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Juliet N. Barker, MBBS (Hons), FRACP Associate Attending Director Cord Blood Transplant Program

Optimising Cord Blood Unit Selection. -7. -6. -5. -4. -3. -2. -1. 0. 30. 100. CSA/ MMF. Juliet N. Barker, MBBS (Hons), FRACP Associate Attending Director Cord Blood Transplant Program Memorial Sloan-Kettering Cancer Center. Acknowledgements. MSKCC Staff of Adult and Pediatric

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Juliet N. Barker, MBBS (Hons), FRACP Associate Attending Director Cord Blood Transplant Program

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  1. Optimising Cord Blood Unit Selection -7 -6 -5 -4 -3 -2 -1 0 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. Retrospective studies suggest improved engraftment & GVL. Barker et al, NEJM 2001, Blood 2003, Blood 2005

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

  6. 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 CB #2 CB #1 -7 0 +100 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 GVHD prophy: CSA/ MMF 3 intensities, mainly Cy-Flu-TBI based, no ATG, no steroids.

  7. Neutrophil Engraftment after DCBT (n = 108) Median 41 yrs (range 6-69), high risk heme malignancies 1.0 NMA*: 96% @ 10 days 0.8 Ablative: 94% @ 25 days 0.6 Cumulative Incidence 0.4 0.2 0.0 30 0 10 20 40 Days Post-Transplant * 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: 2 Year PFS After Double-Unit CB vs RD vs URD Transplant 1.0 0.8 0.6 Progression-Free Survival 0.4 0.2 P = 0.573 0.0 0 12 24 36 48 60 Months Post-Transplant CB (n = 75) RD (n = 108) URD (n = 184) Up-front TRM compensated by reduced late mortality 2 Yr PFS after CBT: comparable to RD or URD transplant. Ponce, BBMT 2011

  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 0.9-15): 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: * 3.3 + 2.6 ** 2.7 + 1.9 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 16-69 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) 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. Updated Data, MSKCC 2012 (n = 597) URD (n=426) CB (n=137) No Graft (n=34) 25% 53% 76% 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 0 +28 +100 +180 +1 year • Immunosuppression: rejection/ GVHD • Supportive care: infection, bleeding, • nutrition • Patient Related Factors • Biology ofMalignancy: 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 1993-2006 100 80 Very high TRM if mismatch & low TNC 4/6 & TNC <2.5 5/6 & TNC <2.5 60 4/6 & TNC 2.5-4.9 CI of Transplant-Related Mortality 5/6 & TNC 2.5-4.9 40 4/6 & TNC ≥5.0 5/6 & TNC ≥5.0 20 6/6 & all doses (mean TNC 4.4) Lowest TRM: 6/6 match 0 1 2 3 Lowest TRM: best HLA-match, not highest dose. Years Post-Transplant 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 in unit selection - revealed in investigation of double unit biology

  21. 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. Unit Quality: Schema of CD34+s of 2 CB Units Total CD34+ Cells in 2 Units BAD UNIT GOOD GOOD UNIT 50% viable 90% viable Unit #1 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) 1.0-2.0 (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 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 p = 0.02 p = 0.001 0.0 0.0 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 TNC CD34+ 0.2 0.2 p = 0.10 p = 0.0007 Sustained Neutrophil Engraftment 0.0 0.0 0 10 20 30 40 50 0 10 20 30 40 50 >6.2 x104/kg: 97% >7.8 x106/kg: 97% <6.2 x104/kg: 90% <7.8 x106/kg: 90% CD3+ CFU 0 10 20 30 40 50 0 10 20 30 40 50 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) 0.37 0.105 80 60 C.I. Grade III-IV aGVHD 40 2-7/10 HLA Match 20 8-9/10 HLA Match 0 0 1 2 3 4 5 6 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: 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. 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 0.4 <0.001 0 HLA MM 0.3 0.012 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 0 1 2 3 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 2011 -How I Treat

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