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Optimising Cord Blood Unit Selection

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Presentation on theme: "Optimising Cord Blood Unit Selection"— Presentation transcript:

1 Optimising Cord Blood Unit Selection
-7 -6 -5 -4 -3 -2 -1 30 100 CSA/ MMF Juliet N. Barker, MBBS (Hons), FRACP Associate Attending Director Cord Blood Transplant Program Memorial Sloan-Kettering Cancer Center

2 Acknowledgements MSKCC Staff of Adult and Pediatric Transplant
Search: Courtney Byam, Rosanna Ferrante Debbie Wells, Kathleen Doshi, Sinda Lee Cytotherapy Lab: esp Allison Schaible CB Research Staff: Marissa Lubin Anne Marie Gonzales , Katie Evans Cellular Immunology Lab: Kathy Smith Malcolm Moore Machi Scaradavou Nancy Kernan & Richard O’Reilly Doris Ponce Marcel van den Brink & Sergio Giralt U of Minnesota John E. Wagner NYBC Pablo Rubinstein Cladd Stevens Machi Scaradavou

3 What have we achieved?

4 One Strategy to Improve Outcome By Augmenting Cell Dose: Use 2.
Barker et al, NEJM 2001, Blood 2003, Blood 2005 Retrospective studies suggest improved engraftment & GVL.

5 MSKCC Donor Algorithm Donors identified for > 95% patients.
Sibling typing → simultaneous URD & CB search Suitable Sibling (match/ donor health) Suitable URD (match/ availability): Suitable CB Graft (match/ dose): 4-6/6 A,B antigen, DRB1 allele 2 units: each > 2 x 107 NC/kg Midi/ Mini + 10/10 donor Hi Dose + TCD 9-10/10 donor Hi Dose Prep Midi or Mini (Unmodified) Children (Young adults) Donors identified for > 95% patients.

6 CBT Preps & Immune Suppression
-7 High (< 50): Acute leuk/ MDS/ hi grade NHL Midi (< 70): AML/ ALL/ MDS/ CML/ NHL/ CLL (or Mel/ Flu for Hodgkins not in CR) Mini (< 70): Hodgkins in CR/ Indolent NHLs/ CLL CB #2 #1 CBT Preps & Immune Suppression High: Cy 120/ Flu 75/ TBI 1375 (or Clo/ Mel/ Thio if no TBI) Midi: Cy 50/ Flu 150/ Thio 10/ TBI 400 (or Mel 140/ Flu 150) Mini: Cy 50/ Flu 150/ TBI 200 GVHD prophy: CSA/ MMF 3 intensities, mainly Cy-Flu-TBI based, no ATG, no steroids.

7 High rates of sustained donor engraftment.
Neutrophil Engraftment after DCBT (n = 108) Median 41 yrs (range 6-69), high risk heme malignancies 10 20 30 40 0.0 0.2 0.4 0.6 0.8 1.0 Days Post-Transplant Cumulative Incidence Ablative: 94% @ 25 days NMA*: 10 days * Early auto recovery – switched to sustained donor engraftment High rates of sustained donor engraftment. Dahi, P., ASBMT 2012

8 MSK Allo Tx for Heme Malignancies 2005-2009:
Months Post-Transplant Progression-Free Survival 12 24 36 48 60 0.0 0.2 0.4 0.6 0.8 1.0 P = 0.573 MSK Allo Tx for Heme Malignancies : 2 Year PFS After Double-Unit CB vs RD vs URD Transplant Ponce, BBMT 2011 2 Yr PFS after CBT: comparable to RD or URD transplant. CB (n = 75) RD (n = 108) URD (n = 184) Up-front TRM compensated by reduced late mortality

9 Comparison of Donor-Recipient HLA-Match:
CB (n = 75, 150 units) vs URD (n = 184) P < 0.001 Ponce, BBMT 2011 CB grafts: marked HLA-disparity. CD34+ cell dose also much lower: RD 7.9, URD 6.0, CB 0.09 ( p < 0.001).

10 DCBT if Acute Leukemia & MDS/MPD: 2-yr DFS
Children* (n = 23, median 9 yrs, range ): 78% Low incidence of relapse (9% children, 6% adults) translates to relatively high survival rates. Adults** (n = 52, median 41 yrs, range 16-69): 64% Disease-Free Survival Inf. TNC: * ** Time Post-Transplant (Months) Barker et al, ASH 2011

11 DCBT if Acute Leukemia & MDS/MPD: 2-yr DFS
Children 0-15 yrs (n = 23): 78% (Europeans 86%, Non-Europeans 75%) No difference between European & non-European patients. In multivariate analysis only CMV serostatus was significant. Adults yrs (n = 52): 64% (Europeans 62%, Non-Europeans 66% ) Disease-Free Survival Time Post-Transplant (Months) Barker et al, ASH 2011

