MATCHMAKER, MATCHMAKER, MAKE ME A MATCH, FIND ME A MISMATCHED TRANSPLANT TO CATCH

Transcription

1 MATCHMAKER, MATCHMAKER, MAKE ME A MATCH, FIND ME A MISMATCHED TRANSPLANT TO CATCH TEJASWINI M. DHAWALE, M.D. HEME FELLOWS CONFERENCE NOVEMBER 08, 2013

2 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 He underwent a second NMA URD donor transplant August 7, 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

3 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?

4

5

6 TERMINOLOGY: WHAT DEFINES A MATCH? Donor Patient HLA -A HLA -B HLA -C HLA DRB1 HLA -DQ

7 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

8 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

9 MISMATCHED TRANSPLANTS (7/8) Lower survival and DFS Higher treatment related mortality More acute GVHD Antigen and allele MM are both risky

10 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:

11 RELATIVE RISKS OF HLA MISMATCH AT EACH LOCUS SURVIVAL HLA N RR CI P 8/8 Match A <0.001 B C DRB 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.

12 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

13 HLA-C ANTIGEN MISMATCH ASSOCIATED WITH SIGNIFICANTLY HIGHER MORTALITY Woolfrey et al. BBMT 2011

14 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

15 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

16 EXPLORATORY QUESTIONS

17 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

18 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

19 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

20 HAPLOTYPE Does haplotype mismatching matter? Petersdorf; Research Clinical Haematology Volume 20, Issue