Beyond Cell Dose: Selection of the Optimal Umbilical Cord Blood Unit. Karen Ballen, MD Massachusetts General Hospital June, 2012

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1 Beyond Cell Dose: Selection of the Optimal Umbilical Cord Blood Unit Karen Ballen, MD Massachusetts General Hospital June, 2012

2 OUTLINE Cell Dose HLA Typing HLA C and KIR HLA Antibodies ABO and Racial/Ethnic Match Cord Blood Banking Techniques

3 Cord Blood: Critical Concerns One time donation Cost--$40,000 per cord blood unit Cell dose important factor for engraftment Nucleated cell dose > 3.7x10 7 /kg most important factor for neutrophil engraftment Average size banked unit 120 x10 7 NC, not sufficient for adult transplant US 10 kg heavier than Europe,15 kg heavier than Asia

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5 Cord Blood: Critical Concerns Expansion of Cord Blood Units Ex vivo expansion trials Pooling of Cord Blood Units Double Cord Blood Transplants Cord Blood + Haplo Transplant Improved Collection/Banking Techniques Larger Volume Units Optimal CB Unit Selection

6 Adult Single Myeloablative Transplant Importance of Cell Dose 68 patients, 71% mismatched at 2 antigens 90% neutrophil engraftment 40% 100 day transplant-related mortality 26% disease-free survival Survival correlated with cell dose, CD 34+ count Most common causes of death: infection (n=22), regimen-related toxicity (n=17) Laughlin et al, NEJM 2001

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8 Multiple Cell Dose Strategies Double vs Single Cord? CTN Randomized Pedi Study Single Cord and Haplo Transplant-Reduced Intensity Engraftment on Day 11, 1 year PFS 42% Direct Intrabone Transplant of Single Cord-Myeloablative Engraftment on Day 23, 1 year OS 45% Expansion of Single Cord in Single or Double Cord Transplant PGE 2 Incubation, Engraftment Day 17, 75% 6 month DFS Liu et al, Blood 2011 Frassoni et al, Lancet Oncology 2008 Cutler et al, ASH 2011

9 Importance of HLA Match Higher Incidence of GVHD and Prolonged Platelet Recovery with Class I and II HLA Mismatches HLA Match Most Important when Cell Dose Low Survival best with 6/6 matched cord blood unit in children Interaction of HLA and Cell Dose 1061 Patients, Myeloablative Conditioning 6/6 Match, Lowest TRM, Regardless of Cell Dose 1 mismatch x10 7 NC/kg equal to 2 mismatch with > 5.0 x 10 7 NC/kg Gluckman et al, Exp Hemat 2004 Eapen et al, Lancet 2007 Barker et al, Blood 2010

10 High Resolution HLA Typing Most Programs, HLA A, B Intermediate Level, DR Allele Level Boston (Massachusetts General/DFCI/BIDMC) Approach Cord Blood Units 4/6 (HLA A, B, DR) Allele Level Match with Patient and with Each Other Neutrophil (p=0.006) and Platelet (p=0.033) Engraftment Faster if HLA-B Matched Lower Risk of GVHD if Matched at HLA-DR (only in patients treated with Cya/MMF) HLA Match No Effect on OS, DFS, Cord Predominance M Delaney et al, Transfusion, 2008

11 Importance of Matching at HLA-C Conflicting Studies All Single Cord, Myeloablative, Mostly Children Eurocord, 619 Patients Mismatch at HLA C no Effect on Count Recovery, Acute GVHD, and Survival CIBMTR/Eurocord,803 Patients Mismatch at HLA-C Increased Transplant Related Mortality Which is Better, Match at HLA C or HLA DR? Rocha et al, Brit J Hematol 2009 Eapen et all,lancet Oncology 2011

12 KIR Typing Early report in Haplo AML Patients: Anti-AML Effect with Class I mismatch that generates donor NK reactivity toward patient Conflicting Results in Both MUD and Cord Blood Transplants Myeloablative Patients KIR-L Mismatch no Effect on GVHD, TRM, Relapse, Survival Reduced Intensity Patients KIR-L Mismatch Increased GVHD, Risk of Death Brunstein et al Blood 2009 Willemze et al Best Pract Clin Hemat 2010

13 NIMA matching, van Rood et al PNAS 2009

14 HLA Antibody Both Single and Double Cord Blood Studies Confirm Poor Outcomes with HLA Antibodies vs Cord Blood Units Single Cord, Myeloablative, 386 Patients HLA Antibody More Common in Older Patients, Woman 2 Year EFS: 43% Ab negative, 15% Ab vs cord, p =0.001 Double Cord, Reduced Intensity, 73 patients Delayed engraftment, increased graft failure with HLA Ab 3 year OS 45% no Ab, 0% Ab vs both cords, p=0.04 Cutler et al Blood 2011 Takanashi et al Blood 2010

15 Blood Type and Racial/Ethnic Match CIBMTR Study, Single Cord, 885 Patients African American Patients worse OS than Hispanic or Caucasian Patients African Americans receive smaller, less well matched units Race/ethnicity of Cord Blood Donor no Impact on Survival Adult Single Cord, 95 Patients ABO match no effect on survival, fewer platelet and RBC transfusions needed if ABO identical or minor mismatch Ballen et al BBMT 2012 Tomonari et al BMT 2007

