Pulmonary alveolar proteinosis is a disease of relative GM-CSF deficiency and preliminary reports indicate that systemic GM-CSF therapy improves the lung disease in a subset of patients. We conducted a prospective,open-label phase II clinical trial with daily subcutaneous rhGM-CSF therapy in adult idiopathic PAP patients.
Adult patients with biopsy proven idiopathic PAP were studied. The protocol consisted of a starting dose of 250 milligram/day that was rapidly escalated to a maximum dose of 18 microgram/kg/day. Patients were monitored monthly with arterial blood gases, pulmonary function studies, radiographs and laboratory studies. Improvement was defined as a > or = 10mmHg decrease in arterial-alveolar oxygen (A-a) gradient and radiographic improvement using predefined scoring criteria.
Twenty-five patients were enrolled. All patients had circulating anti-GM-CSF antibody. The age was 38.3±10.5(Mean±SD) years. 18/25(72%) were men; 21/25(84%) were Caucasian and 10/25(40%) were non-smokers. Mean duration of PAP was 3.5 years and 21/25(84%) had received prior whole lung lavage (WLL). Five of the initial subjects from a pilot trial completed therapy for 12 weeks and 18 patients were treated with the drug for > or =24 weeks. 21/25(84%) completed the trial while four patients terminated early. Baseline room air PaO2 & A-a gradient was 62.5±12.4mm Hg & 42.3±10.5 respectively. 13/21(62%) demonstrated both radiographic and (A-a) gradient improvements and one patient had a radiographic improvement without improvement in oxygenation. The (A-a) gradient decreased from 36.2±8.7 at baseline to 17.9±9.8 on follow up(Mean±SD) in responders to therapy whereas it increased from 40.1±14.3 at baseline to 49.3±10.5 on follow up(Mean±SD) in non-responders. The drug was generally well tolerated. The mean duration of follow-up post therapy was 39 months, where 14/25(56%) remained free of WLL. In 11/25(44%), WLL was required for an average of 2 sessions (range 1-5).
GM-CSF therapy can result in improvement in PAP in over half of the PAP subjects.
GM-CSF therapy may be an alternative to WLL (which is a cumbersome, anesthesia requiring and invasive procedure) in a subgroup of PAP patients.
S.B. Venkateshiah, Berlex Corporation (formerly Immunex)