Umbilical Cord Blood Transplantation (UCBT) at the University of Minnesota: Impact of Double Unit and Fludarabine on Engraftment after Myeloablative Conditioning.
Authors: Brunstein Claudio G. , Defor Todd , Wagner John E. 
Published: October 2019

UCB is increasingly used as a source of hematopoietic stem cells for transplantation in both adults and children. While poor engraftment historically has been the principal obstacle for successful use of UCB, the addition of Fludarabine (FLU) to the cytoreductive regimen and administration of two partially HLA matched UCB units have essentially overcome this complication. While we have hypothesized that FLU is the principal factor for improving engraftment, and that co-administration of two units speeds neutrophil recovery based on higher cell dose, this has previously been unproven. To test this hypothesis we evaluated engraftment results in 147 patients (pts) with hematologic malignancy transplanted between 1994–2005. All pts received cyclophosphamide (Cy) 120mg/kg and total body irradiation (TBI) 1320–1375 cGy either alone (n=67) or with FLU (n=80). All recipients of Cy/TBI received a single UCB unit, while recipients of Cy/TBI/FLU either received a single (n=25) or two (n=55) UCB units. The 3 patient cohorts (Cy/TBI/single vs Cy/TBI/FLU/single vs Cy/TBI/FLU/double) were similar in gender, CMV status, HLA mismatch, diagnosis and nucleated cell dose. Recipients of a Cy/TBI/FLU/double, however, were older and had a greater CD34 cell dose relative to pts in other groups. All received G-CSF until ANC≥500 for 3 consecutive measurements. In univariate analysis there was no obvious difference in terms of neutrophil engraftment, speed of recovery or incidence of primary or secondary graft failure (table). In logistic regression analysis, infused CD34+ cell dose was the only factor associated with engraftment regardless of single vs double UCBT or use of FLU. Patients who received CD34+ cell doses >3.5 X 105/kg had higher odds of engraftment (dose range 3.6–6.9: odds ration [OR] 11.7, 95% CI, 1.3–106.9, p=0.03; dose range 7.0–34.8: OR 10.7, 95% CI, 1.1–98.9, p=0.04). Neither conditioning regimen (p=0.36) nor HLA-matching (p=0.25) were predictors of engraftment. In addition CD34+ cell dose was the only independent predictor of speed of neutrophil recovery. In Cox Regression, patients transplanted with CD34+ cell doses >3.5 X 105/kg had faster engraftment (dose range 3.6–6.9: relative risk [RR] 2.5, 95%CI, 1.5–4.1, p<0.01; dose range 7.0–34.8: RR 3.7, 95%CI, 2.2–6.2, p<0.01). Compared with recipients of Cy/TBI alone, use of FLU was not associated with more rapid recovery (Cy/TBI/FLU/single: RR 1.4, 95%CI, 0.1–4.2, p=0.22; Cy/TBI/FLU/double: RR 0.7, 95%CI, 0.5–1.0, p=0.07). In conclusion, total infused CD34+ cell dose and not FLU is the principal force driving engraftment and rate of recovery after myeloablative UCBT. With results in adults that are now strikingly comparable to those in children, double UCBT after Cy/TBI/FLU is now routinely prescribed for pts for whom an adequate single unit cannot be identified.

Cohorts Proportion > 18 yrs old CD34 X 105/kg Primary Neutrophil Engraftment Days to ANC≥500 Days to PLT≥50K Cy/TBI/Single 18% 2.9 89% 23 75 Cy/Flu/TBI/Single 40% 4.4 96% 21 49 Cy/Flu/TBI/Double 75% 4.5 89% 25 56