Plasmacytoid CD123+ Dendritic Cell Recovery Is An Independent Predictor of Survival after Unrelated Cord Blood Transplant (UCBT).

BACKGROUND: Reconstitution of adaptive immunity is critical for long term survival following hematopoietic cell transplantation. Antigen presenting dendritic cells (DC) and CD4+ T cells are critical for attaining immunity. Unrelated umbilical cord blood transplantation (UCBT) is a suitable option for those who lack HLA-matched sibling donors. However, opportunistic infections remain the major cause of non-relapse mortality. Analysis of the COBLT trial reported that successful recovery of antiviral immunity is associated with a reduced rate of relapse (BBMT. 2006;12:1335). METHODS: Between July, 2005 and December, 2007, 95 children with successful donor cell engraftment were assessed for reconstitution of DC subsets along with CD4+ T cells to analyze their impact on overall survival (OS) following myeloablative conditioning and a single cord blood transplant at Duke University. Utilizing Trucount™ methodology 4-color surface FACS was employed to enumerate absolute cell numbers at 3, 6, 12, 24, 36 months after transplant. RESULTS: 52 (55%) of patients were transplanted for non-malignant diseases while 43 (45%) had malignancies. The median age was 2.7 years (range, 0.1–18.0). 55 (59%) of patients were male and 74 (78%) were white. 38 (40%) were 4/6 HLA match, 39 (41%) were 5/6 and 18 (19%) were 6/6. The median infused TNC was 7.2 x 107/kg (range, 0.8–31.6), median infused CD34+ was 1.9 x 105/kg (range, 0.0–11.0), and median infused CD3+ T cells was 11.7 x 106/kg (range, 0.0–90.3). Of the 95 patients considered in this analysis, 6 patients died before day 180 with a day 180 survival probability of 93.7% (95% CI 86.5%–97.1%), 11 patients died between day 180 and 365 with a 1-year survival probability of 81.7% (95% CI 72.2%–88.2%) and 8 patients died between day 365 and 730 with a 2-year survival probability of 69.1% (95% CI 57.1%–78.3%). In an univariate analysis of OS post-transplant, HLA match of 5/6 or 6/6 (HR=0.41, p=0.02), absolute number of CD123+ “plasmacytoid” dendritic cells (pDC) >8 cells/ul and a non-malignant diagnosis (HR=0.25, p=0.001) were associated with a decreased risk of death, while CD4+ T cell and CD11c+ “myeloid” DC recovery had no statistical impact, Table 1. In this cohort, where all studied patients have successfully engrafted with relatively high cell dose; gender, race, CMV serology, TNC, CD34+ cell dose, TBI had no discernible impact. There were two prognostic factors that maintained statistical significance in a multivariate model; Absolute number of CD123+ DC >8 cells/ul (HR=0.44, p=0.05) and non-malignant disease (HR=0.27, p=0.002), while HLA was not statistically significant (HR=0.53, p=0.10), Table I. Importantly, non-malignant patients do not get TBI, do not die due to relapse, tend to be younger and such receive higher cell doses. CONCLUSION: This is the first analysis to our knowledge to suggests that the absolute number of CD123+ pDC >8 Cells/ul is an independent predictor of survival after UCBT. These cells are the most potent APC providing interferon-alpha mediated activation of the immune system besides presentation of antigenic peptides. There is a need for better understanding of the factors that may impact pDC reconstitution so novel therapeutic approaches may improve survival after UCBT. Univariate Modeling of OS | | HR (95% CI) | p-value | Interpretation | |:---------------------------------------------------------- | ---------------- | ------- | ----------------------------------------------------------------------------------- | | Gender | | | | | Female | 1.52 (0.72–3.21) | 0.27 | NS | | Male | 1.00 | | | | Disease | | | | | Non-Malignant | 0.25 (0.11–0.58) | 0.001 | Non-Malignant patients have a 75% decreased risk of dieing as compared to malignant | | Malignant | 1.00 | | | | TNC/kg | 1.03 (0.97–1.10) | 0.35 | NS | | CD34+/kg | 1.01 (0.86–1.19) | 0.87 | NS | | CD3+/kg | 1.01 (0.98–1.04) | 0.68 | NS | | HLA Match | | | | | 5/6 or 6/6 | 0.41 (0.20–0.88) | 0.02 | 59% decreased risk of dieing with a HLA match of 5/6 or 6/6 | | 4/6 | 1.00 | | | | | | | 41% decreased risk | | Abs CD4+ T cells Time-dependent | 0.59 (0.23–1.52) | 0.28 | of dieing if you get 200 abs CD4+ T-cell | | Absolute Number of CD123+ DC (pDC/ul) Time-Dependent | 0.42 (0.18–0.95) | 0.04 | 58% decreased risk of dieing if you get >8 | | Absolute Number of CD11c+ (Myeloid DC/ul) Time-dependent ( | 1.05 (0.44–2.47) | 0.92 | NS | | CD4+ (%CD4+) Time-dependent | 2.12 (0.80–5.62) | 0.13 | NS | Multivariate Model | | HR (95% CI) | p-value | Interpretation | |:-------------------------------------------------------------:| ---------------- | ------- | ----------------------------------------------------------------------------------- | | HLA Match | | | | | 5/6 or 6/6 | 0.53 (0.25–1.14) | 0.10 | 47% decreased risk of dieing with a HLA match of 5/6 or 6/6 | | 4/6 | 1.00 | | | | Absolute Number of CD123+ (Plasmacytoid DC/ul) Time-Dependent | 0.44 (0.20–1.00) | 0.05 | 56% decreased risk of dieing if you get >8/ul | | Disease | | | | | Non-Malignant | 0.27 (0.12–0.63) | 0.002 | Non-Malignant patients have a 75% decreased risk of dieing as compared to malignant | | Malignant | 1.00 | | |