Evaluation of risk for bronchiolitis obliterans syndrome after allogeneic hematopoietic cell transplantation with myeloablative conditioning regimens

Abstract

Bronchiolitis obliterans syndrome (BOS), as chronic manifestation of graft-versus-host disease (GVHD), is a debilitating complication leading to lung function deterioration in patients after allogeneic hematopoietic cell transplantation (allo-HCT). In the present study, we evaluated BOS development risk in patients after receiving myeloablative conditioning (MAC) regimens. We performed a retrospective analysis of patients undergoing allo-HCT, who received MAC with busulfan/cyclophosphamid (BuCy, n = 175) busulfan/fludarabin (FluBu4, n = 29) or thiotepa/busulfan/fludarabine (TBF MAC, n = 37). The prevalence of lung disease prior allo-HCT, smoking status, GvHD prophylaxis, HCT-CI score, EBMT risk score and GvHD incidence varied across the groups. The cumulative incidence of BOS using the NIH diagnosis consensus criteria at 2 years after allo-HCT was 8% in FluBu4, 23% in BuCy and 19% in TBF MAC (p = 0.07). In the multivariate analysis, we identified associated factors for time to BOS such as FEV1<median (99% of predicted) (HR = 2.39, p = 0.004), CMV patient serology positivity (HR = 2.11, p = 0.014), TLC < 80% of predicted (HR = 0.12, p = 0.02) and GvHD prophylaxis with in vivo T-cell depletion (HR = 0.29, p = 0.001) as predictors of BOS. In summary, we identified risk factors for BOS development in patients receiving MAC conditioning. These findings might serve to identify patients at risk, who might benefit from closely monitoring or early therapeutic interventions.

Fig. 1. Outcome variables by BOS development within the first year after allo-HCT.

To address the influence of BOS development on outcome after allo-HCT we performed a landmark analysis. Patients surviving 365 days after allo-HCT were included in the analysis (n = 195). Outcome variables were analyzed by BOS development within the first year after allo-HCT. Kaplan-Meier curves represent (a) overall survival and (b) progression-free survival and cumulative incidence curve represent (c) non-relapse mortality and (d) relapse incidence in patients conditioned with myeloablative conditioning regimens prior allo-HCT. Pts patients, allo-HCT allogeneic hematopoietic cell transplantation.

Fig. 2. Cumulative incidence of BOS by clinical factors and lung function tests associated with BOS in multivariate analysis.

Cumulative incidence curve represent bronchiolitis obliterans by (a) FEV1 ≥ or <median (99% of predicted), (b) CMV patient positivity or negativity, (c) GvHD prophylaxis with or without in vivo T-cell depletion and (d) TLC ≥ or < 80% of predicted in patients conditioned with myeloablative conditioning regimens prior allo-HCT. Statistical analysis was performed for Fine and Gray regression models in the presence of competing risks. FEV1 forced expiratory volume in 1 s., TLC total lung capacity, Pts patients, allo-HCT allogeneic hematopoietic cell transplantation, SHR subdistribution hazard ratio, CI confidence intervals.

Fig. 3. Cumulative incidence of BOS by cGvHD within the first year after allo-HCT.

We performed a landmark analysis of cGvHD excluding BOS as risk factor for BOS development. Patients surviving 365 days after allo-HCT were included in the analysis (n = 195). Cumulative incidence of BOS was analyzed by cGvHD onset within the first year after allo-HCT. SHR subdistribution hazard risk, CI confidence interval, cGvHD chronic GvHD, allo-HCT allogeneic hematopoietic cell transplantation.