Impact of Pre-Transplant Diffusion Lung Capacity for Nitric Oxide (DLNO) and of Dlno/Pre-Transplant Diffusion Lung Capacity for Carbon Monoxide (DLNO/DLCO) Ratio on Pulmonary Outcomes in Adults Receiving Allogeneic Stem Cell Transplantation for Haematological Diseases
Authors: Le Bourgeois Amandine , Malard Florent , Chevallier Patrice , Guillaume Thierry , Delaunay Jacques , Peterlin Pierre , Lemarchand Patricia , Germaud Patrick , Mohty Mohamad , Moreau Philippe , Chambellan Arnaud 
Published: October 2019

Abstract
Background: Pre-transplant pulmonary function testing (PFT) is required in all patients eligible for allogeneic stem cell transplantation (allo-SCT). Diffusion lung capacity for carbon monoxide (DLCO) is the main parameter taken into account but the overall impact of this factor is debated. Diffusion lung capacity for nitric oxide (DLNO) may be of higher interest to predict pulmonary complications, because radiotherapy and chemotherapy used to treat patients with haematological diseases affect mostly the alveolar-capillary membrane, which destruction is more appreciate by DLNO than DLCO measure. Also, DLNO/DLCO ratio represents a new index of gas exchange and an alternative way of investigating the alveolar membrane and the blood reacting with the gas.
Methods: We considered all patients who received an allo-SCT for hematological malignancies between March 2012 and January 2014 in our department and for whom a pre-transplant PFT, including DLCO and DLNO measures, was validated. Factors influencing pre-transplant DLCO, DLNO and DLNO/DLCO ratio were analyzed as well as impact of those 3 diffusion lung parameters on general outcomes and pulmonary complications (severe pulmonary complications (SPC) defined as any pulmonary complication responsible for hospitalization, pulmonary related mortality (PRM), acute respiratory distress syndrome (ARDS).
Results: We included 103 patients (male: n=68, median age at transplant: 58 years) in this study. Majority of them had a myeloid disease (n=67), and were in complete (n=56) or partial (n=23) remission at transplant. Type of donor was: matched related donor (N=35), haploidentical related donor (n=5), matched unrelated donor (n=43), mismatched unrelated donor (n=9) and umbilical cord blood (n=10). First stem cell source used was peripheral blood stem cell (n=83). Eight five percent of patient received a reduced intensity regimen. With a median follow up of 21.5 months (range: 3.8-34.7), 2 year cumulative incidence of overall survival, Disease free survival, relapse incidence, non-relapse mortality, SPC, ARDS and PRM were respectively 65.4% ( 55.2-73.6), 52.5% (42.7-62.2), 31.8% (22.3-41.7), 15.8% (9.4-23.5), 25.4% (17-34), 7.8% (4-14), and 4.9% (1.8-10.4). Normal DLCO and DLNO percentages of predicted normal value (>80%) were documented in 48 and 44 patients, respectively but median percentages for the all cohort were under the normal at transplant: DLCO: 78.9%, DLNO: 78.1%. Median DLNO/DLCO ratio was 5.3 (range: 2.7-8.6). Regarding factors influencing pre-transplant PFT results, DLCO was significantly decreased in patients with respiratory history (72.3% versus 81.5%, p=0.001), in patients having received therapeutic with cardiac or pulmonary toxicities (74.2% versus 80.6%, p=0.02) and in patients over 58 years (81.0% versus 75.4%, p=0.05). Similarly, DLNO was significantly decreased in patients with respiratory history (74.3% versus 80.9%, p=0.03) and in patients' smokers or with history of smoking (75.3% versus 81.8%, p=0.03). Finally, patients' age was the only parameter with a significant impact on DLNO/DLCO (5.5 in patients >58 years versus 5.2 in patients ≤58years, p=0.04). In univariate analysis, a DLNO value <60% of predicted normal value was associated with higher incidences of SPC (p=0.02) and acute respiratory distress syndrome (ARDS) (p<0.005). When considering DLCO and DLNO as continuous variables, lower percentage were associated with higher risk of SPC for both parameters (p=0.048 and p=0.026, respectively). Also, lower DLNO/DLCO ratio (considered as a continuous variable) was associated with higher PRM (p=0.04). In multivariate analysis, there was a trend for an association between lower value of pre-transplant DLNO (<60%) and higher risk of ARDS (HR: 3.34, 95%CI: 0.99-11.2, p=0.05) and of SPC (HR: 2.5, 95%CI: 0.93-7.12, p=0.06).
Conclusion: DLNO and DLNO/DLCO ratio may be more appropriate to predict pulmonary complications than DLCO alone after allo-SCT. These results have to be confirmed prospectively.

Disclosures
Mohty: Janssen: Honoraria; Celgene: Honoraria. Moreau:Takeda: Other: Adboard; Amgen: Other: Adboard; Novartis: Other: Adboard; Celgene: Honoraria, Other: Adboard; Janssen: Other: Adboard.