Cord Blood: that other stem cell source. Donna Wall, MD Director, Manitoba Blood and Marrow Transplant Program

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1 Cord Blood: that other stem cell source Donna Wall, MD Director, Manitoba Blood and Marrow Transplant Program CBMTG April 2012

2 The problem: In order to perform a BMT from one person to another one needs a sufficiently immunematched donor so that the new blood making system will accepted by the body AND develop a functional immune system Immune matched sibling in only about 20% of families Unrelated adult donor Partially matched donor (haploidentical)

3 Objectives: To review the potential of cord blood as an alternative donor source To identify current limitations and opportunities in incorporating cord blood in your search/transplant strategy

4 What is (umbilical) cord blood? Cord blood is the blood retained in the placenta after delivery of the infant Rich in hematopoietic progenitors Low viral contamination The immune cells contained in the graft are tolerant to fetal-maternal immune differences

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6 Cord blood and Hematopoietic Stem/Progenitor Transplantation A single cord blood unit contains sufficient hematopoietic progenitors to result in durable engraftment Engraftment/count recovery correlates with the number of cells in the cord blood unit Low viral contamination in cord blood and hence low viral immunity Cord blood immune cells are more tolerant and are associated with less graft vs. host disease especially chronic GVHD

7 Advantages of cord blood: Rapidly available Flexibility in timing of transplant HLA mismatches are tolerated with acceptable GVHD with current inventories 95% of children will have at least a 4/6 HLA antigen matched unit Banks can be adjusted to increased ethnic (HLA) diversity Less chronic Graft-vs-Host disease

8 Limitations of cord blood Limited number of cells in a unit Generally transplanting with one log fewer nucleated cells and CD34+ cells Longer time to recovery of neutrophils and platelets One time infusion No opportunity to collect additional cells from the donor Nonengraftment is a problem must have a nonengrafment plan PRIOR to start of transplant

9 Improved hematopoietic progenitor cell reservoir following cord blood vs. bone marrow transplant 2 groups of children: 12 CB recipients and 12 adult BM recipients Recipients of BM transplants received 10-fold more cells and had significantly faster neutrophil and platelet recovery At 1 year after transplantation, the frequency of colonyforming cells (CFCs) and long-term culture initiating cells (LTC-ICs) were compared Frassoni et al, Blood 102:1138

10 Comparison of marrow hematopoietic progenitors following CB vs BM transplant Cord Blood Recipients (n=12) Bone Marrow Recipients (n=12) CFC/2 x 10 4 BM mononuclear cells P =.007 LTC-IC/10 6 BM mononuclear cells P =.001

11 The supply of unrelated donor cord blood is dependent on the network of public cord blood banks World-wide inventory of over 600,000 units Cell dose in units is increasing Increasing representation of ethnic minorities

12 The quality of cord blood units is improving Accreditation and coordination of cord blood banks NETCORD/FACT accreditation National/international effort to coordinate the banks Strong infectious screening and testing limitations in identifying serious hematologic/immunologic disorders With the long storage periods there has been no indication of loss of potency Approaches developed to confirm product identity and hematopoietic progenitor viability

13 Congratulations Héma-Québec FACT accreditation obtained this year Over 6,000 searchable units 20 units released for transplant Median time to neutrophil recovery days Median time to platelet >50 50 days We are now starting to see potential matches for our First Nations patients Smaller public banks in Toronto and Edmonton Fournier, et al CBMTG 2012

14 OneMatch Public Cord Blood Bank The national model includes at least 4 collection cities and 2 labs for processing, storage and distribution. NOTE we will also be working on cord blood collection kits that can be sent to targeted areas outside of the cities listed below, e.g. Aboriginal communities Canadian Blood Services Medical and Scientific Advisory Committee OneMatch National Public Cord Blood Bank (inventory of 20,000 units within 8 years*) Searching, Matching Ottawa Lab Edmonton Lab CBS Support HLA Testing Transmissible Disease Testing CBS Research Ethics Committee (units unsuitable for transfusion) Marketing & Recruitment Canadian Transplant Programs Ottawa Hospitals Edmonton Hospitals Canadian Research Scientists International Registries Toronto Hospitals Vancouver Hospitals *Optimal size of a national cord blood inventory is currently thought to be approximately 20,000 units, which can be achieved within 8 years using this Model. Courtesy of Sue Smith, OneMatch

15 Timelines Phase I will take approximately 2 years, as this is when key pieces of infrastructure (i.e. IT and lab), as well as SOPs will be developed and implemented. With those key components in place, Phase II expansion is expected to take approximately 1 year. FY 2011/12 FY 2012/13 FY 2013/14 FY 2014/15 Ottawa Collection Hospital & Lab Phase I Edmonton Collection Hospital & Lab Vancouver Collection Hospital Toronto Collection Hospital Phase II Phase II Phase II Courtesy of Sue Smith, OneMatch

16 Public cord blood banking is costly Despite heavy support by national bodies the cost of units is high and likely to increase $25-40,000/unit This will not be a made in Canada project We need to use the best products for our patients

