Insufficient recovery of thymopoiesis predicts for opportunistic infections in allogeneic hematopoietic stem cell transplant recipients

Abstract

Background: Recovery of thymopoiesis after allogeneic hematopoietic stem cell transplantation is considered pivotal for full immune competence. However, it is still unclear to what extent insufficient recovery of thymopoiesis predicts for subsequent opportunistic infections and non-relapse mortality.

Design and methods: A detailed survey of all post-engraftment infectious complications, non-relapse mortality and overall survival during long-term follow-up was performed in 83 recipients of allogeneic stem cell grafts after myeloablative conditioning. Recovery of thymopoiesis was assessed using analysis of signal joint T-cell receptor rearrangement excision circles. The impact of recovery of thymopoiesis at 2, 6, 9 and 12 months post-transplantation on clinical outcome beyond those time points was evaluated by univariate and multivariate Cox regression analyses.

Results: The cumulative incidence of severe infections at 12 months after transplantation was 66% with a median number of 1.64 severe infectious episodes per patient. Patients in whom thymopoiesis did not recover were at significantly higher risk of severe infections according to multivariable analysis. Hazard ratios indicated 3- and 9-fold increases in severe infections at 6 and 12 months, respectively. Impaired recovery of thymopoiesis also translated into a higher risk of non-relapse mortality and outweighed pre-transplant risk factors including age, donor type, and disease risk-status.

Conclusions: These results indicate that patients who fail to recover thymopoiesis after allogeneic hematopoietic stem cell transplantation are at very high risk of severe infections and adverse clinical outcome.

Figure 1.

Outcome. (A) Cumulative percentage of overall survival (OS), non-relapse mortality (NRM), and relapse mortality (REL) in months following allogeneic HSCT; OS, NRM and REL (which are competing risks) sum up to 100% at all time points. (B) Cumulative percentage of OS stratified by EBMT risk score in months following allogeneic HSCT (log rank: P=0.01).

Figure 2.

Immune reconstitution. Box plots are shown of (A) CD4⁺ T-cell recovery (CD4⁺ T cells/μL blood) and (B) sjTREC⁺ T-cell recovery (sjTREC⁺ cells/mL blood) in recipients in time following allogeneic HSCT and values in normal donor controls. Each box shows the median, quartiles, and extreme values. Outliers are represented by •.

Figure 3.

CTC grade ≥ 3 infections in patients with or without recovery of thymopoiesis. Cumulative incidence of first CTC grade ≥3 infection in months beyond the time-points of measurement in patients with (>0) or without (0) sjTREC⁺ T-cell recovery as measured at 2 (A), 6 (B), 9 (C) and 12 (D) months after allogeneic HSCT. N: number of patients evaluated; d: number of patients reaching the endpoint. P values of likelihood ratio testing: 0.45 (2 months); 0.06 (6 months); 0.81 (9 months); and 0.01 (12 months).

Figure 4.

Non-relapse mortality in patients with or without recovery of thymopoiesis. Cumulative incidence of non-relapse mortality in months beyond the time-points of measurement in patients with (>0) or without (0) sjTREC⁺ T-cell recovery as measured at 2 (A), 6 (B), 9 (C) and 12 (D) months after allogeneic HSCT. N: number of patients evaluated; d: number of patients reaching the endpoint. P-values of likelihood ratio testing: 0.37 (2 months); 0.03 (6 months); 0.01 (9 months); 0.13 (12 months).