12 Why are these results important?

13 Best Matched URD & Best CB
if Combined Search by Patient Ancestry (n = 525) Best Donors Europeans (n = 341) Non-Europeans (n = 184) p Best URD 10/10 (n = 218) 180 (53%) 38 (21%) <0.001 9/10 (n = 148) 99 (29%) 49 (27%) <8/10 (n = 159) 62 (18%) 97 (53%) Best CB 5-6/6 (n = 401) 270 (79%) 131 (71%) 4/6 (n = 90) 56 (16%) 34 (18%) No CB (n = 34) 15 (4%) 19 (10%) Volunteer unrelated donors: poor HSC source for non-Europeans. Barker et al 2010, BBMT

14 CB Extends Transplant Access to “Minorities”:
URD vs CB vs No Graft by Ancestry (n = 385) Barker et al 2010, BBMT

15 Greater than 50% of CBTs had non-European ancestry
Updated Data, MSKCC 2012 (n = 597) URD (n=426) CB (n=137) No Graft (n=34) 25% % % NW Europe Asian Eastern Europe African Southern Europe White Hispanic Europe Mix Middle Eastern Non-Europe Mix Greater than 50% of CBTs had non-European ancestry

16 Variables that Determine Outcome
Transplant Related Factors CB: Dose, match, quality Conditioning: High, Midi , Mini -7 +28 +100 +180 +1 year Immunosuppression: rejection/ GVHD Supportive care: infection, bleeding, nutrition Patient Related Factors Biology of Malignancy: determines need for hi dose prep vs reliance on GVL Patient Characteristics: age, extent of prior Rx, co-morbidities.

17 How to Select Units?

18 TRM by Combined TNC Dose & A,B Antigen, DRB1 Allele-Match
1061 NYBC Single Unit Myeloablative CBT CI of Transplant-Related Mortality Years Post-Transplant 4/6 & TNC <2.5 4/6 & TNC ≥5.0 4/6 & TNC 5/6 & TNC 5/6 & TNC <2.5 5/6 & TNC ≥5.0 80 100 20 40 60 6/6 & all doses (mean TNC 4.4) Very high TRM if mismatch & low TNC Lowest TRM: 6/6 match Lowest TRM: best HLA-match, not highest dose. Barker et al, Blood 2010

19 Implications for Unit Selection
(applies to single unit CBT, may also apply to double) Biggest cell dose not necessarily the best. 6/6 units highly attractive (?cell dose threshold). Sliding scale: more mismatch, greater required cell dose. Converse also true: match can compensate for low dose. Implies: Above a cell dose threshold best matched unit the best. New measures needed if best unit is mismatched. Barker, Blood 2010

20 Additional factors to consider revealed in investigation
in unit selection - revealed in investigation of double unit biology

21 Engraftment in 44 Double Unit CBTs Engrafting with a Single Unit.
% CD34+ Cell Viability Engrafting Unit (N=44) Non-Engrafting <75% (N=16) 1 15 ≥75% (N=72) 43 29 Using CD34+ viability threshold of 75% (mean-2SD), all but one (43/44) engrafting units had CD34+ viability >75% (p=0.0006) OR Only 1/16 poor viability units engrafted. Poor CD34+ viability correlated with lower CFUs (p=0.02). Scaradavou, BBMT 2010

22 BAD UNIT GOOD UNIT Unit Quality: Schema of CD34+s of 2 CB Units GOOD
Total CD34+ Cells in 2 Units BAD UNIT GOOD GOOD UNIT 50% viable 90% viable Unit # Unit #2 Units similar infused viable CD34+ doses-but very different. In part, double unit CBT effective as increases chance of transplanting at least one good quality unit. Scaradavou, BBMT 2010

23 Implications Unit quality varies from unit to unit, & bank to bank.
Not all banks are the same. Factors that dictate unit quality need to be determined eg collection standards, processing methodology, red cell content, cryo volume, age. Methods to test unit quality prior to thaw should be priority eg testing the segment.

24 Do the principles of single unit CBT also apply to double unit CBT?

25 Sustained Neutrophil Engraftment After Myeloablative DCBT
by CD34+ Cell Dose of Engrafting Unit (n = 61) (n=13): 100% @ 20 days >2.0 (n=10): 100% @ 16.5 days <1.0 (n=38): 89% @ 27.5 days P < 0.001 High rate sustained engraftment directly dependent on infused CD34+ of winner; if low can be very slow. Avery, Blood 2011

