The Value of Cord Blood Stem Cells. Mona Shafey, MD, FRCPC Medical Grand Rounds October 25 th, 2011

Transcription

1 The Value of Cord Blood Stem Cells Mona Shafey, MD, FRCPC Medical Grand Rounds October 25 th, 2011

2 Objectives To discuss umbilical cord blood as a stem cell source and the role of umbilical cord blood transplantation (UCBT) in the treatment of malignant and non-malignant disorders in children and adults To describe the outcomes of UCBT in the province of Alberta and the potential strategies used to improve outcome following UCBT To describe the state of cord blood banking in Canada

3 None to declare Disclosures

4 Stem Cells 101 Embryonic stem cells under appropriate microenvironmental influences within the fetus differentiate into all derivatives of the three germ layers (ectoderm, mesoderm, endoderm) Hematopoietic stem cells reconstitute and maintain a functional hematopoietic system over extended periods of time Mesenchymal stem cells differentiate into connective tissue (osteocytes, chondrocytes, tenocytes, adipocytes, muscle cells)

5 Hematopoietic Stem Cells Represent ~1/10 4 bone marrow cells Extensive proliferative capacity estimated 50 million self-renewing pluripotent HSCs in healthy persons giving rise to mature blood cells in a lifetime Pluripotent differentiate to produce major progeny of all myeloid & lymphoid blood cell lineages Self-renewal capacity to replace cells that become progressively committed to differentiation Stem cell plasticity ability to generate cellular components of non-hematopoietic tissues (fibrous tissue, muscle, nerves) Target for leukemic transformation

6 The Value of Cord Blood Stem Cells First successful UCBT in yr old male with severe Fanconi s anemia received an UCBT from a HLA-identical sibling decades later his graft remains durable with no evidence of disease Well-established source of hematopoietic stem cells for allogeneic stem cell transplantation estimated >20,000 patients to date have undergone UCBT for malignant & non-malignant conditions In 2007 in Canada, 68% of all unrelated pediatric stem cell transplants and 9% of adult stem cell transplants were performed with cord blood 1 Gluckman et al. NEJM :

7 The Value of Cord Blood Stem Cells Cord-blood derived embryonic-like stem cells ethical stem cells not quite as primitive as embryonic, but more versatile than adult stem cells Cord blood mesenchymal stem cells regenerative medicine research animal models of Type I DM, brain injury, Parkinson s disease, stroke, cardiovascular repair No clinical application as yet

8 Hematopoietic Stem Cell Transplantation (HSCT) Main goal of treatment: Long-term disease control including cure of disease Main indications for stem cell transplants lymphoma (55%) leukemia/myelodysplasia (32%) solid tumours (8%) non-malignant diseases (5%, e.g multiple sclerosis, aplastic anemia, immunodeficiencies, sickle cell anemia) Two basic types of stem cell transplantation autologous (AUTO) or allogeneic (ALLO)

9 Allogeneic Stem Cell Transplantation 33% of all HSCTs, usually age<65 Malignant conditions when graft-versus-tumour effect is desired immunotherapy for immunologically responsive tumors to avoid relapse after clinical complete remission Non-malignant conditions source of normal stem cells to replace defective stem cells bone marrow failure syndromes replacing defective hematopoiesis correction of inherited immunologic defects inborn errors of metabolism

10 Donor Selection Need to consider impact on transplant outcomes engraftment, graft-vs-host-disease, treatmentrelated mortality, and survival outcomes Options include matched related (10/10) mismatched related (8-9/10) or haploidentical matched unrelated (10/10) mismatched unrelated (8-9/10) cord blood transplantation (related/unrelated, matched/unmatched 4-6/6) Other donor factors to consider are age & gender of donor, CMV status, ABO typing

11 Advantages & Disadvantages of UCBT Advantages Rapid availability median days sooner than unrelated bone marrow Larger donor pool tolerance of 1-2/6 HLA mismatches (4-6/6 HLA-A, -B antigen, DRB1 allele) some ethnic minorities may be better represented Lower incidence & severity of acute GVHD Lower risk of viral transmission (e.g. CMV, EBV) Lack of donor attrition Lack of risk to donor Disadvantages Lower number of progenitor cells & stem cells higher risk of graft failure delayed hematopoietic engraftment limited to children and small adults Increased risk of infection leading to death Not possible to obtain more cells for future treatment (2 nd SCT, DLI) Genetic history of donor unknown

