Thymic Recovery and De Novo T Cell Production During the First Year After Unrelated Cord Blood Transplant (UCBT) Predicts Overall Survival: A Multivariate Analysis of 93 Patients Following Myeloablative Conditioning and a Single Unit Graft.

Reconstitution of adaptive immunity is critical for long term survival following HCT. UCBT is a suitable option for those who lack HLA-matched sibling donors, however, infections and leukemic relapse remain the major causes of death. Effective reconstitution of T cell immunity has been associated with reduced risk of relapse, as demonstrated in the COBLT study, presumably by enhanced GVL effect. We have previously demonstrated that attaining threshold levels of plasmacytoid/CD123+ dendritic cells (DC) and reduced activation state of circulating CD8+ T cells correlate with improved survival after UCBT (BBMT;2009:115:2,#380).

We set out to determine if the tempo and quality of immune recovery will predict survival, in particular asessing the impact of the first year after UCBT.

A pediatric patient cohort (n=93) was transplanted between July 2005 and September 2008 at a single center. All patients engrafted with full donor chimerism following myeloablative conditioning and a single cord blood graft. Patients were assessed by a uniform 4 color FACS panel for reconstitution of WBC, ALC, B and NK cells, DC and T cell subsets including recent thymic emigrants (RTE), naïve, central, and effector memory T cells, CTL, Tregs, and activated CD8+ T cells at 3, 6, 12, 24, and 36 months after UCBT. Two sided t-test was employed in univariate analyses to test for differences between the mean values generated from all time points (n=432) between those alive and those who eventually died. Multivariate logistic regression models were created comparing those above and below the median values obtained during the first 365 days post-UCBT using forward selection method with p value of 0.05.

63 and 30 children were transplanted for non-malignant and malignant diseases, respectively. The median age was 2.1 years, 58%were male, 36% were 4/6 HLA match, 41% were 5/6 and 23% were 6/6 HLA match. Of the 93 patients 87 patients were evaluable for 1-year survival. Overall, 68 patients (73%) are alive. The univariate analysis for OS is presented in Table I. In this cohort where all studied patients have engrafted and where death was not a frequent event, gender, race, CMV serology, TNC, CD34+ cell dose, TBI, acute GVHD 2-4 or aGVHD 3-4 had no impact on overall survival. However, malignant disease remained a predictor for lower OS. (HR=3.38(1.37 -7.3 at 95% CI, p=0.007). In multivariate analysis of OS modeling, comparing mean values acquired only between day 0 to Day 365, only one of the immune parameters identified previously significant in Table I had predictive value on overall survival. Those children with a more accelerated thymic recovery in the first year ( >9% of circulating T cells with a RTE phenotype [CD62L+/CD45RA+]), had a reduced risk of death at any time point, HR 0.20 (0.07-0.60, 95%CI), p=0.004.

Even among children with relatively better preserved thymus compared to adults, those with more rapid recovery of thymic function and consequently more rapid emergence of RTE will have superior clinical outcome regardless of disease, patient, and or graft specific features. These findings should spur further research aiming to enhance recovery of the central thymic derived pathway of de novo T cell generation.

No relevant conflicts of interest to declare.