The donor search: the best donor or cord blood unit

Transcription

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

2 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

3 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

4 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

5 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

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

7 Bone Marrow Donors Worldwide Total > 23 million donors ~23, UD ~ UCB 73 stem cell donor registries from 52 countries 47 cord blood banks from 33 countries

8 Numbers of HLA antigens and alleles

9 HLA scoring algorithm VF F R VF H M L F M M L R L L L Success: 90%, median 22 days 58% H 29% M 10% L 20 3% VL Hirv et al, BMT 2009

10 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

11 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

12 Map of the human MHC on chromosome 6

13 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

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

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

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

17 % 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) DPB1 match (n=72) DPB1 mismatch (n=189). 2 P= 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

18 IHWG study 5932 transplants: Acute graft versus host disease Number DPB1 Mismatches Number DPB1 Mismatches Adjusted Model for Acute GvHD Odds Ratio 95% CI p-value Grades II-IV Grades III-IV < Shaw et al, Blood, 2007

19 p=.0001 Shaw et al, Blood, 2007

20 Shaw et al, Blood, 2007

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

22

23 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

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

25 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

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

27 Multivariate Analysis - Donor Age Age years 1.46 Age 50 years Mortality Baseline age: years Engraftment AGVHD CGVHD Mortality Baseline age: years Engraftment AGVHD CGVHD

28 Multivariate Analysis - Donor-recipient ABO match Baseline: ABO Match Minor ABO MM Major ABO MM Overall survival Overall survival

29 Donor CMV matching P=0.011

30 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

31 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) CD x 10 5 /kg Rocha, Gluckman et al, BJH, 2009

32 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 Survival 5/6 Match 4/6 Match 5/6 match 4/6 match Cell Dose ( 10 7 /kg) 70% >10 50% % < <2.5 time after transplant 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) : Abstract 333

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

34 Probability, % Children with Acute Leukemia: Treatment-related Mortality 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% Months Eapen M et. al. Lancet 2007

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

36 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/ ( ) /234 vs 23/ ( ) /293 vs 17/ ( ) Eapen et al, Lancet Oncology, 2011

37 HLA: High resolution Eapen, Blood, 2014

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

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

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

41 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 (> ) 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

42 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

43 Quality of UCB Querol, S. BMT 2010

44 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

45 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

46 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

47 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