE HSCT patients: 30% HLA Immunization in MALE HSCT patients: 10% 3.3 % present antibodies against HLA-DP (1/2 MUD TX have one or two DP mismatches and DSA anti HLA-DP)
  29. 29. Other Associations: Gender, Number of Pregnancies and anti-HLA antibodies Variable N Coefficie nt SE P-value OR 95% CI Intercept -2.71 0.60 <0.0001 - - Male vs. Females 0 pregnancies 356 0.73 0.62 0.24 2.1 0.62 - 6.94 Female: Number of pregnancies = 1 (vs. 0) 37 1.85 0.70 0.008 6.3 1.62 - 24.85 Female: Number of pregnancies ≥ 2 (vs. 0) 152 2.25 0.62 0.0003 9.5 2.83 - 32.02 Significant association between gender and the presence of AHA: 30.8% females vs 12.1% males had anti-HLA antibodies (p<0.0001) 7/8 pts with DSA were females
  30. 30. 31 Lower Expression of HLA in CBU- CD34 Bone Marrow CD34 Cord Blood CD34
  31. 31. Anti-HLA antibodies in CBU transplantation  DSA in Single Unit CBU TX  Double CBU and DSA: • DSA against both Units • DSA against one Unit • No DSA
  32. 32. 33 Evaluation of DSA by a Solid Phase Assay with Single Antigen Beads
  33. 33. 34 “The impact of anti-HLA antibodies on unrelated cord blood transplantations” Takanashi M, Atsuta Y, Fujiwara K, Kodo H, Kai S, Sato H, Kohsaki M, Azuma H, Tanaka H, Ogawa A, Nakajima K, Kato S Blood. 2010 Oct 14;116(15):2839-46 • 386 Single CBT; myeloablative, Median age 33 • HLA Immunization: 89 patients (23%); 20 cases with DSA • Neutrophil recovery @ day +60 : • 83% for the ab-negative • 73% for ab-positive/No-DSA • 32% ab-positive/Yes-DSA • Anti-HLA antibodies should be tested and considered pre-transplantation in the selection of cord blood
  34. 34. Cumulative incidence of neutrophil/platelet recovery and survival for 386 CBT cases. ab- negative indicates patient does not have anti-HLA antibody; ab-positive, patient has anti-HLA antibody but the CB does not have the corresponding antigen for the antibod... Takanashi M et al. Blood 2010;116:2839-2846 ©2010 by American Society of Hematology
  35. 35. 36 “Donor-specific anti-HLA antibodies predict outcome in double umbilical cord blood transplantation” Cutler C, Kim HT, Sun L, Sese D, Glotzbecker B, Armand P, Koreth J, Ho V, Alyea E, Ballen K, Ritz J, Soiffer RJ, Milford E, Antin JH Blood. 2011 Dec 15;118(25):6691-7 • 73 Double CBT; myeloablative (27%)or RIC/ATG (73%); Median age 48 • 18 patients with DSA (11 Single Unit DSA, 7 DSA against both CBU)
  36. 36. Cumulative incidence of graft failure. Cutler C et al. Blood 2011;118:6691-6697 ©2011 by American Society of Hematology no DSA DSA against one unit DSAs against both units
  37. 37. Cumulative incidence of neutrophil engraftment. Cutler C et al. Blood 2011;118:6691-6697 ©2011 by American Society of Hematology no DSA DSA against one or both units
  38. 38. Cumulative incidence of early death or relapse. Cutler C et al. Blood 2011;118:6691-6697 ©2011 by American Society of Hematology no DSA DSA against one unit DSA against both units
  39. 39. DSA in the Study by Brunstein et al • Lower cut-off for calling positve anti-HLA antibodies • DSA against 1 Unit: n = 12; 2 graft failures • DSA> 3000 MFI: n = 3; 1/3 had graft failure • DSA against both Units: n= 6; 1 graft failure • One had DSA> 3000 MFI : n = 4 ; 1/3 had graft failure
  40. 40. Impact of donor specific anti-HLA antibodies on graft failure and survival after reduced intensity conditioning- unrelated cord blood transplantation. A Eurocord, Societe Francophone d'Histocompatibilite et d'Immunogenetique (SFHI) and Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC) analysis Boudifa A, Coeffic B, Devys A, De Matteis M, Dubois V, Hanau D, Hau F, Jollet I, Masson D, Pédron B, Perrier P, Picard C, Ramouneau-Pigot A, Volt F, Charron D, Gluckman E, Loiseau P Haematologica. 2012 Dec 14. [Epub ahead of print] PubMed PMID: 23242594
  41. 41. 43 Anti-HLA antibodies in CBU transplantation • HvG vector, Serologic Level mismatches (class I) • Sensitivity, specificity and quantitation of antibody detection are greatly enhanced by novel solid phase assays • Variations in end points and cut-off values • Cross-match testing is not be practical in HSCT • High risk of graft rejection in patients with D.S. Antibodies • Higher mortality and morbidity associated to DSA • Allo-antibodies directed against both class I and II HLA antigens • Less mismatches in MUD than in CBU • Anti-DP antibodies in MUD (mostly matched at other HLA loci) • Anti-HLA antibody testing is warranted to all HSCT with known or presumed HLA mismatches • Further analysis for different graft sources and diseases is warranted
