Sleep and pulmonary outcomes for clinical trials of airway plexiform neurofibromas in NF1

Abstract

Objective: Plexiform neurofibromas (PNs) are complex, benign nerve sheath tumors that occur in approximately 25%-50% of individuals with neurofibromatosis type 1 (NF1). PNs that cause airway compromise or pulmonary dysfunction are uncommon but clinically important. Because improvement in sleep quality or airway function represents direct clinical benefit, measures of sleep and pulmonary function may be more meaningful than tumor size as endpoints in therapeutic clinical trials targeting airway PN.Methods: The Response Evaluation in Neurofibromatosis and Schwannomatosis functional outcomes group reviewed currently available endpoints for sleep and pulmonary outcomes and developed consensus recommendations for response evaluation in NF clinical trials.Results: For patients with airway PNs, polysomnography, impulse oscillometry, and spirometry should be performed to identify abnormal function that will be targeted by the agent under clinical investigation. The functional group endorsed the use of the apnea hypopnea index (AHI) as the primary sleep endpoint, and pulmonary resistance at 10 Hz (R 10 ) or forced expiratory volume in 1 or 0.75 seconds (FEV 1 or FEV 0.75 ) as primary pulmonary endpoints. The group defined minimum changes in AHI, R 10 , and FEV 1 or FEV 0.75 for response criteria. Secondary sleep outcomes include desaturation and hypercapnia during sleep and arousal index. Secondary pulmonary outcomes include pulmonary resistance and reactance measurements at 5, 10, and 20 Hz; forced vital capacity; peak expiratory flow; and forced expiratory flows.Conclusions: These recommended sleep and pulmonary evaluations are intended to provide researchers with a standardized set of clinically meaningful endpoints for response evaluation in trials of NF1-related airway PNs. Plexiform neurofibromas (PNs) are complex, benign nerve sheath tumors that occur in approximately 25%-50% of individuals with neurofibromatosis type 1 (NF1). The frequency and type of PN-associated morbidities are influenced by tumor location and volume (figure).1-7 A total of 15%-38% of all PNs occur in the head/neck region and 6%-25% occur in the thorax/mediastinum. Airway PNs are a subset of PNs that arise in close proximity to the airway. Symptomatic PNs that cause airway compromise or pulmonary dysfunction are uncommon (reported in 5%-7% of children with PNs) but clinically important. If left untreated, these lesions can be fatal. Surgical resection is often not feasible, and tracheostomy is required in some patients. 3,5 Obstructive sleep apnea (OSA) is caused by repeated collapse of the airway during sleep resulting in partial obstruction (hypopnea) or total obstruction (apnea). In the general pediatric

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