16 Cord Blood Banking Factors: Bank of Origin No Study to Show One Bank Better than Another Many Centers Prefer their own Domestic Banks In Utero vs Ex Utero Collection Similar Cell Counts Large CIBMTR Study Underway to Correlate Cord Blood Bank of Origin, Processing, and Thawing Techniques with Cord Blood Outcomes Extensive Variability in Cord Unit Quality Low CD34 Viability Predict for Poor Engraftment Scaradavou et al BBMT 2010 Laskey et al Transfusion 2002

17 Cord Blood Banking Factors RBC vs Plasma Depleted Units Retrospective Study of 188 Plasma Depleted Single UCBT Reduce Nucleated Cell Dose Loss Comparable ANC/Platelet Engraftment on Days 22 and 50 Reports on Infusional Reactions with Plasma Depleted Units May need vigorous wash strategy Chow et al BBMT 2007

18 Graft Quality Characteristics Infused (post thaw) Colony Forming Units Correlated Best with Neutrophil and Platelet Engraftment No Correlation Between Storage Times and Transplant Outcomes Viability of CD34+ Cells Correlated Best with Colony Forming Unit Recovery Prasad et al Blood 2008 Wall et al BMT 2008 Solomon et al Transfusion 2010

19 Cord Blood Apgar Score Single Center Retrospective 435 Single CB, Myeloablative Evaluate Nucleated Cell Count, CD34+, Colony Forming Units, Mononuclear Cell Count, Volume Pre and post Cryopreservation Scores Correlate with Neutrophil Engraftment Applied Analysis to Inventory of Carolinas CBB For 10 kg patient, 90% of Inventory above median score For 40 kg patient, 5.3% Inventory above median score Page et al Transfusion 2012

20 Different Center Selection Criteria MD Anderson Use Double Cords Among Cords >2 x10 7 NC/kg choose highest HLA Match Use C and DQ for Typing Avoid RBC replete units if possible Use FACT Accredited Banks Only Prefer US unit over International Unit due to Time Constraints Courtesy of Dr. Shpall

21 Different Center Selection Criteria Seattle Use TNC and HLA A, B Antigen Level, DR Allele Level Total Cell Dose > 3x10 7 NC/kg, Each Unit >1.5 x10 7 NC/kg 4/6 Match with Patient and Other CB Unit Select Best HLA Matched Unit First Use 2 CB if 6/6 Match <3.0, 5/6 Match <4.0, 4/6 Match <6.0 Then Select Second Unit, Prioritize HLA Match if Over Minimal Cell Dose HLA C/Allele Matching Not Used in Standard Criteria, May be Used to Optimize Selection Courtesy of Dr. C Delaney

22 Different Center Selection Criteria Duke University Cell Dose HLA Pediatric >3 x10 7 NC/kg, >5 for non malignant Adult 2 cords >3x10 7 NC/kg > 4/6 Match with 1 match at each A,B, DR locus High resolution matching if possible Match at least 1 HLA C locus when possible Bank of Origin Priority High Quality Banks-Reliable Experience Courtesy of Dr. Kurtzberg

23 Different Center Selection Criteria Genoa, Italy Perform Only IntraBone CB over last 5 years Cell Dose > 1.5x10 7 NC/kg- No Cell Dose Effect Noted Select 5/6 HLA Match over 4/6 HLA Match Prefer ABO Match Prefer Italian Banks Don t Use KIR Matching Courtesy of Dr. Bacigalupo

24 Different Center Selection Criteria Harvard/Boston Programs Mostly Double Cord (Single Cord PGE2 Study) Total Cell Dose >3.7 x10 7 NC/kg, each cord >1.5x10 7 NC/kg Above >2.0 Cell Dose, Prioritize HLA Match, Unless >50% Bigger Cord 4/6 HLA Allele Level Match with Patient and Other Unit Exclude Units with HLA Antibodies Do Not Use HLA C, KIR, NIMA in Match Strategy Use Domestic and International Banks

25 Conclusions Cell Dose is Important, but Just the Beginning 1 Cord/2 Cords/Cord + Haplo? 6/6 HLA Match Improved Survival For 4/6 and 5/6 Units, which Alleles are Most Important? Within Best Available Match Grade, Choose Larger Units HLA Antibodies vs CBU Associated with Worse Prognosis No Clear Advantage to Racial/Ethnic Match, ABO Match but Studies Small Unknown Factors of CB Bank of Origin and Processing Techniques

26 Future Directions Study HLA C in Double Cord Blood Transplants Racial/Ethnic Match in Double Cord Blood Transplants CIBMTR Study of Cord Blood Banks, Processing and Thawing Techniques Primary Outcome ANC Engraftment Race/Gender/ABO/Time to Processing/Maternal Age RBC/PD Units, Storage Conditions,Thawing/Infusion Develop Score of CB Units Accounting for all important factors More Guidance by ISCT 2013!

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