MATCHMAKER, MATCHMAKER, MAKE ME A MATCH, FIND ME A MISMATCHED TRANSPLANT TO CATCH TEJASWINI M. DHAWALE, M.D. HEME FELLOWS CONFERENCE NOVEMBER 08, 2013
CASE PRESENTATION 51 yo M with history of MDS (unilinear dysplasia) associated with RUNX1 mutation who developed graft failure after a previous NMA URD transplant in October 2012. He underwent a second NMA URD donor transplant August 7, 2013. Conditioning: Fludarabine, TBI GVHD: CSP + Sirolimus + MMF Day +15: Diffuse Alveolar Hemmorhage Donor 1: DRB1 allele mismatched PBSCT Donor 2: DRB1*01 antigen mismatched PBSCT Day +15: DAH
CLINICAL QUESTIONS 1. What risk does DRB1 antigen mismatching confer on anticipated outcome (survival, acute GVHD, TRM)? 2. How does that risk compare to HLA-mismatching at other loci?
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TERMINOLOGY: WHAT DEFINES A MATCH? Donor Patient HLA -A HLA -B HLA -C HLA DRB1 HLA -DQ
TERMINOLOGY: ANTIGEN VS. ALLELE MISMATCH DRB1 DRB1 Patient *01:02 *04:04 URD *01:03 *04:04 Allele mismatch: unique sequence variant of a gene Antigen mismatch: distinct serologic reactivity pattern
WHAT IS THE RELATIVE IMPORTANCE OF VARIOUS HLA LOCI? Key components: N= 3857 Diseases : ALL, AML, CML, MDS Conditioning: Myeloablative (all patients) Source: 94% of patients received bone marrow End points: overall survival, GVHD, TRM
MISMATCHED TRANSPLANTS (7/8) Lower survival and DFS Higher treatment related mortality More acute GVHD Antigen and allele MM are both risky
Survival of patients with early, intermediate, and advanced disease depending on degree of HLA matching (8/8, 7/8, and 6/8) for HLA-A, -B, -C, and -DRB1. Pre-transplant: Early stage disease Pre-transplant: Advanced stage disease 2007 by American Society of Hematology Lee S J et al. Blood 2007;110:4576-4583
RELATIVE RISKS OF HLA MISMATCH AT EACH LOCUS SURVIVAL HLA N RR CI P 8/8 Match 1840 1.00 - A 274 1.36 1.17-1.58 <0.001 B 116 1.16 0.92 1.47 0.20 C 478 1.19 1.05-1.35 0.006 DRB1 117 1.48 1.19-1.85 0.001 Mismatching Conclusions: 1. HLA-A and DRB1 MM do worse than B and C. 2. Allele and antigen MM equally risky* 3. * HLA-C antigen MM are more risky than allele MM. 4. Single MM at HLA-DQ or DP were not found to affect survival.
Key components: N= 1933 Diseases : ALL, AML, CML, MDS Conditioning: Myeloablative (65%), RIC/NM (35%) Source: 100% of patients received PBSC End points: overall survival, GVHD, TRM
HLA-C ANTIGEN MISMATCH ASSOCIATED WITH SIGNIFICANTLY HIGHER MORTALITY Woolfrey et al. BBMT 2011
CONCLUSIONS : HLA MISMATCHING 1. MM not a contraindication to transplant. 2. The risk for mortality increases with the number of mismatches 3. Marrow: Risk of MM A & DRB1 > B or C 4. PBSC: Minimize HLA-C antigen MM 5. Risk of allele and antigen MM are equivalent, with the exception of HLA-C 6. DQB1 and DP may be the most permissible MM
CASE PRESENTATION: FOLLOW UP: DAY +91 Day 15 Day 90 Day 84 BM with NED, 30-40% cellularity, chimerism 100% donor 2 GVHD: Skin GVHD (first transplant), second transplant: none. DAH: Tapered off prednisone 9/18 10/26
EXPLORATORY QUESTIONS
CORD BLOOD TOLERANCE What explains the higher tolerance of cord blood transplants for HLA mismatching compared to BM or PBSCT? HLA-A, -B, and DRB1 (six total determinants) Acute GVHD is lower, chronic GVHD more responsive Major limitation: cell dose
MINOR (H) ANTIGENS Why do recipients of bone marrow grafts from HLA-matched sibling donors still develop GVHD? Genetic loci outside the MHC minor H antigens freesymmetry.org
PERMISSIBLE MISMATCHES DPB1 Can we risk stratify mismatched transplants based on the degree of their alloreactive T cell response? Exons sequenced encode critical portions of the peptide binding grooves of class I and class II molecules. Zino, Blood 2003
HAPLOTYPE Does haplotype mismatching matter? Petersdorf; Research Clinical Haematology Volume 20, Issue 2 2007 155-170