Multivariate Analysis of Patient and Graft Specific Factors among 330 Recipients of Unrelated Cord Blood Transplant (UCBT) To Predict Risk of Death from Opportunistic Infections in the First 6 Months after UCBT.
Authors: Szabolcs Paul , Peterson Bercedis L. , Niedzwiecki Donna , Chao Nelson , Kurtzberg Joanne 
Published: October 2019

Abstract
Unrelated umbilical cord blood transplantation (UCBT) is a suitable option for those who lack HLA-matched sibling donors. However, opportunistic infections (OI), with the majority detected in the first 100 days, remain the major cause of of non-relapse mortality with almost all death ocurring in the first 6 months. Over the past 5 years we have studied the reconstitution of immunity in the immediate post-UCBT period in >150 pediatric UCBT recipients to identify those at risk for OI. Several graft and patient-specific variables were identified as significant confounders when the laboratory measurements of dendritic and T cell reconstitution was analyzed. Here, we set out to analyze the impact of these factors on the 6 months post-UCBT OI-related mortality by analyzing all consecutive patients transplanted during the same time period. Between June 1999 and Oct. 2005, 330 pediatric recipients of single UCB grafts were identified. Those receiving a second transplant for primary graft failure were not analyzed. 220 of the 330 patients were alive at 6 months (67%). Of the 110 children who died by 6 months, 46 patients were identified where OI (viral, fungal, protozoal infections) could not be implicated as a cause of death. After removing these from the analysis, 284 patients remained; 200 (77%) were alive at 6 onths and 64 (23%) died at or before 6 months related to OI. Using these 284 patients, nine predictors were tested in logistic regression models to test for risk to die due to OI by 6 months. First, six variables describing the demographic and clinical characteristics of the patients were entered into the model. These variables were gender, race (white/non-white), age at UCBT, CMV serology (pos/neg), HLA mismatches (0,1,2,3 antigen mismatch), and a 3-level categorical variable indicating whether indication for UCBT was non-malignant condition treated with chemotherapy alone (n=121, 42%), malignancy treated with regimens including TBI (n=116, 41%) or malignancy treated with no TBI (n=47, 17%). Gender and race did not predict death (p-values=0.45 and 0.99, respectively). A greater probability of death was found for patients who were CMV positive (p=0.0002), had a greater number of HLA mismatches (p=0.02), and were older (0.002). Patients with malignancy treated without TBI had the greatest probability of death (0.39), followed by those with no malignancy (0.25); patients with malignancy treated with TBI had the smallest probability of death related to OI (0.17) (p= 0.006). Since the three dosing variables, CD34+, CD3+, and total cell dose/kg were highly correlated with each other, they were entered separately into this model (resulting in p-values = 0.05, 0.23, 0.02, respectively). When all three dosing variables were entered simultaneously into the model the resulting p-values were 0.36, 0.27, and 0.07, respectively, demonstrating the superiority of total cell dose/kg to the CD34+ dose of the graft. This analysis demonstrates that patient and graft-specific confounders will have significant impact on mortality due to OI. Opportunistic infections (most being viral) is the most prevalent cause of death in the first 6 months after UCBT. This data can serve to develop risk models to stratify patients into risk groups and determine who may benefit from novel therapeutic interventions.