The donor search: the best donor or cord blood unit

The donor search: the best donor or cord blood unit Dr Bronwen Shaw Consultant in haematopoietic cell transplantation Royal Marsden Hospital /Anthony Nolan

Overview Where do we find donors/units for transplantation Stem cell sources Availability HLA Factors that influence our choice of unrelated donor HLA Other genetic factors Other donor characteristics Factors that influence our choice of cord blood unit HLA Cell numbers Quality and other factors An algorithm for selection

The HLA Family A1 A2 A3 A26 Cw7 Cw5 Cw7 Cw8 B8 B44 B7 B14 A1 A3 A1 A26 A2 A3 Cw7 Cw7 Cw7 Cw8 Cw5 Cw7 B8 B7 B8 B14 B44 B7

The HLA Family A1 A2 A3 A26 Cw7 Cw5 Cw7 Cw8 B8 B44 B7 B14 A1 Cw7 B8 A3 Cw7 B7 A1 A26 Cw7 Cw8 B8 B14 A2 Cw5 B44 A3 Cw7 B7 A1 Cw7 B8 A3 Cw7 B7

The HLA Family A1 A2 A3 A26 Cw7 Cw5 Cw7 Cw8 B8 B44 B7 B14 A1 Cw7 B8 A3 Cw7 B7 A1 A3 A1 A26 A2 A3 Cw7 Cw7 Cw7 Cw8 Cw5 Cw7 B8 B7 B8 B14 B44 B7

Stem cell source HLA-identical sibling First choice Unrelated donor Availability 1/3 in caucasian population >23 million donors worldwide Cord blood ~600 000 cords Other related donor Haploidentical Inevitably

Bone Marrow Donors Worldwide www.bmdw.org Total > 23 million donors ~23,000.000 UD ~600.000 UCB 73 stem cell donor registries from 52 countries 47 cord blood banks from 33 countries

Numbers of HLA antigens and alleles 1968-2014

HLA scoring algorithm VF F R VF H M L F M M L R L L L 100 80 60 40 20 25 37 Success: 90%, median 22 days 58% H 29% M 10% L 20 3% 50 100 150 200 VL Hirv et al, BMT 2009

Not all donors are available Proportion of patients affected by at least 2 incidences of donor attrition (p<0.059) Other ethnicity White Northern European 0% 10% 20% 30% 40% 50% Lown, ASH, 2013

Why is HLA so important? Human Leukocyte Antigen Discovered: in mice (1937), humans (1954) Function: to present peptides to T cells, thus allowing elimination of foreign particles and recognition of self (so in transplants this has to be modulated) HLA is in the MHC on Chr6: One of the most genedense regions of the genome

Map of the human MHC on chromosome 6

Overview Where do we find donors for transplantation Stem cell sources Availability HLA Factors that influence our choice of unrelated donor HLA Other genetic factors Other donor characteristics Factors that influence our choice of cord blood unit HLA Cell numbers Quality and other factors An algorithm for selection

Impact of HLA mismatches on OS 1454 patients Lee et al, Blood 2007; 110:4576-83

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. 2007 by American Society of Hematology Lee S J et al. Blood 2007;110:4576-4583

Impact of HLA matching on overall survival (10/10) 727 patients

% R e l a p s e The impact of DPB1 matching in 282 UD transplant pairs matched from HLA A - HLA DQB1 (10/10 alleles) 1. 0. 8 DPB1 match (n=72). 6. 4 DPB1 mismatch (n=189). 2 P=0.001 0. 0 0 5 0 0 1 0 0 0 1 5 0 0 2 0 0 0 2 5 0 0 3 0 0 0 D a y s u n t i l R e l a p s e Cox regression: DP mismatch HR 0.56 (p=0.004) Shaw et al, Blood, 2006

IHWG study 5932 transplants: Acute graft versus host disease Number DPB1 Mismatches 0 1 2 Number DPB1 Mismatches 0 1 2 Adjusted Model for Acute GvHD Odds Ratio 95% CI p-value Grades II-IV 1 1.31 1.36 Grades III-IV 1 1.18 1.26 --- 1.14-1.50 1.18-1.57 --- 1.01-1.36 1.08-1.48 ---.0001 <.0001 ---.03.004 Shaw et al, Blood, 2007

