Combined Analysis of Early CD4+ T Cell Counts and CMV Serostatus May Improve CMV Risk Assessment after Allogeneic Hematopoietic Cell Transplantation.

Saskia Leserer,Esteban Arrieta-Bolaños,Ulrike Buttkereit,Amin T Turki,Dietrich W Beelen

doi:10.3390/cells10123318

Abstract

The incidence and severity of viral complications after cellular therapy are highly variable. Recent publications describe relevant interactions between the human Cytomegalovirus (CMV) and host immunity in recipients of allogeneic hematopoietic cell transplantation (HCT). Although immune monitoring is routinely performed in HCT patients, validated cut-off levels correlating with transplant outcomes such as survival or CMV reactivation are mostly limited to day +100, which is later than the median time for CMV reactivation in the absence of medical prophylaxis. To address this gap in early risk assessment, we applied an unsupervised machine learning technique based on clustering of day +30 CD4+ helper T cell count data, and identified relevant cut-off levels within the diverse spectrum of early CD4+ reconstitution. These clusters were stratified for CMV recipient serostatus to identify early risk groups that predict clinical HCT outcome. Indeed, the new risk groups predicted subsequent clinical events such as NRM, OS, and high CMV peak titers better than the most established predictor, i.e., the positive CMV recipient serostatus (R+). More specifically, patients from the R+/low CD4+ subgroup strongly associated with high CMV peak titers and increased 3-year NRM (subdistribution hazard ratio (SHR) 10.1, 95% CI 1.38–73.8, p = 0.023), while patients from the R-/very high CD4+ subgroup showed comparable NRM risks (SHR 9.57, 95% CI 1.12–81.9, p = 0.039) without such an association. In short, our study established novel cut-off levels for early CD4+ T cells via unsupervised learning and supports the integration of host cellular immunity into clinical risk-assessment after HCT in the context of CMV reactivation.

Highlights

Cytomegalovirus (CMV) reactivation remains the most frequent viral complication after hematopoietic cell transplantation (HCT) [1]
R+ serostatus guides the use of CMV prophylaxis with letermovir [2], as CMV recipient (CMV-R)+ patients have been previously associated with worse clinical outcome after HCT [9,10]
A total of 266 patients with HCT between January 2012–December 2017 were included in this retrospective analysis and independently analyzed, with a focus on the identification of clinically relevant predictors and the interaction between CMV serostatus and early host immune reconstitution

Summary

Introduction

Cytomegalovirus (CMV) reactivation remains the most frequent viral complication after hematopoietic cell transplantation (HCT) [1]. Increased evidence of synergic processes between immune reconstitution and viral reactivation that influence clinical outcome after HCT has been reported in recent studies, focusing both on CMV biology and host immunity [3,4]. Recent publications have highlighted the importance of the absolute copy number of CMV viral loads, as a surrogate of CMV’s burden of disease [5–7] for clinical outcome, and associated lower early CD3+ /CD4+ counts after HCT with the incidence of later high. R+ serostatus guides the use of CMV prophylaxis with letermovir [2], as CMV-R+ patients have been previously associated with worse clinical outcome after HCT [9,10]. Predicting the overall incidence of CMV reactivation, previous data suggested that the R+ serostatus alone does not stratify patients for clinically relevant CMV peak titer risk groups [5]

Methods

Results

Conclusion