The Dose-Match Interaction in Umbilical Cord Blood (UCB) Transplantation: An Analysis of the Impact of Cell Dose and HLA-Match on the Disease-Free Survival (DFS) of 989 Patients Transplanted with Single Units for Hematologic Malignancy.
Authors: Barker Juliet N. , Scaradavou Andromachi , Stevens Cladd , Rubinstein Pablo 
Published: October 2019

Total nucleated cell (TNC) dose and HLA-match are both recognized determinants of engraftment, transplant-related mortality (TRM), and DFS after UCB transplantation (UCBT). However, how to “trade off” dose and match in unit selection is not well defined. Therefore, we analyzed the impact of pre-freeze TNC dose and HLA-match upon 3 year transplant outcomes after 3-6/6 HLA-A, B antigen, DRB1 allele matched UCBT provided by the NCBP. Patients were transplanted with myeloablative conditioning using single units for the treatment of acute (n = 768) or chronic (n = 156) leukemia or myelodysplasia (n = 65) between 1993–2005. The 989 patients with outcome data to date (91% of single unit grafts provided in this interval) had a median age of 9 years (range 0–62). Individually, decreasing TNC dose adversely affected engraftment, TRM, and DFS as previously shown, whereas increasing HLA-mismatch adversely impacted these outcomes as well as the incidence of severe acute graft-vs-host disease (aGVHD). For example, using recipients of 5/6 units as a reference, the relative risk (RR) for grades III-IV aGVHD for recipients of 6/6 units was 0.3 (p = 0.03); for 4/6 unit recipients was 1.6 (p = 0.003); and for 3/6 unit recipients was 2.1 (p = 0.002). An analysis of the 3 year DFS combining both pre-freeze TNC dose and HLA-match, using recipients of 5/6 matched 2.5–4.9 x 107/kg units as the reference, is shown.

Match/ Dose N RR: Death or Relapse (95%CI) p 6/6: any dose 50 0.4 (0.2–0.7) 0.002 5/6: TNC 0.7–2.4 66 1.7 (1.2–2.4) 0.003 5/6: TNC 2.5–4.9 116 1.0 (Reference) - 5/6: TNC ≥ 5.0 141 0.9 (0.6–1.2) 0.5 4/6: TNC 0.7–2.4 132 1.8 (1.4–2.5) < 0.001 4/6: TNC 2.5–4.9 222 1.3 (0.95–1.7) 0.12 4/6: TNC ≥ 5.0 198 0.9 (0.7–1.3) 0.9 3/6: any dose 64 1.5 (1.0–2.1) 0.045

Notably, within the dose range transplanted to date, recipients of 6/6 units had a significantly superior DFS which was not explained by other variables such as age, disease risk, or transplant center. In contrast, recipients of 3/6 units had inferior DFS, also regardless of dose. Further, recipients of 5/6 units with a TNC 2.5–4.9 x 107/kg (mean 3.5) had a DFS that was similar to those receiving larger 4/6 units ≥ 5.0 x 107/kg (mean 5.9) but with a lower risk of severe aGVHD. Recipients of small (< 2.5 x 107/kg) units that were either 5/6 or 4/6 matched had significantly inferior outcome. This data has significant implications for the practice of unit selection for patients with hematologic malignancy. Most importantly, it suggests that the best transplant survival can be obtained by selecting a 6/6 HLA-matched unit, although the cell dose threshold for these units has not been established. If no 6/6 units are available, 5/6 units above a dose of 2.5 x 107/kg are superior to 4/6 units of any dose. In addition, small (< 2.5 x 107/kg) 5/6 or 4/6 units are inadequate as a single unit graft. Units that are 3/6 HLA-matched should also be avoided. Finally, this analysis suggests improved UCBT outcome will be dependent upon the ability to obtain units that are both of sufficient TNC dose and HLA-match requiring an increase in the global inventory of ethnically and racially diverse UCB units of high cell dose.