Post-Transplant Pulmonary Function Abnormalities Nadir At Five Years and Then Fully Normalize by the Second Decade in Allogeneic Stem Cell Transplantation Survivors

Late onset non-infectious pulmonary injury complicates >10% of allogeneic stem cell transplants (SCT), particularly in subjects conditioned with high dose Total Body Irradiation (TBI), and contributes to transplant related mortality. To characterize the kinetics of recovery from pulmonary injury in long term survivors we collected data on 138 (78 male, 60 female) subjects surviving >5 years after SCT from their HLA-matched siblings. The median age at transplant was 36 years. Transplant indications were CML (63), AML (31), MDS (19), ALL (12) and others (14). 126 subjects received ≥1200 cGy TBI-based conditioning with or without lung shielding, 3 received 400 cGy TBI-based conditioning and 9 patients received no irradiation. Ex vivo T cell depleted grafts were given to 131 recipients, except for six who received a non-myeloablative SCT. Of the 138 long term survivors, 26 had no cGvHD, 70 had cGvHD lasting less than 3 years; and 42 had prolonged cGvHD requiring systemic immunosuppression for > 3 years. Among the 17 patients who died after 5 years, 4 died of pulmonary causes, including two with lung cancer. Pre-transplant abnormalities (< 80% predicted) in PFTs were found in 15.9% of subjects in the following declining frequency: FVC%, VC, TLC, FEV1, DLCO_Adj (adjusted for hemoglobin and alveolar ventilation) Hb/VA and FEV1/FVC.  Baseline (BL) PFTs served as the reference for all subsequent measurements at 3, 5, 10 and 15 years for each survivor. The only parameter showing a clinically significant decline post transplant was DLCO_Adj which reached a nadir at 5 years, with subsequent normalization at the 10 year mark [paired t-test]. An abnormal (<80% of baseline) DLCO Adj was found in 19.6, 21.0, 0.7 and 0% of survivors at 3, 5, 10 and 15 years. The mean DLCO_Adj at 3, 5, 10 and 15 years were 91% (p=0.003), 88% (p<0.001), 98% (p=NS) and 100% (p=NS) of BL, respectively. Multivariable modeling (forward-stepwise multiple regression) identified the presence of chronic GVHD (p=0.017) and abnormal Baseline DLCO_Adj (P=0.023) as the only significant factors associated with the decline in DLCO_Adj at 5 years but excluded smoking, conditioning intensity, baseline C-reactive protein level, TBI dose to the lungs and demographic variables. In conclusion, DLCO_Adj is the only PFT marker associated with pulmonary injury in our TBI-conditioned transplant population. DLCO_Adj nadirs at 5 years post-SCT, and normalizes by 10 years. Chronic GVHD and pre-transplant DLCO_Adj are important contributory factors to the decline in DLCO_Adj.