p=.0001 Shaw et al, Blood, 2007

Shaw et al, Blood, 2007

DPB1- permissive mismatch: HVR A B C D E F

Donor DPB1 TCE group Functional T cell epitope (TCE) Matching DPB1 TCE Classification TCE Group T Cell Epitope DPB1* Alleles Immunogenicity 12/12: 20% matched 1 TCE-3 and TCE-4 2 TCE-3 and TCE-4 09:01 10:01 17:01 03:01 104:01 14:01 45:01 86:01 02:01 TCE3: 50% permissive TCE4: 30% permissive 3 TCE-4 02:02 02:03 4 Lowest Immunogenicity Others Recipient DPB1 TCE group Algorithm Group Matching 1/1 1/2 1/3 1/4 2/2 2/3 2/4 3/3 3/4 4/4 Algorithm for DPB1 TCE Matching 1/1 1/2 1/3 1/4 2/2 2/3 2/4 3/3 3/4 Permissive Non permissive GvH Non permissive HvG Permissive Permissive 4/4 Perm

Survival in 10/10 matched transplants IHWG Hematopoietic Cell Transplantation Working Group

Selection algorithm 12/12 (20%) agvhd TRM Relapse OS = TCEM (~ 50%) TCED (~ 30%) OS TRM agvhd Relapse = 10/10 (80%) OS TRM agvhd Relapse = OS similar and significantly better than TCED Higher incidence of complications Avoid IHWG Hematopoietic Cell Transplantation Working Group

Non-HLA genetics type of matching Haplotypes Next generation sequencing IRG (SNPs) NOD2, TGF, IL10 Other complex systems KIR

Multivariate Analysis - Donor Age - 1.60 1.50 Age 33-50 years 1.46 Age 50 years 1.40 1.30 1.29 1.33 1.20 1.10 1.00 0.80 1.20 1.13 1.05 1.15 0.96 0.80 1.16 1.09 1.02 1.11 1.03 0.95 1.14 1.09 0.78 1.17 1.03 1.16 0.99 0.84 0.50 0.56 0.00 Mortality Baseline age: 18 32 years Engraftment AGVHD CGVHD Mortality Baseline age: 18 32 years Engraftment AGVHD CGVHD

Multivariate Analysis - Donor-recipient ABO match - 1.60 1.60 1.50 1.50 1.40 1.40 1.30 1.30 1.20 1.21 1.21 1.20 1.10 1.10 1.13 1.10 1.00 1.05 1.05 1.00 0.80 0.80 0.50 Baseline: ABO Match 0.50 0.00 0.00 Minor ABO MM Major ABO MM Overall survival Overall survival

Donor CMV matching P=0.011

Overview Where do we find donors for transplantation Stem cell sources Availability HLA Factors that influence our choice of unrelated donor HLA Other genetic factors Other donor characteristics Factors that influence our choice of cord blood unit HLA Cell numbers Quality and other factors An algorithm for selection

HLA matching Selection criteria: HLA and cell dose Standard criteria for CB HLA A and B (intermediate resolution) DRB1 (allele-level) Allele-level HLA typing at A and B are generally not considered Matching at HLA-C is not considered A or B mismatch preferable to DRB1 mismatch TNC 5/6: Minimum 2.5 x10 7 /kg (at freezing) 2.0 x10 7 /kg (after thawing) 4/6: Minimum 3.5 x10 7 /kg (at freezing) 3.0 x10 7 /kg (after thawing) CD34 1.2 1.7 x 10 5 /kg Rocha, Gluckman et al, BJH, 2009

Impact of cell dose and HLA Match on survival. Data presented by Dr Pablo Rubinstein at the 5 th International Umbilical Cord Blood Symposium held in Los Angeles in May 2007. Survival 5/6 Match 4/6 Match 5/6 match 4/6 match Cell Dose ( 10 7 /kg) 70% >10 50% 5.0-9.9 30% <2.5 2.5-4.9 <2.5 time after transplant 12 12 24 Barker J et al. The Dose-Match Interaction in Umbilical Cord Blood (UCB) Transplantation: An Analysis of the Impact of Cell Dose and HLA-Match on the Disease-Free Survival (DFS) of 989 Patients Transplanted with Single Units for Hematologic Malignancy. Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 333

Probability, % Children with Acute Leukemia: Neutrophil Recovery 100 80 BM (n=116), 97% CB matched (n=35), 85% CB MM high dose (n=362), 79% 60 CB MM low dose (n=97), 64% 40 20 0 0 20 40 60 80 100 Days Eapen M et. al. Lancet 2007

