Rapid and Robust CD4+ and CD8+ T-, NK-, B-Cell, Dendritic Cell, and Monocyte Reconstitution after Nicotinamide-Expanded Cord Blood Transplantation

Abstract

Introduction Nicotinamide-expanded cord blood (NiCord) is a potential alternative source for allogeneic hematopoietic cell transplantation (HCT) when an HLA-id donor is lacking. A phase 1/2 trial with standalone NiCord HCT showed rapid neutrophil- (11 days) and platelet engraftment (34 days). We previously reported that successful CD4+ immune reconstitution (IR) is crucial for infectious and relapse control associated with favorable survival (JACI 2017) and is a better predictor for event-free survival than neutrophil reconstitution. We performed unique in-depth immune monitoring to evaluate and compare IR after NiCord and conventional HCT. Methods In this phase1/2 international multicenter trial, we compared IR after NiCord HCT to cohorts of adolescent and young adult (AYA) patients receiving either unmanipulated cord blood transplantation (unCBT) or T-repleted-unrelated bone marrow transplantation (BMT). All patients received HCT for a hematologic malignancy with myeloablative conditioning without serotherapy. Immune monitoring was performed (harmonized sampling, handling and analyses) in a central lab. The primary endpoint was probability of achieving CD4+ IR (>50*106/L within 100 days). Secondary endpoints were IR of B-cells, CD4+ and CD8+ T-cells, natural killer (NK)-cells, monocytes, and dendritic cells (DC) 7-365 days after HCT. In addition, TREC analyses were performed on CD3+ MACs-sorted cells. Linear-mixed effects modelling in LOESS-regression curves and two-sided log-rank test for univariate comparisons in cumulative incidence plots were used. Results 27 NiCord recipients (median 41.5; 13.4-61.7yrs) were included. NiCord cell dose consisted of median 6.4*106 CD34+/kg, and 2.3*106 CD3+T-cells/kg of the co-infused negative fraction (following CD133+ selection). Of these patients, 91% achieved successful CD4+ IR, which was comparable (p=0.76, Figure 1) to the 27 unCBT (median 15.4; 12.2-22.1 yrs) and 20 BMT (median 14.3; 12.1-19.7 yrs) recipients included in this study. We observed similar reconstitution of T-cells (p=0.15), monocytes (p=0.94), conventional DCs (p=0.41), and plasmacytoid DCs (p=0.52). Interestingly, reconstitution of NK-cells (p Conclusions In-depth immune monitoring reveals fast and full IR after NiCord HCT in adult patients, which is equal or even faster to IR after unCBT or BMT, despite the younger age of the AYA cohorts (expected to reconstitute faster). This may be explained by the higher stem cell dose and higher proliferative capacity of the NiCord-expanded product. Optimal comparison of IR in NiCord vs. unCBT in a randomized phase 3 trial is underway.