  42. 42. “Complement (C1q) fixing solid-phase screening for HLA antibodies increases the availability of compatible platelet components for refractory patients” Fontaine MJ, Kuo J, Chen G, Galel SA, Miller E, Sequeira F, Viele M, Goodnough LT, Tyan DB. Transfusion. 2011 Dec;51(12):2611-8 • 13 highly sensitized refractory patients received 177 PLT units incompatible by the IgG-SAB method • The mean CPRA value was significantly lower by C1q-SAB (60%) than by IgG-SAB (94%; p < 0.05) • Patients showed significantly better corrected count increment with C1q-compatible than with C1q-incompatible PLTs • Results show that 75% of PLT units previously considered incompatible were actually compatible • For highly refractory patients to PLT transfusion, the C1q-based SAB binding assay may be a better method for identifying clinically relevant HLA antibodies and selecting PLT units that will result in acceptable CCI
  43. 43. 0 5000 10000 15000 20000 25000 A*23:01 A*80:01 A*01:01 A*24:02 A*36:01 A*29:02 A*24:03 A*66:02 A*33:01 A*33:03 A*29:01 A*34:01 A*32:01 A*11:02 A*43:01 A*11:01 A*03:01 A*74:01 A*26:01 A*34:02 A*69:01 A*68:02 A*25:01 A*02:06 A*66:01 A*02:01 A*68:01 A*02:03 A*30:01 A*30:02 A*31:01 IgG C1Q FluorescenceIntensity Self HLA-A A*02, A*24, A*25, A*26,A*34, A*68, A*69, A*43 may be acceptable by the C1q Assay Antibody Tests by Assays
  44. 44. 46 Anti-HLA antibodies in CBU transplantation • Only 16-24 % PGF have DSA • T-cell immunity • Conditioning, Immunosuppressive regimens (ATG, post TX Cyclophosphamide) • Preservation of patient’s Immune System (Primary Disease and Stage) • Graft type and variations in HLA expression • Graft Manipulation
  45. 45. 4747 Goals of Allogeneic BMT • Absence of Graft versus Host Disease: GvHD is mediated by donor’s T-cells • Effective Immune reconstitution: T-cells of donor origin may interact with patient’s tissues and in some instances patient’s APCs • Prevent Relapse: GvL may be mediated by both, T-cells and NK cells of donor origin; donor’s T cells causing GvHD may also prevent relapse • GvH: Major factor in Mortality and Morbidity: Once engraftment is achieved; the mismatches in the GvH vector play a major role in transplant outcome
  46. 46. Homozygosity at a given locus vs Heterozygosity • Patients homozygous at a given locus when presenting humoral sensitization tend to make anti-HLA antibodies reactive with many (in some instances all but self antigens) HLA antigens of the same locus • Novel anti-HLA antibody screening techniques allow to precisely identify anti-HLA antibodies defining unacceptable or high risk mismatches. Therefore, donors can be excluded or given lower priority on the basis of their HLA mismatch and the patient’s antibody reactivity. • However, in light of current conditioning/immunosupression (ATG) this risk for primary graft loss mediated by T-cells may be greatly reduced
  47. 47. 49 Differences in the number of Mismatched Epitopes when the Patient is Homozygous or Heterozygous at the Mismatched locus
  48. 48. 50
  49. 49. Neutrophil Engraftment (absence @ day+28) Mismatch n RR L-R HR p 8/8 4779 1.00 - - 0.0009 C*03 PMM 134 0.84 0.33 2.16 0.72 C-allele 61 0.41 0.04 4.69 0.47 C-antigen 700 1.66 1.27 2.18 0.0002 A, B or DRB1 959 1.46 1.13 1.89 0.0034
  50. 50. Histocompatibility Factors Affecting Engraftment • HLA-mismatches in the Host versus graft direction (HvG mismatch) • Serologic level HLA-class I mismatches • Patient’s Homozygosity (HvG mismatch) • Donor-specific anti-HLA Antibodies • ABO Major Mismatch
  51. 51. Univariate Logistic Regression Model for Graft Failure in MUDT Variable Parameter Estimate Parameter Standard Error Univariate P-value Odds Ratio Male (vs. female) -0.53 0.47 0.26 0.59 Black (vs. white) 1.17 0.78 0.14 3.22 Others (vs. white) -12.15 316.51 0.97 0.00 AHA= yes (vs. no) 0.91 0.49 0.06 2.48 DSA = yes (vs. no) 3.06 0.77 0.0001 21.33 HEL HvG = 8 (vs. 7) -0.31 0.64 0.62 0.73 LEL HvG = 6 (vs. <6) -0.53 0.64 0.41 0.59 CD34 cell numbers infused -0.51 0.38 0.18 0.60 CMV mismatch = yes (vs. no) 0.27 0.47 0.56 1.31 Sex mismatch = yes (vs. no) 0.60 0.47 0.21 1.82 ABO mismatch = yes (vs. no) 1.35 0.63 0.03 3.86 AHA – anti HLA antibodies; DSA – donor-specific AHA; HEL – high expression loci; LEL – low expression loci; HvG – host versus graft direction MVA: DSA (p=0.0001) and ABO mm (p=0.04) remained significantly associated with GF
  52. 52. Cumulative incidence of neutrophil and platelet recovery in subgroups of CD34 cell dose. ab- negative indicates patient does not have anti-HLA antibody; ab-positive, patient has anti-HLA antibody but the CB does not have the corresponding antigen for the ant... Takanashi M et al. Blood 2010;116:2839-2846 ©2010 by American Society of Hematology
  53. 53. Progression-free (A) and overall survival (B) Cutler C et al. Blood 2011;118:6691-6697 ©2011 by American Society of Hematology no DSA no DSA DSA against both units DSA against both units
  54. 54. Anti-HLA antibodies in CBU transplantation  DSA in Single Unit CBU TX  Double CBU and DSA  DSA against both Units  DSA against one Unit  Even though the authors do not agree: Higher mortality and morbidity associated to DSA. Variations in end points and cut-off values

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