Exhaled Nitric Oxide (eNO) and Pulmonary Function after Total Body Irradiation (TBI) Based Non Myeloablative Conditioning Regimens and Allogeneic Hematopoietic Cell Transplant.
Authors: Giaccone Luisa , Bucca Caterina B. , Sorasio Roberto , Rotta Marcello , Aitoro Gabriele , Panaro Erica , Brussino Luisa , Rolla Giovanni , Boccadoro Mario , Bruno Benedetto 
Published: April 2020

The introduction of non myeloablative/reduced intensity conditioning regimens for allografting has broadened the application of a potentially curative treatment to patients who, for age or medical controindications, could not tolerate conventional high dose preparative regimens. However, pulmonary causes account for a high percentage of post transplant complications. Between May 2001 and December 2004, lung function tests, methacholine inhalation challenge and eNO were evaluate pre transplant and then at 3, 6 and 12 months post allografting in 31/40 of patients affected by hematological malignancies and undergoing non myeloablative transplant at our Institution. Median age was 56 (23–64). Conditioning regimens consisted of fludarabine (90mg/m2 total) and low dose (200 cGy) TBI in 16 patients, TBI only in 14, and penthostatin + TBI in 1. Donors were matched-siblings in all but 4 patients whose donor was matched unrelated. Post-grafting immunosuppression consisted of oral cyclosporine and mycophenolate mofetil. Nine patients died within 6 months from transplant (group A); causes of death were pulmonary infection in 3, mesothelioma in 1, cerebral toxicity in 3, and progressive disease in 2. Nine died after 12 months from transplant (group B) from bronchiolites obliterans (BO), 1, lung cancer, 1, myocardial ischemia, 1, progressive disease, 4. The remaining 13 are alive (group C) after a median follow-up of 26 months (18–49 months). Patients in groupA were evaluated at baseline only. Overall, baseline rate of carbon monoxide uptake (KCO) was mildly decreased (median 65%, range 42–118%), but significantly lower when compared group A to group C (61% vs 72% p=0.01). A decline of KCO was also observed in group B.

Table 1. KCO % Baseline 3 months 6 months 12 months * n=3 in group B; n=7 in group A Group A (range) 60 (45–69) - - - Group B (range) 62 (42–118) 56 (40–82) 55 (36–117) 67 (64–76) GroupC (range) 72 (51–105) 63 (29–65) 72 (61–123) 66 (45–123)

Despite similar baseline values, at 6 months, there was evidence of higher eNO in group B when compared to group C (12 vs 31 ppb, p=0.02). Patients who received 2 or more lines of chemotherapy before allografting showed significant higher increases of eNO at 3 and 6 months post transplant: 12 vs 21 ppb (p=0.01) and 12 vs 37 ppb (p=0.0003), respectively. Co-morbidities, disease status, donor type, conditioning regimen and GVHD did not influence any of the parameters studied. BO developed in 2 patients who showed progressive worsening lung function tests and raising eNO. In summary, reduced KCO appeared to be associated with increased transplant related mortality. Previous heavy chemotherapy might predispose transplant patients to higher risk of tissue inflammation as suggested by increased eNO. Moreover, the clinical impact of elevated eNO should be further investigated as it might define a subset of patients at higher risk of pulmonary inflammation and lethal transplant related complications.