Inhaled GM-CSF reduces the need for whole lung lavage and improves gas exchange in autoimmune PAP patients

Rationale Whole lung lavage (WLL) is a widely accepted palliative treatment for autoimmune pulmonary alveolar proteinosis (aPAP) but does not correct myeloid cell dysfunction or reverse the pathologic accumulation of surfactant. In contrast, inhaled recombinant granulocyte/macrophage-colony stimulating factor (GM-CSF) is a promising pharmacologic approach that restores alveolar macrophage functions including surfactant clearance. Here, we evaluate WLL followed by inhaled GM-CSF (sargramostim) as therapy of aPAP. Methods Eighteen patients with moderate-to-severe aPAP were enrolled, received a baseline WLL, were randomized into GM-CSF and Control groups receiving inhaled sargramostim or no scheduled therapy, respectively, and followed for 30 months after WLL. Outcome measures included additional unscheduled “rescue” WLL for disease progression, assessment of arterial blood gases, pulmonary function, computed tomography, health status, biomarkers, and adverse events. Patients requiring rescue WLL were considered to have failed their assigned intervention group. Results The primary end point, the time to first rescue WLL, was longer in GM-CSF-treated patients than Controls (30 versus 18 months; n=9/group; p=0.0078). Seven (78%) Control patients and only 1 (11%) GM-CSF-treated patient required rescue WLL – a 7-fold increase in relative risk (p=0.015). Compared to Controls, GM-CSF-treated patients also had greater improvement in PaO 2 , A-aDO 2 , DLco%, and aPAP biomarkers. One patient from each group withdrew for personal reasons. No serious adverse events were reported. Conclusions This long-term, prospective, randomized trial demonstrated inhaled sargramostim following WLL reduced the requirement for WLL, improved lung function, and was safe in aPAP patients. WLL plus inhaled sargramostim may be useful as combined therapy for aPAP.