1. Should the number of collected CD34+ cells be considered major criteria for UCB unit choice in adults? Reunión anual GETH 2011 Madrid, 11 marzo 2011 Guillermo Sanz Hospital Universitario La Fe, Valencia, Spain

2. Main prognostic factors after UCBT Number of TNC infused Degree of HLA match

3. Gluckman E et al. Exp Haematol 2004; 32:397-407. Guidelines for UCB unit choice Guidelines for UCB unit choice Eurocord 2004 criteria At least 4/6 HLA match Collected TNC above 2.5 – 3.0 × 10 7 /kg

4. Policy on cell dose for UCB unit choice Most transplant centers use the number of collected TNC as the only cell dose criteria for unit choice –Greater TNC dose threshold for higher degree of HLA mismatch 2.5 × 10 7 /kg if 0 or 1 HLA mismatches 3.5 × 10 7 /kg if 2 HLA mismatches Is this cell dose criteria enough?

5. Should the number for guiding UCB unit choice? Should the number of collected CD34+ cells be considered an additional major cell dose criteria in adults for guiding UCB unit choice?

6. Reasons for not including the number of collected CD34+ cells among criteria for guiding UCB unit choice Not enough data on impact of CD34+ cells (infused or collected) Measurement of CD34+ cells not well standardized –Great differences among CB banks could emerge TNC dose could be a good surrogate of CD34+ cells No available data on correlation between number of CD34+ cells collected and infused Number of collected CD34+ cells not available for 25 – 50% UCB units worldwide

7. Number of infused CD34+ cells is relevant after UCB transplants Impact on engraftment (children and adults) Impact on survival (children and adults – some series) Review by Rocha V & Gluckman E on behalf of Eurocord/EBMT. Br J Haematol 2009; 147:262-274.

8. Prognostic value of infused CD34+ cells (× 10 5 /kg) after myeloablative UCBT in adults with hematologic malignancies 1 N Engl J Med 2001;344:1815-22. 2 Br J Haematol 2007;139:464-74. 3 Biol Blood Marrow Transplant 2008;14:1341-7. 4 Biol Blood Marrow Transplant 2010;16:86-94. 5 Biol Blood Marrow Transplant 2010;16:1589-95. Reference PMN engraftmentDFS Cut-off point P value Cut-off point P value Laughlin, 2001 1 1.20.05NS Van Heekeren, 2007 2 NSHigher0.015 Ooi, 2008 3 NS1.0< 0.0001 Sanz, 2010 4 NS1.50.009 Sanz, 2010 5 NS0.60.02

9. CD34 + > 1 x 10 5 /kg (n = 111) CI: 94% Median: 20 days CD34 + ≤ 1 x 10 5 /kg (n = 66 ) CI: 89% Median: 25 days P = 0.0002 Myeloid engraftment after myeloablative single UCBT in adults with malignant disorders (n = 177) by infused CD34+ cells

10. CD34 + > 1.5 x 10 5 /kg (n = 92) CI: 96% Median: 20 days CD34 + ≤ 1.5 x 10 5 /kg (n = 73) CI: 90% Median: 23 days P = 0.007 Myeloid engraftment after myeloablative single UCBT in adults with malignant disorders (n = 165) by collected CD34+ cells

11. TNC ≤ 2.5 × 10 7 /kg (n = 58) CI: 93% Median: 22 days TNC > 2.5 × 10 7 /kg (n = 120) CI: 92% Median: 22 days P = 0.6 Myeloid engraftment after myeloablative single UCBT in adults with malignant disorders (n = 178) by collected TNC

12. Correlation between collected TNC and infused CD34+ cells after myeloablative single UCBT in adults with malignant disorders (n = 164)

13. Correlation between collected and infused CD34+ cells after myeloablative single UCBT in adults with malignant disorders (n = 164)

14. CD34+ measurement is now almost standardized CD34+ quantification performed at NetCord CB banks according to a uniform protocol (ISHAGE) Quality control available and likely required for accreditation in near future –i.e. Proficiency testing UKNEQAS

15. Capacity of collected TNC and CD34+ cells of reaching a target number of infused CD34+ cells (1 × 10 5 /kg) Experience in 164 UCB transplants Number of cells collected No. of patients (%) No. of patients (%) with infused CD34+ cells > 1 × 10 5 /kg > 2.5 × 10 7 TNC/kg112 (68)82 (73) ≤ 2.5 × 10 7 TNC/kg52 (32)23 (44) > 1 × 10 5 CD34+ cells/kg131 (80)97 (74) ≤ 1 × 10 5 CD34+ cells/kg33 (20)8 (24) Collected CD34+ cells perform better that TNC

16. Guidelines for UCB unit choice Guidelines for UCB unit choice Eurocord 2009 criteria for malignant disorders UCB unit with 5/6 or 6/6 HLA match –Collected TNC > 2.5 × 10 7 /kg –Collected/infused CD34+ cells > 1.2 × 10 5 /kg UCB unit with 4/6 HLA match –Collected TNC > 3.5 × 10 7 /kg –Collected/infused CD34+ cells > 1.7 × 10 5 /kg Rocha V & Gluckman E on behalf of Eurocord/EBMT. Br J Haematol 2009; 147:262-274.

17. Guidelines for UCB unit choice Guidelines for UCB unit choice Eurocord 2009 criteria for malignant disorders UCB unit with 5/6 or 6/6 HLA match –Collected TNC > 2.5 × 10 7 /kg –Collected/infused CD34+ cells > 1.2 × 10 5 /kg UCB unit with 4/6 HLA match –Collected TNC > 3.5 × 10 7 /kg –Collected/infused CD34+ cells > 1.7 × 10 5 /kg Rocha V & Gluckman E on behalf of Eurocord/EBMT. Br J Haematol 2009; 147:262-274. These thresholds are difficult to achieve for many adults

18. Capacity of Eurocord 2009 criteria of reaching a target number of infused CD34+ cells (1 × 10 5 /kg) Experience in 164 UCB transplants Eurocord 2009 criteria No. of patients (%) No. of patients (%) with infused CD34+ cells > 1 × 10 5 /kg Fulfilled65 (40)52 (80) Absent99 (60)53 (54) Thresholds may be excessive

19. Should it be possible to use a lower CN and CD34+ threshold for UCB transplants in adults with a single unit if BOTH cell dose criteria are included in UCB unit choice?

20. Capacity of current GETH/Hospital La Fe criteria* for CB unit choice of reaching a target number of infused CD34+ cells (1 × 10 5 /kg) Experience in 164 UCB transplants GETH/Hospital La Fe criteria* No. of patients (%) No. of patients (%) with infused CD34+ cells > 1 × 10 5 /kg Fulfilled129 (79)52 (74) Absent35 (21)10 (29) * Collected TNC > 2 × 10 7 /kg and collected CD34+ cells > 1 × 10 5 /kg Criteria almost as efficient as Eurocord 2009 criteria and accessible in a higher number of patients

21. Concluding remarks The number of collected CD34+ cells must be included among the criteria for UCB unit choice Currently accepted thresholds for collected TNC and CD34+ cells in adults with hematologic malignancies need to be properly reviewed Additional criteria for accurately predicting the potency of the UCB graft are required