Related haploidentical donors versus matched unrelated donors

Transcription

1 Related haploidentical donors versus matched unrelated donors Bronwen Shaw, MD PhD Professor of Medicine, MCW Senior Scientific Director, CIBMTR

2 Definition Matched Unrelated donor Refers to HLA matching typically for 4 loci = 8/8 HLA-A,-B,-C, -DRB1 May include DQB1, -DPB1 (but these are often mismatched even in a MUD ) Haplo-identical donor Typically refers to any close relative who is matched for 4-7/8 Might be a true haplo (one chromosome the same the other is not: 4/8) Often not the case 2

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5 Donor acquisition Matched UD Haplo Availability 75% Caucasian 16-46% other race/ethnicity Almost always HLA match Restrictive (with traditional GVHD prophylaxis) Less restrictive Speed of acquisition Medium Fast Donor Complications Few/possible Increased compared to UD Subsequent donations Possible Possible 5

6 Haplo-identical donors Often only one choice Cannot select for CMV, ABO, sex Many haplo donors are older Outcomes better with younger MUD, not well studied in haplo Increased risk for CHIP (clonal hematopoiesis) in older/related donors More risk to the donor related to the donation (even in younger related donor compared to UD) 6

7 Related donor safety: 51,024 donations Halter et al, 2009 BM PB /36317 RELATED 0/14706 UNRELATED deaths / donations related 0 unrelated 7

8 Cell product Matched UD Haplo Cell dose Predictable Predictable (although large numbers sometimes required) Quality Predictable Predictable Donor Specific Antibodies Recognized More common, can be problematic Cost Medium Lower 8

9 Studies of DSA impact in different settings in AHSCT Reference Patients (n) Stem cell source Conditioni ng Anti- HLA% DSA% Graft failure with/without DSA Spellman et al. 115 Mismatched unrelated RIC ND 9 24 versus 1% Ciurea et al /10 and 9/10 unrelated MACorRIC versus 2.7% Yoshihara et al. 79 Haplo-identical RIC versus 3% Ciurea et al. 24 Haplo-identical RIC ND versus 5% Chang et al. 345 Haplo-identical MAC % (MFI>10,000) versus 3.2% Ciurea et al. 122 Haplo-identical Nonspecified ND versus 4% Morin-Zorman et al, Front Immunol. 2016; 7:

10 Clinical outcomes: 10 comparative studies All retrospective 2 registry studies, 1 multi-center, 7 single center Generally small numbers (haplo pts: ) Different diseases, stages, conditioning, GVHD prophylaxis Shaw, 2017, Blood Advances 10

11 Clinical outcomes: 10 comparative studies Engraftment 6/8 report slower neutrophil, platelet (or both) engraftment with haplo donors (vs other sources) Relapse: 1 study showed higher relapse in Haplo (AML with RIC) 1 study showed lower relapse in haplo in HD (vs UD) 8 studies no difference Shaw, 2017, Blood Advances 11

12 Clinical outcomes: 10 comparative studies GVHD 3/10 show a significant reduction in acute GVHD in haplo (no difference in others or severe agvhd) 6/10 comparative studies show haplo patients to experience less chronic GVHD either overall or moderate/extensive None show higher acute or chronic GVHD Shaw, 2017, Blood Advances 12

13 Overall survival: AML 2015 by American Society of Hematology Stefan O. Ciurea et al. Blood 2015;126:

14 GVHD Outcome Grade 2-4 acute GVHD Transplant conditioning regimen intensity Myeloablative * Reduced intensity Hazard ratio (95% CI) Hazard ratio (95% CI) Matched unrelated donor Haploidentical donor 0.40 ( ) 0.68 ( ) P <.0001 P =.05 Grade 3-4 acute GVHD Matched unrelated donor Haploidentical donor 0.47 ( ) 0.20 ( ) P =.03 P =.006 Chronic GVHD Matched unrelated donor Haploidentical donor 0.46 ( ) 0.51 ( ) P <.0001 P =.0006 Stefan O. Ciurea et al. Blood 2015;126:

15 NRM and Relapse Stefan O. Ciurea et al. Blood 2015;126:

16 Clinical outcomes Matched UD Haplo Speed of engraftment Fast Slower Graft failure Rare More common (esp with DSA) GvHD High without TCD High without TCD. Lower than MUD with conv prophylaxis Immune reconstitution Slow Slower Relapse Lower than HLA-id sibling Higher in some studies (loss of heterozygosity) Survival Similar to HLA-id sibling Similar to UCB and MMUD 16

17 Summary Haplo HCT is growing Outcomes are improving and at least comparable to MMUD and UCB (maybe UD) (retrospective studies) Donor are generally readily available Cost is lower than other stem cell sources for graft acquisition Expands HCT to patients with ethnicities under-represented on donor registries 17

18 Cautions Haplo HCT is young, long term outcomes are not well known Many comparative studies have very small numbers Donor may have greater risk than UD (all RD) DSA is a problem Clonal hemopoiesis may be an issue (all RD) Cost overall may not be lower than other stem cell sources 18