12 The need for cord blood stem cells >840 Canadian patients need a stem cell transplant each year 70% of these patients must look outside of their families for donors Unrelated volunteer registries are limited in ability to provide prompt hematopoietic stem cell source for many patients ethnic minorities in particular

13 National Marrow Donor Program (US)

14 Cord Blood Stem Cell Transplants in Canada by Year

15 Cord Blood vs. Related or Unrelated Marrow/PBSC Donors No randomized trials have compared the transplantation of UCB vs. related or unrelated marrow/pbsc donors Retrospective, comparative data is available for both children and adults

16 UCBT Related Donors Performed almost exclusively in children Eurocord and IBMTR joint study compared children who received UCB from HLA-identical siblings (n=113) to children who received marrow from HLA-identical siblings (n=2052) UCB recipients slower engraftment, lower risk of GVHD no difference in relapse-related deaths, 100-day mortality and overall survival (3-yr OS 64% vs. 66%) authors concluded UCBT as useful as BMT 3-yr OS 86% vs. 84% (non-malignant), 46% vs. 53% for malignant (p=ns for both) Rocha et al. NEJM :

17 Factors Influencing Outcomes After Related HLA-identical UCBT in Children 147 patients with malignancies reported to Eurocord EBMT median age 5 years (range 1-32) acute leukemia 74% Outcomes acute GVHD 12%, chronic GVHD 10% NRM 9% DFS 44%, OS 55% Cell dose, GVHD prophylaxis not including MTX, and disease status at transplantation were important outcome factors Herr Blood :

18 UCBT vs. Unrelated Marrow Donors in Children with Acute Leukemia (n=35) p=0.04 (n=267) Lower rates of agvhd in HLA-matched UCB vs. HLA-matched BM: RR 0.45, p= Similar survival outcomes between BM and 1 or 2 antigen-mismatched UCB. Improved survival seen with HLA-matched UCB. Eapen Lancet :

19 UCBT vs. Unrelated Marrow/PBPC Donors in Adults Largest retrospective EBMT/CIBMTR study comparing leukemia-free survival for UCB, PBPC, and marrow transplantation in 1525 patients aged 16 or older UCB vs. 7-8/8 allele-matched PBPC or BMT comparable leukemia-free survival higher TRM lower GVHD Authors concluded that data support UCB for adults with acute leukemia when no HLAmatched donor available for urgent transplants Eapen Lancet Oncol :653-60

20 TNC dose and HLA-match affect survival via effect on TRM Barker Blood :1843-9

21 UCBT in Calgary N=15 Patient characteristics median age 35 (range 19-63), females 60% high risk disease 6 AML/ALL beyond CR1 5 high risk MDS/AML/ALL in CR1 2 CML-CP2 2 lymphoma CLL-PR3, HD-PR3 FLUBUP/ATG in 14/15 patients CSA prophylaxis alone in 13/15 patients HLA matching 4/6 in 8, 5/6 in 7 median CD34 + cell dose (pre thaw) 1.2 x 10 5 /kg median TNC cell dose (pre thaw) 3.35 x 10 7 /kg

22 UCBT in Calgary N=15 Engraftment median day+18 (14-29) for neutrophils, day+45 for platelets (34-51) 2 patients never engrafted neutrophils, 5 never engrafted platelets GVHD agvhd 3 with stage I, 2 with stage II cgvhd 3 patients Relapse in 2 patients 7 deceased 2 progressive disease 5 infectious complications including one with concurrent PTLPD 8 alive 4 alive and well 1 required second allo-sct for graft failure recurrent viral infections (3), autoimmune disease (2) and PTLPD (1)

23 SURVIVAL ADULT CBT % (N = 15)

24 UCBT vs. Allogeneic SCT with Related/Unrelated Donors Survival Adult Allogeneic SCT Survival mismatched adult UD SCT - by degree of mismatching N=13

25 Strategies to improve outcomes Choice of cord blood unit must take into account: Diagnosis (malignant vs. non-malignant) Cell dose HLA incompatibility Accelerating engraftment Increasing cell dose improved collection techniques ex vivo expansion of cord blood cells Double unit cord blood transplantation Direct intra-bone infusion of cord blood stem cells Reducing condition-related mortality Improving immune reconstitution infection is the main cause of death (~50% of TRM)

26 Patients with Malignant Disease Single UCBT Cell dose found to be the most important factor >3x10 7 nucleated cells/kg at collection Increased number of HLA mismatches associated with delayed engraftment TRM chronic GVHD decreased relapse no effect on OS, PFS Similar findings in patients with non-malignant disease but higher cell dose required >4.9 x10 7 nucleated cells/kg TRM DFS N=925 Gluckman & Rocha Curr Opin Immunol :565-70

