Azithromycin Use and Increased Cancer Risk among Patients with Bronchiolitis Obliterans after Hematopoietic Cell Transplantation.

Azithromycin exposure during the early phase of allogeneic hematopoietic cell transplantation (HCT) has been associated with an increased incidence of hematologic relapse. We assessed the impact of azithromycin exposure on the occurrence of relapse or new subsequent neoplasm (SN) in patients with bronchiolitis obliterans syndrome (BOS) after HCT who are commonly treated with azithromycin alone or in combination with other agents. In a retrospective study of patients with BOS from 2 large allograft centers, the effect of azithromycin exposure on the risk of relapse or SN was estimated from a Cox model with a time-dependent variable for treatment initiation. The Cox model was adjusted on time-fixed covariates measured at cohort entry, selected for their potential prognostic value. Similar models were used to assess the exposure effect on the cause-specific hazard of relapse, SN, and death free of those events. Sensitivity analyses were performed using propensity score matching. Among 316 patients, 227 (71.8%) were exposed to azithromycin after BOS diagnosis. The corresponding adjusted hazard ratio (HR) in patients exposed to azithromycin versus unexposed was 1.51 (95% confidence interval [CI], 0.90 to 2.55) for relapse or SN, 0.82 (95% CI, 0.37 to 1.83) for relapse, and 2.00 (95% CI, 1.01 to 3.99) for SN. Patients exposed to azithromycin had a significantly lower cause-specific hazard of death free of neoplasm and relapse (adjusted HR, 0.54; 95% CI, 0.34 to 0.89). In conclusion, exposure to azithromycin after BOS after HCT was associated with an increased risk of SN but not relapse.

Effect of Ruxolitinib on Lung Function after Allogeneic Stem Cell Transplantation.

Ruxolitinib, a selective Janus kinase (JAK)1/2 inhibitor, has recently been proposed for steroid-refractory chronic graft-versus host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT), particularly in severe skin cGVHD. Lung function impairment is common in severe skin cGVHD through concomitant bronchiolitis obliterans syndrome (BOS) or restrictive lung disease (RLD) from skin sclerosis. To date, no treatment has shown a benefit on lung function in this context. We retrospectively assessed the effect of ruxolitinib on lung function in a cohort of 70 patients diagnosed with sclerotic-type skin cGVHD between March 2015 and April 2018. Among these patients, 36 received ruxolitinib. To handle confounding by indication bias, exposure groups were matched on the propensity score to receive ruxolitinib, incorporating age, myeloablative conditioning, total body irradiation, BOS, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and tobacco use at the time of cohort entry, as well as the time from transplantation. The 1:1 matching used a greedy-matching algorithm with replacement, with a caliper of 0.10. FVC and FEV1 trajectories during follow-up were compared in the matched samples, using linear mixed-effects models. The median duration of follow-up of the 46 matched patients was 58 months (interquartile range, 32 to 84 months). Ten patients had an RLD (6 exposed, 4 unexposed), and 13 patients were diagnosed with BOS (8 exposed, 5 unexposed). FEV1 decreased significantly over time independent of exposure to ruxolitinib (P < .0001). The FEV1 trajectory was similar in the exposed patients and the unexposed patients (P = .11). In conclusion, ruxolitinib administration did not demonstrate any improvement in the course of respiratory function in allogeneic HSCT recipients with sclerotic-type skin cGVHD.

Recurrent thoracic air leak syndrome in patients affected by pulmonary graft-versus-host disease: Surgical strategies and outcome.

BACKGROUND AND AIMS: Thoracic air leak syndrome (TALS) is a complication related to chronic pulmonary graft-versus-host disease (pGvHD) that affects approximately 0.83%-3.08% patients after allogenic hematopoietic stem cell transplant. Such complication is defined as the occurrence of any form of air leak in the thorax, including spontaneous pneumomediastinum or pneumopericardium, subcutaneous emphysema, interstitial emphysema and pneumothorax and has a negative impact on post-transplant survival. The aim of the present study is to describe a single-center experience in the surgical management of recurrent TALS in adolescents and young adults and its outcome. METHODS: We retrospectively reviewed the clinical notes of patients with previous allogenic hematopoietic stem cell transplant who underwent surgical procedures for recurrent TALS from January 2016 until March 2021. We analyzed clinical data, number of episodes of thoracic air leak, surgical procedures and relative outcome. RESULTS: In the examined period, four patients, aged 16-25 years, underwent surgical procedures for TALS, including thoracostomy tube placement, thoracoscopic pleurodesis and thoracotomy. All the patients had been diagnosed with pGvHD before the onset of TALS, with a mean time lapse of 276 days (range 42-513). These patients experienced on average 4.5 air leak episodes (range 3-6). All the patients experienced at least two episodes before surgery. One patient underwent emergency tube thoracostomy only, three patients underwent thoracoscopic pleurodesis and two patients underwent thoracotomy. After surgery, patients were free from air leak symptoms for a mean time of 176 days (range 25-477). Pulmonary function progressively deteriorated, and all the patients eventually died because of respiratory failure after a mean time of 483 days (range 127-1045) after the first episode of air leak. CONCLUSIONS: Surgery provides temporary relief to symptoms related to TALS but has limited effects on the underlying pathophysiologic process. The development of TALS in a sign of progressive pulmonary function worsening and is associated with high risk of respiratory failure and mortality.

Hematopoietic Stem Cells Transplant (HSCT)-Related Chronic Pulmonary Diseases: An Overview.

Recipients of HSCT have a high risk of infective and non-infective pulmonary diseases. Most patients with pulmonary involvement present multiple pathogenetic mechanisms simultaneously with complex interactions. Therefore, it can be difficult to distinguish the contributions of each one and to perform studies on this subject. In this opinion article, we discuss only chronic pulmonary manifestations, focusing on LONIPCs (late-onset non-infectious pulmonary complications). This term embraces drug-related toxicity, allergies, and chronic pulmonary graft versus host disease (GvHD) in all its recently identified clinical variants. Among LONIPCs, GvHD represents the most critical in terms of morbidity and mortality, despite the rapid development of new treatment options. A recently emerging perspective suggests that pulmonary lung rejection in transplant patients shares striking similarities with the pathogenesis of GvHD. In a pulmonary transplant, the donor organ is damaged by the host immune system, whereas in GvHD, the donor immune system damages the host organs. It constitutes the most significant breakthrough in recent years and is highly promising for both hematologists and thoracic transplant surgeons. The number of patients with LONIPCs is scarce, with heterogenous clinical characteristics often involving several pathogenetic mechanisms, making it challenging to conduct randomized controlled trials. Therefore, the body of evidence in this field is scarce and generally of low quality, leading to jeopardized choices in terms of immunosuppressive treatment. Moreover, it risks being outdated by common practice due to the quick evolution of knowledge about the diagnosis and treatment of LONIPCs. The literature is even more pitiful for children with pulmonary involvement related to HSCT.