Incidence, Risk Factors and Outcome of Late Onset Noninfectious Pulmonary Complications after Allogeneic Hematopoietic Stem Cell Transplantation: A Prospective Cohort Study
Authors: Bergeron Anne , Chevret Sylvie , Peffault De La Tour Regis , Chagnon Karine , De Bazelaire Cedric , Rivière Frédéric , Robin Marie , Mani Jean , Lorillon Gwenael , Gérard Socié , Tazi Abdellatif 
Published: October 2019

Abstract
Introduction: Late onset noninfectious pulmonary complications (LONIPCs) occurring beyond the third month following allogeneic hematopoietic stem cell transplantation (HSCT) are various and are associated with a poor outcome. Bronchiolitis obliterans (BO) is the most frequent LONIPC. Available epidemiological data are conflicting and exclusively come from retrospective studies.
Methods: We conducted a prospective observational cohort study where all consecutive patients who were scheduled to receive an allogeneic HSCT between January, 31, 2006 and December, 31, 2008 at the university-teaching Saint Louis Hospital (Paris, France) were prospectively screened for inclusion in the study. Those allogeneic HSCT recipients surviving at day 100 were included in the cohort. They were followed-up for at least three years after HSCT. Clinical outcomes were the 3-year incidence and mortality of LONIPC, and the identification of early risk factors for LONIPC and specifically BO. This study is registered with ClinicalTrials.gov, number NCT 01219972.
Results: 198 patients were included after a median of 101 [IQR: 99-106] days following HSCT, from a total of 243 screened patients. The actual median follow up of the 198 included patients was 72.3 months [IQR: 15.2-88.5]. 68 patients died within the first 36 months resulting in a 3-year overall survival after inclusion of 65.4% (95%CI: 59.1-72.4%). Fifty five episodes of LONIPC were diagnosed in 43 patients. These 55 LONIPC were diagnosed as BO (n=22), interstitial lung disease (n=12), and others. Ten patients had more than one LONIPC during the follow-up. At 36 months after inclusion, the estimated cumulative incidence of LONIPC was 19.8% (95%CI: 14.2-25.3%). The 36 months cumulative incidence of BOS was 10.7%, (95%CI: 6.3-15.1%). 18 patients with a LONIPC died during the follow up with an estimated median survival of 78.5 months (95%CI: 20.0-not reached) after the diagnosis of LONIPC. The occurrence of LONIPC was associated with an increased hazard of death (HR=2.18, 95%CI= 1.14; 4.15; p= 0.0181). Based on a multivariable Cox model, a chest irradiation prior to HSCT, a history of pneumonia within the 100 days post HSCT and a low FEF 25-75 at day 100 were associated with the development of LONIPC. The use of PBSC was predictive for BOS based on a multivariable Cox model both after multiple imputation and on the complete cases whereas both a history of post transplantation pneumonia and bronchial abnormalities on CT scan at day 100 were also identified as predictive factors after multiple imputation and a 10% FEV1 decline from baseline to day 100 was a predictive factor for BOS on the complete cases.
Conclusion: our data give clues to identify high-risk patients for developing LONIPC/BO. These patients should be targeted for close monitoring, and so offer earlier treatment of LONIPC or prophylactic treatment to improve the outcome.
Funding: The study was supported by an institutional grant from the French Ministry of Health (CRC 04118).

Disclosures
Peffault De La Tour: PFIZER: Consultancy, Honoraria, Research Funding; ALEXION: Consultancy, Honoraria, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding.