Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper.

Monoclonal antibodies targeted against the immune checkpoint molecules CTLA-4 and PD-1 have recently obtained approval for the treatment of metastatic melanoma and advanced/refractory non small-cell lung cancers. Therefore, their use will not be limited anymore to selected hospitals involved in clinical trials. Indeed, they will be routinely prescribed in many cancer centers across the world. Besides their efficacy profile, these immune targeted agents also generate immune-related adverse events (irAEs). This new family of dysimmune toxicities remains largely unknown to the broad oncology community. Although severe irAEs remain rare (∼10% of cases under monotherapy), they can become life-threatening if not anticipated and managed appropriately. Over the last 5 years, Gustave Roussy has accumulated a significant experience in the prescription of immune checkpoint blockade (ICB) antibodies and the management of their toxicities. Together with the collaboration of Gustave Roussy's network of organ specialists with expertise in irAEs, we propose here some practical guidelines for the oncologist to help in the clinical care of patients under ICB immunotherapy.

[Acute interstitial pneumonia: diagnostic approach and management]. / Les pneumopathies infiltrantes aiguës : démarche diagnostique et approche thérapeutique.

Acute interstitial pneumonia (AIP) encompasses a spectrum of pulmonary disorders characterized by involvement of the lung interstitium and distal airways (bronchioles and alveoli). The onset of respiratory symptoms is acute, most often within two weeks. Most AIP take place de novo, but sometimes represent an acute exacerbation of chronic lung disease. The clinical presentation of AIP comprises rapidly progressive dyspnoea, associated sometimes with cough, fever, myalgia and asthenia. Chest radiography shows diffuse pulmonary opacities. The associated hypoxemia may be severe enough to cause acute respiratory failure. Underlying aetiologies are numerous and variable, particularly in relation to the underlying immune status of the host. Various histopathological entities may be responsible for AIP although diffuse alveolar damage is the predominant pattern. The diagnostic approach to a patient presenting with AIP is to try to determine the most likely underlying histopathological pattern and to search for a precise aetiology. It relies mainly on a meticulous clinical evaluation and accurate biological investigation, essentially guided by the results of bronchoalveolar lavage performed in an area identified by abnormalities on high resolution computed tomography of the lungs. Initial therapeutic management includes symptomatic measures, broad-spectrum antibiotic treatment adapted to the clinical context, frequently combined with systemic corticosteroid therapy.

[Prospective evaluation of the efficacy of the combination of budesonide/formoterol in obstructive airway disease after allogeneic hematopoietic stem cell transplantation]. / Efficacité de l'association budésonide/formotérol dans le trouble ventilatoire obstructif survenant après allogreffe de cellules souches hématopoïétiques.

BACKGROUND: Although it has not been evaluated prospectively, the usual treatment for obstructive airway disease after allogeneic hematopoietic stem cell transplantation, which is related to graft versus host disease, consists of intensification of systemic immunosuppressive therapy. However, this treatment has a limited efficacy and is associated with a significant number of serious adverse effects, particularly infectious. Alternative treatments are therefore required. Recently, clinical and functional improvement in patients with obstructive airway disease following allogenic hematopoietic stem cell transplantation treated with inhaled combined Budesonide/Formoterol has been retrospectively reported. METHODS: The present prospective multi-centered, randomised double-blind trial is designed to evaluate the efficacy of the combination of budesonide/formoterol (400/12 microg 2 inhalations bid) versus placebo in patients with moderate to severe obstructive airway disease, not requiring initiation or intensification of systemic immunosuppressive therapy for extra thoracic graft versus host disease. The primary outcome will be the improvement of FEV1 at 1 month of treatment. The secondary outcomes will be the clinical and functional pulmonary improvements at 6 months. EXPECTED RESULTS: The leading hypothesis is that patients treated with inhaled combined Budesonide/Formoterol will show significant improvement of their clinical symptoms and pulmonary functional testing.

Endobronchial Epstein-Barr Virus Associated Post-transplant Lymphoproliferative Disorder in Hematopoietic Stem Cell Transplantation.

The Epstein-Barr virus (EBV) associated Post-Transplant Lymphoproliferative Disorders (PTLD) are increasingly recognized as a fatal complication of hematological stem cell transplantation (HSCT). Thoracic involvement, that may be isolated or part of a disseminated disease, usually encompasses pulmonary nodules or masses and mediastinal lymph node enlargement. The current case study presents 2 patients who underwent HSCT, one allogenic and the other autologous, who developed an exceptional endobronchial EBV related PTLD. The first patient had a fleshy white endobronchial mass resulting in a right upper lobe atelectasis and the second had an extensive necrotising mucosa from trachea to both basal bronchi without any significant change of lung parenchyma on the CT scan. In both cases, the diagnosis was made by bronchial biopsies. Physicians should be aware of an endobronchial pattern of EBV associated PTLD after HSCT to permit quick diagnosis and therapeutic intervention.

[Late onset, non-infectious pulmonary complications after haematological stem cell transplantation]. / Les complications pulmonaires tardives non infectieuses après allogreffe de cellules souches hématopoïétiques.

INTRODUCTION: Non infectious pulmonary complications which frequently occur in the late follow-up of haemopoietic stem cell transplant (HSCT) recipients account for an increase in mortality and morbidity. Different histological entities have been described among which bronchiolitis obliterans is the most common. BACKGROUND: Because of the absence of prospective epidemiological studies and the difficulties in obtaining surgical lung biopsies from these frail patients little is known about these conditions. Although their pathogenesis is poorly understood they probably result from a chronic pulmonary graft versus host disease (GVHD). The introduction of or increase in systemic immunosuppressive treatment, usually indicated for controlling extra-thoracic manifestations of GVHD, may lead to the resolution of an organising pneumonia but is usually ineffective in the treatment of bronchiolitis obliterans. VIEWPOINTS: Current prospective cohort studies together with randomised prospective studies evaluating more targeted treatments should help determine the frequency, the risk factors and the precise characteristics of the different entities of late non-infectious pulmonary diseases following HSCT and should also improve their management. Furthermore, the recent demonstration of lung abnormalities in animal models of chronic GVHD, similar to those observed in humans, should allow a better understanding of the pathogenesis. CONCLUSION: The prevalence of these diseases is increasing throughout the world. More precise analysis, the identification of risk factors and study of the pathophysiological mechanisms involved should allow better understanding and management than at present.