17 Cell processing laboratory has an important role The cell product is much smaller than the lab is used to working with. Important to practice thaws Minimize cell loss Contingency plan to handle broken bags Validated thaw procedure Most labs use a modified Rubinstein method (dextran/albumin) Thaw and dilute vs. thaw and wash (avoid centrifugation) vs. bedside thaw and infuse

18 Evolving strategies in selecting cord blood unit(s) for transplantation Size matters TNC vs CD34 vs CFU Nucleated red cells (0-50% of TNC) HLA matching Historically low resolution HLA A and B with high resolution HLA DR have been used in cord blood selection

19 Cell dose is the only consistent factor impacting cord blood outcomes For other stem cell sources we are routinely well above engraftment threshold Rich marrow -- > 3x10 8 nucleated cells/kg Minimum 1 x 10 8 nucleated cells/kg PBPC target 5 x 10 6 CD34/kg recipient Minimum 2 x 10 6 CD34/kg Cord blood is much closer to that threshold TNC target 5 x 10 7 TNC/kg Minimum 2-3 x 10 7 TNC/kg

20 Time to count recovery, engraftment, survival, transplant related morbidity all correlate with cell dose. Difficult to find >2 x 10 7 TNC/kg in adults hence the move to double cord blood transplants One unit usually ends up being a bridging unit We take one best match then second largest Issues with possible infusional toxicity complete one infusion prior to thaw of second unit.

21 Other approaches to improving engraftment Expansion of hematopoietic stem/progenitors Bridging grafts Coinfusion of pooled cord blood products (Peletier) Coinfusion of CD34 selected haploidentical cells Coinfusion of expanded cord blood using activation of the Notch signaling pathway Altering SDF1- CXCR4 axis to enhance homing (Marquez-Curtis) Intrabone infusion

22 Is the cord HLA convention correct? Low resolution HLA A and B with high resolution DR NHLBI COBLT trial utilized units selected by convention but then typed to high resolution No impact on survival, GVHD or engraftment

23 CIBMTR analysis of the effect of donor-recipient HLA-A,B,C and DRB1 on survival 92/803 patients receiving single unit CBT for leukemia or myelodysplastic s were matched at HLA A,B,DR 69 patients were matched at HLA C and compared to 23 who had HLA A, B, DR matching but mismatched at C The HLA C matched patients had lower transplant related mortality (HR % CI ; p=0.018) No difference in survival Transplant mortality risk in general increased with increasing degree of mismatch Issue of competing variables (cell dose and HLA matching) Eapen et al Lancet Oncology Oct 2011

24 The noninherited maternal allele The fetus is a half immunologic match to mother If the HLA mismatches in a cord blood transplant results in reexposure of the cord blood to the HLA antigens that it had already seen in utero there is better transplant outcome Van Rood et al, PNAS :19952

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26 Reduced Intensity Transplantation: Comparison of double cord blood to other donor sources CIBMTR registry report of RIC transplants : 523 AML, 50 ALL Cord blood HLA matching by cord convention 85% were double cords (ducb) 70% mismatched at 2 of 6 antigens Prep regimen TBI200/cy/flu (N=120) vs other (alkylator/flu/ with ATG in most, N=40) 20 centers, only 2 centers >10 One center contributed 89/121 TCF Brunstein, Blood epub April 10, 2012

27 PBPC were separated into 8/8 vs 7/8 1/3 received regimens which included LD TBI No center effect detected ducb-tcf had better pretransplant performance status and greater number in CR at transplant ducb-other were younger, more were CMV positive, 30% had active disease at txp

28 Leukemia-free survival for patients transplanted in remission

29 Transplant-related mortality

30 Probability of neutrophil recovery

31 No difference in relapse agvhd in cords mostly grade II cgvhd is a major difference ducb-tcf vs 8/8 or 7/8 PBPC RR 0.43 ( ) p<0.001 Similar reports from EBMT (Rocha, Curr Opin Onc 2009) and BMTCTN multicenter trial (Brunstein, Blood 2011)

32 Manitoba unrelated donor search strategy Preliminary search identifies if there are many vs. few potential matches on the adult registries Cord search immediately (with separate query to HémaQuébec) if timing is tight or if few/no potential matches on registry We routinely assess both cord and adult donor options In the past 3 years we have had only 2 patients who did not have a graft available at the time they were ready for transplant. During that time approximately 45 unrelated donors and 6 cord blood donors for adult patients.

33 Cost is an issue However with less chronic GVHD the total health care spending may not be different. Importance of a Canadian transplant registry coming soon

34 Special circumstance: the expectant family with a known risk factor for needing an allogeneic transplant Child or known family risk for thalassemia, sickle cell anemia, other inherited blood disorder treated by allogeneic transplant Child with leukemia who may need transplant Manitoba Family Cord Blood Bank Remember the cord blood donor will be an HLA match

35 Cord blood is an important alternative donor option in transplantation Rapidly available, tolerant of immune mismatches, less graft-vs.-host disease especially cgvhd Public banking must be supported Banking cord blood in high risk families is reasonable

36 Thank you and we hope to see you in Winnipeg for CBMTG 2013!

37 The Haunted??? Hotel Fort Garry

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