Pulmonary Mortality after High-Dose Oral Busulfan and Autologous Stem Cell Transplant (ASCT) in Patients with Non-Hodgkin Lymphoma (NHL).

Many high-dose chemotherapy preparative regimens include agents known to cause pulmonary toxicity such as BCNU. Chemotherapy induced pulmonary toxicity may be fatal. From 1/1/93 to 12/31/04 we treated 533 NHL patients with oral busulfan 14mg/kg, VP-16 60 mg/kg, and cyclophosphamide 120 mg/kg followed by ASCT. Busulfan levels were not measured. We have followed these patients for toxicity, survival, and cause of death (COD). Of these 533 patients, 214 have died, and 53 have died without relapse (15%). Most patients (n=329; 62%) had intermediate grade NHL by the IWF system. The median age was 50 years (range, 16–77) and 43% had a history of smoking. Radiotherapy was delivered to 27% and less than 3 chemotherapy regimens were administered to 75% of patients before ASCT. Sixteen patients (3%) died of non-relapse pulmonary complications. The median time to pulmonary mortality was 5 months (range, 2.5 – 21.4 months). We routinely screen patients with pulmonary function tests including DLCO before ASCT and most patients (n=490; 92%) were screened at a median of 45 days after ASCT (range, 7–90 days). For patients for whom data was available, there was no significant decrease in the median pre-ASCT and the post-ASCT DLCO in the either the whole cohort of patients or the patients dying of pulmonary complications. However, a lower baseline DLCO before ASCT predicted for pulmonary mortality after ASCT in univariable and multivariable analysis. Patients with a baseline DLCO <94% predicted, had an increased risk of pulmonary mortality compared to patients with a baseline DLCO ≥94% predicted (p=0.016). Other significant risk factors included older age, lower baseline FEV1, prior radiotherapy, and longer time from diagnosis to ASCT. A history of smoking and disease status at the time of ASCT did not predict for pulmonary mortality. Because patients died of pulmonary complications at other institutions, we could neither determine treatment, nor confirm chemotherapy induced pulmonary toxicity. However, the early onset of pulmonary mortality after ASCT suggests the possibility of a toxic insult. Busulfan is a known pulmonary toxin, but the dose in this series of patients is relatively low and we have not seen similar pulmonary complications in 95 patients (median age 52 years) with myeloma treated with the combination of busulfan 16 mg/kg and cyclophosphamide 120mg/kg. Nonetheless, caution is warranted for older patients being treated with high-dose oral busulfan.