Failure to Recover Thymopoiesis After Allogeneic Hematopoietic Stem Cell Transplantation Predicts for High Incidence of Opportunistic Infections and Non-Relapse Mortality
Authors: Wils Evert-Jan , van der Holt Bronno , Broers Annoek E.C. , Sluijs Sandra J. Posthumus-van , Gratama Jan W. , Braakman Eric , Cornelissen Jan J. 
Published: October 2019

Abstract
Abstract 832
Recovery of thymopoiesis after allogeneic hematopoietic stem cell transplantation (alloSCT) is considered pivotal for full immune competence. Failure to recover thymopoiesis after alloSCT is suggested by the absence of newly developed T-cells that contain signal joint T-cell Receptor Excision Circles (sjTREC), which are produced during T-cell receptor rearrangement. Higher age, reduced pre-transplant thymic function, and graft versus host disease have all been associated with impaired thymic recovery after alloSCT. However, it is still unclear to what extent insufficient thymic recovery itself predicts for subsequent opportunistic infections and non-relapse mortality (NRM). A detailed, prospective survey of all post-engraftment infectious complications, NRM, overall survival (OS), and lymphocyte subsets and thymic recovery during long-term follow-up after alloSCT was performed in 83 high-risk recipients of T cell depleted related or unrelated donor grafts after myeloablative conditioning. A cumulative incidence of common toxicity criteria (CTC) grade 3 and 4 severe infections at 12 months after alloSCT was 66% with a median number of 1.6 severe infectious episodes per patient. The rate of severe post-engraftment infections was 0.64 per 100 patient days during the first year and 0.16 in the second year. After a median follow-up of 118 months, OS was 52%, as determined by a NRM of 25% and relapse mortality of 23%. Outcome was significantly predicted for by the European Group for Blood and Marrow Transplantation (EBMT)-risk score (Gratwohl et al, Cancer, 2009), based on age, gender, risk-status, donor-type and time to SCT (p=0.01). Lymphocyte recovery was slow with median CD4+ T cells exceeding 200/ul by 12 months post alloSCT. At that time, median sjTREC content measured 5.629/ml, which was significantly lower than the median sjTREC content in stem cell donors (19.044/ml, p=0.001). The recovery rate of overall lymphocyte counts as well as T cell subsets did not consistently predict for opportunistic infections and NRM. Patients without thymic recovery at 2, 6, 9, or 12 months were at 3- to 9-fold higher risk for severe infections, which remained significant following multivariable analysis (hazard ratio (HR)-6 months: 0.30 (95%CI 0.09–1.02, p=0.04), HR-12 months: 0.11 (0.01-0.93 p=0.02)). Impaired thymic recovery also translated into a higher risk for NRM (HR-6 months: 0.06 (0.01-0.47 p=0.008), HR-12 months: 0.00 (0.00-1.42 p=0.0005)) and outweighed pre-transplant risk factors including age, donor-type, risk-status when evaluated individually or collectively as the EBMT risk score. Impaired thymic recovery at 6 months was also predictive for lower OS (HR; 0.35 (0.12-1.00 p=0.05)). In conclusion, these results indicate that patients, who fail to recover thymopoiesis after alloSCT are at very high risk for severe infections and adverse clinical outcome, independent of other pre-transplant risk factors and despite intensive monitoring and prophylactic antimicrobial measures. These results indicate that monitoring thymopoiesis after alloSCT may be applied more routinely and strategies to reduce NRM should be directed at thymic regeneration.

Disclosures:
No relevant conflicts of interest to declare.