26 Total Graft Cell Dose & DCB Engraftment (n = 61)
1.0 1.0 >4.3 x107/kg: 100% >1.8 x105/kg: 97% 0.8 0.8 <4.3 x107/kg: 87% <1.8 x105/kg: 90% 0.6 0.6 0.4 0.4 0.2 TNC 0.2 CD34+ p = p = 0.10 Sustained Neutrophil Engraftment 0.0 0.0 p = 0.02 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 p = 0.001 >6.2 x104/kg: 97% >7.8 x106/kg: 97% <6.2 x104/kg: 90% <7.8 x106/kg: 90% CD3+ CFU Time Post Transplant (Days) Total TNC & CD3+ dose of graft also have an effect. Avery, Blood 2011

27 Grade III-IV aGVHD by Engrafting
Unit-Recipient 10 Allele HLA-Match (n = 115) 100 Recipient-Unit Match HR P 2-7/10 (n = 88) Reference 8-9/10 (n = 27) 80 60 C.I. Grade III-IV aGVHD 40 2-7/10 HLA Match 20 8-9/10 HLA Match Months Post-Transplant P = 0.07 on multivariate: HLA-match likely critically important Ponce, D., ASBMT 2012

28 Evaluate search for units 4-6/6 & > 2.0 x 107/kg.
Review info & bank for each unit. Obtain missing info, CT units of interest. Prepare CB Search Summary Report. Review CTs, update Search Summary Rank units by A,-B antigen, -DRB1 allele match* Hi to low TNC within each match grade (correct for RBC). 1st 2nd 3rd 6/6 units: Choose largest. 5/6 units: Choose largest. 4/6 units: Choose largest. Make final selection of unit(s) (1a & 1b if double). Prepare domestic back-up unit(s). Plan shipment(s) * Ignore unit-unit match in double unit CBT

29 Require att. segment for identity testing & complete IDMs.
Select on bank, dose, match, other (RBC content).

30 What about higher resolution
match?

31 COBLT Single CBT: OS in Pediatric Malignancies
A, B, DRB1 allele match: < 5/6 allele match associated with higher severe aGVHD. Trend toward improved OS with better match. Kurtzberg, J. et al, Blood 2008

32 Effect of C: A,B,C Antigen, DRB1 Allele
N = 803, median 10 yrs (<1 – 62), leukemia/ MDS Inferior neut engraftment with hi degree MM (< 5/8). Worse GVHD if < 5/8 including HLA-A MM. Relapse lower if any MM vs match (but no advantage to multiple mismatches. TRM significantly worse if < 6/8 (trend for 7/8). 3 year TRM: 8/8 9%; 7/8 (non-C) 19%; 7/8 (C) 26%; 6/8 (C + other) 31%. Significance lost in overall mortality except for 6/8 (C + other). Contributed to by rel. high TNC of group? C is important-but how to trade off against cell dose? What is new lower limit of acceptable match? Eapen, M. et al, Lancet, 2011

33 New…… & Easy to Implement

34 Incorporating Vector of HLA-Match: CI of Neutrophil Engraftment
1202 Single Unit CBT, NYBC CI of Neutrophil Engraftment Significant advantage to both 0 & GVHD vector only mismatches Stevens C E et al. Blood 2011

35 HLA-Match Vector: 1202 Single Unit CBT
CI of 3 Year TRM In heme maligs: GVH only mismatch equal to 0 mismatch. Stevens C E et al. Blood 2011;118:3969

36 But More Difficult to Implement
New……… But More Difficult to Implement

37 NIMA-Match: 1121 Single Unit CBT, NYBC
3 Year TRM in Patients > 10 Years Old If 1 MM, advantage if this is a NIMA match (predom. due to better neutrophil engraftment). van Rood J et al. PNAS 2009

38 Relapse by Shared IPA: 845 Singles (AML/ALL)
1.0 1-3 HLA MM, No Shared IPA Reference 1-3 HLA MM, Shared IPA <0.001 0 HLA MM 0.8 0.6 Cox Regression: Multivariate No Shared IPA (n=49) C.I. of Relapse 0.4 0 HLA Mismatch (n=45) 0.2 Shared IPA (n=751) 0.0 Years Post-Transplant Patient shares IPA = reduced relapse. ??Indirect evidence that maternal T-cells mediate GVL?

39 Implications for Unit Selection
CB banks should report maternal HLA type. Should: Select for NIMA match – expands no. of “well matched” units. Avoid “No Shared IPA” grafts in leukemics.

40 MSKCC Strategy for Unit Selection
1) TNC/ HLA-match: Above 2.0 x 107/kg prioritize match Within match grade choose largest. Consider vector & C. 2) Also consider bank of origin (speed, reliability, quality). 3) For malignancy use 2: Increase chance of transplanting at least one unit of good quality PLUS unit vs unit effects may augment engraftment & reduce relapse. 4) For doubles same rules apply to selecting units 1 & 2. Ignore unit-unit HLA-match. 5) Consider hi res match if possible-esp in children. 6) Unresolved issues: selecting based on CD34+ dose, red cell content, testing of segment, high res match vs dose, incorporation of NIMA & IPA. Barker, Blood How I Treat


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