27 Eurocord Proposed Algorithm for Cord Blood Unit Choice Malignant disorders CBU with 6/6 or 5/6 HLA match HLA-A or HLA-B mismatch preferred over DRB1 Nucleated cell dose at freezing x10 7 /kg Nucleated cell dose at thawing x10 7 /kg CD34 + cell dose at freezing/thawing x10 5 /kg CBU with 4/6 HLA match HLA-A or HLA-B mismatch preferred over DRB1 Nucleated cell dose at freezing 3.5 x10 7 /kg Nucleated cell dose at thawing 3.0 x10 7 /kg CD34 + cell dose at freezing/thawing >1.7 x10 5 /kg If criteria above for single UCBT is not achieved, a double CBT should be considered Other considerations HLA antibodies (more important for non-malignant disorders) Accredited cord blood bank and location ABO compatibility Allele HLA typing of HLA-A and -B Rocha Biol Blood Marrow Transplant :S126-32; Rocha BJH : ; Gluckman Exp Haematol :

28 UCBT in Calgary N=15, Patient Age & Sex HLA Matching pre-thaw CD34 count (x10 5 /kg) pre-thaw TNC dose (x10 7 /kg) Current Status 1 35F 4/6 4.3 Alive and well Y 2 21M 5/ nd Sib-SCT for graft failure, recurrent infx, AVN of hips, adrenal insufficiency 3 45M 4/6 1.4 Deceased - PD N 4 63F 4/6 1.3 Deceased MOF, pneumonia N 5 28F 4/ Alive, CDIP, AIHA, AIN, PTLPD, shingles 6 39F 4/ Deceased PD N 7 32F 5/ Deceased CMV/pneumonia N 8 41F 5/ Alive and well Y 9 55M 4/ Deceased enteritis, pneumonia 10 35M 4/ Alive, CMV pneumonia, AIHA N 11 30F 5/ Alive, Viral pneumonia, HPV Y 12 53M 5/ Deceased H1N1 N Met minimum cell dose criteria [Eurocord]? Y/N N N N 13 32F 5/ Deceased PTLPD, CMV/EBV/adenovirus 14 19M 5/ Alive and well N 15 39F 4/ Alive and well Y N *

29 Double Unit Cord Blood Transplants Single unit UCBT is limited by low total nucleated cell dose Double unit UCBT as a strategy to augment cell dose of the graft has been successful with improved sustained donor engraftment and posttransplantation survival compared with historic single unit controls sustained hematopoiesis is accounted for by only 1 of the 2 units, with demonstration of dominance as early as Day+21 post-transplant higher CD3 + cell doses and % of CD34 + cell viability associated with unit dominance Avery Blood :

30 Double Cord Blood Transplantation Preliminary data support the use of the procedure to overcome cell dose barrier in adults Myeloblative UCBT study (n=177) higher agvhd (48% vs. 29%) and cgvhd (18% vs. 10%) lower risk of relapse in double unit recipients vs. single at 5- years (19% vs. 34%) leukemia-free survival in this study was 40% with single UCBT and 51% for double UCBT (p=0.35) Verneris Blood :

31 Transplantation of Ex Vivo Expanded Cord Blood Currently being studied in attempt to improve time to engraftment and reduce the graft failure rate Feasibility study of 37 patients fraction (40-60%) of each patient s CB allograft was CD34- selected and culture ex-vivo for 10 days prior to transplantation patients received a median of 0.99x107/L total nucleated cells (expanded + unexpanded) per kg median time to neutrophil engraftment was 28 days, platelet engraftment 106 days acute GVHD in 40%, extensive chronic GVHD in 63% patients! 35% survival at 30 months Clinical efficacy still under study Shpall Biol Blood Marrow Transplant :

32 Intrabone Infusion of Cord Blood Thought to decrease cell loss during circulation before homing First performed in mice 1 intrabone infusion of CD34 + cord blood cells conferred engraftment advantage 15x greater than after IV infusion Phase I/II trial of 32 adults with acute leukemia transplanted with mean dose of 2.6 x10 7 /kg infused into the posterior iliac crest 2 median time to engraftment was 23 days for neutrophils, 36 days for platelets 16 patients alive and in remission at 13 month F/U Cells 1 Castello et al. Exp Hematol : Frassoni et al. Lancet Oncol :831-9

