Chronic graft vs host disease (GVHD) of the lung is a significant post-transplant complication that impacts patients' quality of life and overall survival. It manifests as bronchiolitis obliterans syndrome (BOS), an irreversible progressive airflow obstruction. Risk factors identified include busulfan, peripheral blood stem cell source, post-transplant viral infections, history of lung disease, and acute GVHD. Diagnosis involves changes in pulmonary function tests (PFTs), ruling out infection and presence of chronic GVHD in other organ systems. Without routine monitoring patients can present with moderate to severe symptoms. The predictive value of pre-transplant PFTs has not been clearly elucidated. In this retrospective study, we examined the role of pre-transplant PFT parameters with respect to the development of lung GVHD.
Patients receiving allogeneic HCT at Princess Margaret Cancer Centre between 2004 to 2013 were included in the analysis. Pre-HCT PFT results were routinely obtained within 30 days prior to transplant. PFT parameters included % predicted FEV1, DLCO, TLC, RV, RV/TLC, FRC, FVC, FEV1/FVC, FEF50% and FEF75%. After transplant, PFT was repeated around day 120, then annually, or when clinically indicated.
Our definition of lung GVHD required at least the first two of the 2005 NIH consensus criteria for the diagnosis of chronic lung GVHD: 1) FEV1/forced vital capacity ratio <0.7 and FEV1<75% predicted, 2) evidence of airway obstruction on high-resolution computed tomography or a residual volume on PFTs >120%, 3) absence of infection in the respiratory tract, and 4) histologic diagnosis of BOS or at least 1 other manifestation of chronic GVHD in an additional organ system.
The primary endpoint was cumulative incidence (CI) of lung GVHD at 3 years. The cut-off values in each PFT parameter with respect to development of lung GVHD were calculated using binary recursive partitioning (rpart) method provided by rpart package using R. Pearson's correlation test was used to look for relationship among the PFT parameters. The parameters with cut-offs identified by rpart were analyzed by factor analysis with Varimax rotation method.
For multivariable analysis, Fine-Gray proportional hazard regression with competing risks was applied. The clinical variables included in the model were busulfan, acute GVHD, and stem cell source (peripheral vs bone marrow). All statistical tests were performed using EZR and SPSS.
A total of 605 patients with available PFTs were reviewed. The CI of lung GVHD at 3 years was 10.6% (7.9 - 13.7) with a median onset at 12.6 months (range of 1.7 - 55.8).
Univariate analysis of each PFT parameter as a continuous variable did not show an impact on development of GVHD. With recursive partitioning, cut-offs were identified for DLCO (68%), FEF50% (39%), FRC (130%) and RV (93%).
In Pearson's correlation analysis, DLCO and FEF50% did not have a significant association with the other PFT parameters selected from rpart, while RV was significantly associated with TGV (r= 0.65). In the factor analysis, based on the factor loading, FEF50% and RV were selected for multivariate analysis.
Multivariate analysis showed that FEF50% < 39% and RV ≥ 93% were independent risk factors of lung GVHD development. The patients with pre-transplant FEF50 ≥ 39% had significantly less risk compared to those with < 39% (p=0.025; HR 0.389), and RV ≥ 93% showed a 2 fold higher risk than those < 93% (p=0.036, HR 2.63).
A risk score model was created using the cut-offs from FEF50% and RV. For FEF50%, score 0 was assigned to ≥ 39% while score 1 was < 39%. For RV, score 0 was assigned to < 93%, while score 1 was ≥ 93%. A risk score was summed from the two parameters. Risk scores of 2 were classified as high risk, scores of 1 intermediate risk and score of 0 low risk. The 3 year CIs of lung GVHD were then compared according to the new risk score. The high risk group had an incidence of 33.5% (11.8 - 57.0%; n=28, 4.6%), intermediate risk 11.4% (8.3 - 15.2%; n=445, 73.6%) and low risk 3.0% (0.8 - 8.2%; n=132, 21.8%; p = 0.003; Figure).
1) Pre-transplant PFT parameters can predict the risk of lung GVHD development.
2) FEF50% and RV were predictive of lung GVHD development independent from the other clinical risk factors acute GVHD, busulfan and stem cell source which were not confirmed in our cohort.
3) A risk score model using pre-transplant FEF50% and RV may help in prediction of lung GVHD.
Kim: Paladin: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy.
Asterisk with author names denotes non-ASH members.