Late Pulmonary Dysfunction in Long-Term Survivors after allogeneic Hematopoietic Stem Cell Transplantation with Intensified Conditioning Regimen Including Thiotepa, Cyclophosphamide, and Total Body Irradiation.
Authors: Ito Satomi , Hagihara Maki , Motohashi Kenji , Maruta Atsuo , Ishigatsubo Yoshiaki , Kanamori Heiwa 
Published: April 2020

Abstract
Background: Late pulmonary dysfunction is a clinical problem influencing on quality-of-life (QOL) in long-term survivors after allogeneic hematopoietic stem cell transplantation (HSCT). In this study we retrospectively assessed pulmonary function test (PFT) in patients surviving 5 years or more after HSCT with intensified conditioning regimen and identified pre-and post-transplant risk factors.
Methods: Sixty-five long-term survivors transplanted between May 1994 and March 2003 (minimum 5 years follow-up after HSCT) were included in this analysis. There were 36 males and 29 females. Median age was 39 years, with a range of 16 to 53 years. All patients were transplanted because of hematologic malignancies (20 patients with AML, 16 with ALL, 9 with MDS, and 20 with CML). The pre-transplant conditioning regimen consisted of thiotepa (200 mg/m2 for 2 days), cyclophosphamide (2,000–2,250 mg/m2 for 2 days), and total body irradiation (12.5 Gy in five fractions). The prophylaxis of graft-versus-host disease (GVHD) consisted of short-term methotrexate and cyclosporine or tacrolimus. Bone marrow (BM) from related donor or unrelated donor, and peripheral blood stem cell (PBSC) from related donor were transplanted in 33 patients, 22, and 10, respectively. PFT was performed pre-conditioning and then post-transplant at 3 months, 1 year, and thereafter annually. Forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and FEV1/FVC ratio were used to measure ventilatory capacity. Vital capacity (VC) and total lung capacity (TLC) were used to measure lung volumes. Diffusion capacity for carbon monoxide (DLCO) was determined by using a carbon monoxide single-breath technique with correction for hemoglobin concentration.
Results: Seven (11%) patients showed abnormalities in PFT after HSCT. Temporary abnormality (restrictive pattern) within 1 year was detected in 2 patients. Five patients developed late-onset and continuous abnormality (restrictive pattern in 2 patients, obstructive in 2, and mixed in 2) with a cumulative incidence of 8%. These were clinically diagnosed as having bronchiolitis obliterans in 3 patient and interstitial pneumonia in 1. DLCO was significantly lower after transplantation of PBSC than after BM (P=0.02 at 3 year and P=0.00 3 at 5 year). More than 40 years old, female, high risk of disease status, and abnormal PFT pre-transplant were related with a decline of PFT within 1 year after HSCT, but there were no association with PFT abnormality at 3 or 5 years. The cumulative incidence of late PFT abnormality in patients with CML was significantly higher than that in those with other than CML (P=0.01).Other factors including age, sex, smoking, disease status, and donor sources were not significant for developing late pulmonary dysfunction. Extensive chronic GVHD was associated with late PFT abnormality with statistical significance (P=0.002 for VC and P=0.01 for FEV1). Three of 7 patients receiving immunosuppressant at 5 years after HSCT had pulmonary complication.
Conclusions: The results showed relatively a low incidence of PFT abnormality in long-term survivors who received HSCT with intensified conditioning regimen. However, late pulmonary dysfunction lowers QOL in survivors despite long-term remission of leukemia Longer follow-up should be needed to determine whether more patients with chronic GVHD will develop PFT abnormality.