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Juliet N. Barker, MBBS (Hons), FRACP Associate Attending Director Cord Blood Transplant Program Memorial Sloan-Kettering Cancer Center Optimising Cord.

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Presentation on theme: "Juliet N. Barker, MBBS (Hons), FRACP Associate Attending Director Cord Blood Transplant Program Memorial Sloan-Kettering Cancer Center Optimising Cord."— Presentation transcript:

1 Juliet N. Barker, MBBS (Hons), FRACP Associate Attending Director Cord Blood Transplant Program Memorial Sloan-Kettering Cancer Center Optimising Cord Blood Unit Selection CSA/ MMF

2 Acknowledgements U of Minnesota John E. Wagner NYBC Pablo Rubinstein Cladd Stevens Machi Scaradavou 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

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 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 10 7 NC/kg Hi Dose Prep Midi or Mini (Unmodified) Children (Young adults) Midi/ Mini + 10/10 donor Hi Dose + TCD 9-10/10 donor MSKCC Donor Algorithm Donors identified for > 95% patients.

6 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 CB #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 Days Post-Transplant Cumulative Incidence Ablative: 25 days NMA*: 10 days Neutrophil Engraftment after DCBT (n = 108) Median 41 yrs (range 6-69), high risk heme malignancies * Early auto recovery – switched to sustained donor engraftment Dahi, P., ASBMT 2012 High rates of sustained donor engraftment.

8 Months Post-Transplant Progression-Free Survival P = MSK Allo Tx for Heme Malignancies : 2 Year PFS After Double-Unit CB vs RD vs URD Transplant Ponce, BBMT 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) CB grafts: marked HLA-disparity. CD34+ cell dose also much lower: RD 7.9, URD 6.0, CB 0.09 ( p < 0.001). P < Ponce, BBMT 2011

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

11 Time Post-Transplant (Months) Disease-Free Survival Adults yrs (n = 52): 64% (Europeans 62%, Non-Europeans 66% ) Children 0-15 yrs (n = 23): 78% (Europeans 86%, Non-Europeans 75%) DCBT if Acute Leukemia & MDS/MPD: 2-yr DFS No difference between European & non-European patients. In multivariate analysis only CMV serostatus was significant. 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 DonorsEuropeans (n = 341) Non- Europeans (n = 184) p Best URD 10/10 (n = 218)180 (53%)38 (21%)< /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)

15 URD (n=426) CB (n=137) No Graft (n=34) NW Europe Asian Eastern Europe African Southern Europe White Hispanic Europe Mix Middle Eastern Non-Europe Mix Updated Data, MSKCC 2012 (n = 597) Greater than 50% of CBTs had non-European ancestry 25% 53% 76%

16 Immunosuppression: rejection/ GVHD Supportive care: infection, bleeding, nutrition year0 Conditioning: High, Midi, Mini 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. CB: Dose, match, quality Transplant Related Factors Variables that Determine Outcome

17 How to Select Units?

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

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 in unit selection - revealed in investigation of double unit biology

21 % CD34+ Cell Viability Engrafting Unit (N=44) Non- Engrafting Unit (N=44) <75% (N=16) 115 ≥75% (N=72) 4329 Engraftment in 44 Double Unit CBTs Engrafting with a Single Unit. 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 GOOD UNIT 90% viable 50% viable Unit Quality: Schema of CD34+s of 2 CB Units 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. Total CD34+ Cells in 2 Units Unit #1 Unit #2 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) >2.0 ( n=10): 16.5 days (n=13): 20 days <1.0 ( n=38): 27.5 days P < High rate sustained engraftment directly dependent on infused CD34+ of winner; if low can be very slow. Avery, Blood 2011

26 Sustained Neutrophil Engraftment Avery, Blood 2011 Total Graft Cell Dose & DCB Engraftment (n = 61) Time Post Transplant (Days) p = p = p = p = >4.3 x10 7 /kg: 100% <4.3 x10 7 /kg: 87% >1.8 x10 5 /kg: 97% <1.8 x10 5 /kg: 90% >6.2 x10 4 /kg: 97% <6.2 x10 4 /kg: 90% >7.8 x10 6 /kg: 97% <7.8 x10 6 /kg: 90% TNCCD34 + CFU CD3 + Total TNC & CD3+ dose of graft also have an effect.

27 Months Post-Transplant C.I. Grade III-IV aGVHD /10 HLA Match 8-9/10 HLA Match Grade III-IV aGVHD by Engrafting Unit-Recipient 10 Allele HLA-Match (n = 115) Recipient-Unit Match HRP 2-7/10 (n = 88)Reference 8-9/10 (n = 27) 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 10 7 /kg. Review info & bank for each unit. Obtain missing info, CT units of interest. Prepare CB Search Summary Report. Rank units by A,-B antigen, -DRB1 allele match* Hi to low TNC within each match grade (correct for RBC). 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). 1st2 nd 3rd Plan shipment(s) Review CTs, update Search Summary Prepare domestic back-up unit(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 Kurtzberg, J. et al, Blood 2008 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.

32 Eapen, M. et al, Lancet, 2011 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?

33 New…… & Easy to Implement

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

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

36 New……… But More Difficult to Implement

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

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

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

40 1) TNC/ HLA-match: Above 2.0 x 10 7 /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. MSKCC Strategy for Unit Selection Barker, Blood How I Treat

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