33 Cord Blood Banking Exists for the purpose of storing cord blood for future transplantation Regulation & Accreditation All banks are regulated (e.g. FDA in US) Accreditation by Netcord-FACT standards to promote highquality cord blood banking and clinical use of UCB for SCT this is voluntary 3 types of banks public private directed (sibling) for families who have a child or other family member with a potentially transplant-treatable disease and who are expecting another child reserved for use by the family

34 Public Cord Blood Banks Collect and store cord blood units for use by any individual who has a medical indication for HSCT Voluntary donation by women delivering healthy term babies Public database accessible to health care providers >600,000 units stored worldwide in ~112 public cord blood banks in 52 countries Usually non-profit Only available in a limited number of hospitals Not guaranteed to be available later to original donor or their family

35 Cord Blood Banking in Canada With the lack of a national public cord blood bank Canada is far behind the rest of the world Canadian transplant centres rely on units imported internationally, at a cost of ~$37K per unit 3 small public banks Héma-Québec (funded), Alberta Cord Blood Bank, Victoria Angel Registry of Hope (Ontario) total inventory ~1500 cord blood units Funding for Canada s first national, publicly-funded umbilical cord blood bank announced March 14, 2011 To be developed and managed by Canadian Blood Services on behalf of the provinces and territories except Québec $48 million committed, with $12.5 million to be fund-raised by Canadian Blood Services over the next 3 years

36 National Umbilical Cord Blood Bank First phase (Operational by April 2013) The national public bank will first begin in Ottawa and will include an accredited stem cell lab, collections at hospitals Second phase (Fall 2014) Expansion nationally to have collections of cord blood in Toronto, Vancouver, and Edmonton hospitals Second accredited stem cell lab in Edmonton Kits to be developed to be made available to hospitals across Canada that are not part of the national collection network Target inventory of 20,000 UCB units by 2019 Canadian cord blood units will be provided at no charge to Canadian hospitals, and will be made available internationally at a competitive price

37 Cord Blood Donation Donor selection screening questionnaire for both parents infectious diseases, inherited diseases, malignancy maternal blood testing hepatitis, HIV, CMV, syphilis, HTLV-I/II, WNV Labour & delivery factors heavier babies, larger placentas, longer gestations, and women with fewer live births associated with higher cell counts earlier clamping of the cord also increases collection volume, but at higher risk to the baby Cesarean delivery associated with higher counts Key principles must not interfere with delivery of the baby & must never compromise the safety of the mother or the infant sterility of collection maximization of volume collected (i.e. # of stem cells)

38 Private Cord Blood Banks Provide a for-profit service for families who are willing to pay for advertised life-saving biological insurance initial processing fee (~$1750) and annually ($125/yr) for continued storage Reserved for use by the family as a source of stem cells for the child or another member of the family should the need arise ~800,000 units in >130 banks worldwide Promise more than can be delivered at this point in time theoretical options in regenerative medicine, focus on the potential uses Ethical issues Who owns the cord blood unit the child or the parents? What happens to the unit if the family stops paying the storage fees?

39 Should I store my infant s cord blood? What is the future need for stem cells? estimated that 1 in 20,000 collections performed in families without any medical indication may be used for autologous transplantation Allogeneic stem cells preferred in most cases Leukemia leukemia-free graft & for graft-vs.-leukemia effect 1 reported case of using autologous cord blood for leukemia 1 Non-malignant conditions sickle cell disease, thalassemia, immunodeficiencies Availability of alternatives autologous peripheral blood stem cells can be obtained in most patients Should be strongly considered in families within which a transplant-treatable disease exists Routine storage of cord blood as biologic insurance not recommended by both Pediatric & Obstretrics Societies however, theoretical application of stem cell technologies for other diseases (e.g. spinal cord injury, diabetes, parkinson s disease, etc.) is unknown interpreted as you don t have to, but I can t tell you not to 1 Hayani et al. Pediatrics :

40 Summary Key points Umbilical cord blood is increasingly being used as a stem cell source for patients who require stem cell transplantation UCBT appears to be an acceptable alternative to matched unrelated BM in children UCBT is feasible in adults lacking an HLA-matched donor selection should be based on urgency of the transplant, UCB cell dose & HLA compatibility Applications for umbilical cord blood stem cells in regenerative medicine and other therapies is an active area of research but without practical application currently A national public cord blood bank is finally coming to Canada voluntary donation should be offered to all women delivering term infants