Probability, % Children with Acute Leukemia: Treatment-related Mortality 100 80 60 CB 1-Ag MM high (n=157) 29% CB 2-Ag MM (n=267) 49% 40 CB 1-Ag MM low (n=44) 43% 20 BM matched (n=116) 19% 0 0 CB matched (n=35) 6% 12 24 36 60 Months Eapen M et. al. Lancet 2007

Adjusted Probability, % Children with Acute Leukemia: Leukemia-free Survival 100 80 CB matched (n=35) 60% CB 1-Ag MM high (n=157) 45% BM matched (n=116) 38% 60 40 20 0 0 CB 2-Ag MM (n=267) 33% CB 1-Ag MM low (n=44) 35% Relapse at HCT RR 1.69, p<0.001 12 24 36 48 60 Eapen M et. al. Lancet 2007 Months

Results of multivariate analysis for transplant-related mortality Mismatch at C vs match at C Number of events over number that could be assessed Hazard ratio (95% CI) p value Zero mismatch at A, B, or DRB1 One locus mismatch at A, B, or DRB1 Two loci mismatch at A and/or B and/or DRB1 6/23 vs 6/69 3 97 (1 27 12 40) 0 018 66/234 vs 23/127 1 70 (1 06 2 74) 0 029 101/293 vs 17/57 1 25 (0 74 2 09) 0 404 Eapen et al, Lancet Oncology, 2011

HLA: High resolution Eapen, Blood, 2014

Nonrelapse mortality and overall survival. Eapen M et al. Blood 2014;123:133-140 2014 by American Society of Hematology

Nonrelapse mortality by total nucleated cell dose. Eapen M et al. Blood 2014;123:133-140 2014 by American Society of Hematology

The relationship between the infused cell doses of the dominant unit and neutrophil engraftment. Avery S et al. Blood 2011;117:3277-3285

What about quality? Characteristics of 5267 CBUs donated to the Carolinas Cord Blood Bank were retrospectively analyzed High-quality CBUs were defined as those with higher post- TNCC (>1.25 10 9 ) with CD34+ and CFUs in the upper quartile Factors associated with higher CD34+ or CFU content included a shorter interval from collection to processing (<10 hr), younger gestational age (34-37 weeks; CD34+ and CFUs), Caucasian race, higher birth weight (>3500 g), and larger collection volumes (>80 ml) Page et al, Transfusion, 2014

UK consensus: WHICH UNIT OR UNITS? Search step Search criteria Comments 1st Cell Dose Same cell dose required for RIC and MAC >3.0 x10 7 NC/kg and/or >1x10 5 CD34+/kg 2nd HLA match 0-1 MM better than 2 - avoid 3-4 MM Avoid 4/8 units Prefer class I mismatches to class II Avoid C MM 3rd Transplant indication Malignant diseases: cell dose (>3.0x10 7 NC/kg ) is the best prognostic factor because HLA differences reduce relapse (GVL) Non malignant diseases: increase cell dose (>5.0x10 7 NC/kg ) and find the best HLA match (avoid CB 4/8 units) 4 th Other considerations (if several options available) ABO important only in RIC setting Cord bank accreditation and location Notes: Where a single unit meeting these criteria cannot be identified, a double unit may be used

Quality of UCB Querol, S. BMT 2010

Overview Where do we find donors for transplantation Stem cell sources Availability HLA Factors that influence our choice of unrelated donor HLA Other genetic factors Other donor characteristics Factors that influence our choice of cord blood unit HLA Cell numbers Quality and other factors An algorithm for selection

Adult malignant disease Choice Family Donor Unrelated Donor Unrelated CB 1st MFD (BM, PBSC or CB) - - 2nd - 10/10 9/10 8/10 (with one DQ mismatch) 6-8/8 (>3x10 7 ) 3rd Haplo FD (on trial) 8/10 with TCD 5/8 (>5x10 7 ) Shaw et al, BMT, 2009; unpublished, 2014

Who selects the graft? Graft Identification and Advisory Service To provide the BEST available graft (unrelated/cord) to all patients requiring an allogeneic transplant (allomandatory) in a TIMELY manner in order to improve clinical outcome Takes into account HLA haplotypes and LD irrespective of level of available typing Takes availability into account Takes other donor factors into account Searches for UD and cord in a simultaneous algorithm based on availibility Platform for investigating novel selection criteria

Conclusions Donors are available for most patients Unrelated donors HLA matching critical for optimal outcomes Other genetic factors likely to be relevant Donor age impacts on OS, but impact of other donor characteristics less certain Umbilical cord blood trade off between HLA matching and cell dose Quality indicators are important Strategies for selection and rapid acquisition are critical