Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis

Abstract

Rationale: Inhaled granulocyte/macrophage-colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied.

Objectives: To evaluate safety and efficacy of inhaled GM-CSF in patients with unremitting or progressive PAP.

Methods: We conducted a national, multicenter, self-controlled, phase II trial at nine pulmonary centers throughout Japan. Patients who had lung biopsy or cytology findings diagnostic of PAP, an elevated serum GM-CSF antibody level, and a Pa(O(2)) of less than 75 mm Hg entered a 12-week observation period. Those who improved (i.e., alveolar-arterial oxygen difference [A-aDO(2)] decreased by 10 mm Hg) during observation were excluded. The rest entered sequential periods of high-dose therapy (250 microg Days 1-8, none Days 9-14; x six cycles; 12 wk); low-dose therapy (125 microg Days 1-4, none Days 5-14; x six cycles; 12 wk), and follow-up (52 wk).

Measurements and main results: Fifty patients with PAP were enrolled in the study. During observation, nine improved and two withdrew; all of these were excluded. Of 35 patients completing the high- and low-dose therapy, 24 improved, resulting in an overall response rate of 62% (24/39; intention-to-treat analysis) and reduction in A-aDO(2) of 12.3 mm Hg (95% confidence interval, 8.4-16.2; n = 35, P < 0.001). No serious adverse events occurred, and serum GM-CSF autoantibody levels were unchanged. A treatment-emergent correlation occurred between A-aDO(2) and diffusing capacity of the lung, and high-resolution CT revealed improvement of ground-glass opacity. Twenty-nine of 35 patients remained stable without further therapy for 1 year.

Conclusions: Inhaled GM-CSF therapy is safe, effective, and provides a sustained therapeutic effect in autoimmune PAP. Clinical trial registered with www.controlled-trials.com/isrctn (ISRCTN18931678), www.jmacct.med.or.jp/english (JMA-IIA00013).

Figure 1.

Profile of the study cohort. GM-CSF = granulocyte/macrophage–colony stimulating factor; PAP = pulmonary alveolar proteinosis.

Figure 2.

Alveolar-arterial oxygen difference (A–aDO₂) of the response to inhaled granulocyte/macrophage–colony stimulating factor (GM-CSF) in patients with pulmonary alveolar proteinosis (PAP). (A) The overall mean (± SE) A–aDO₂ for all participants receiving inhalation therapy with GM-CSF. *P < 0.05; **P < 0.001. Thirty-nine patients completed the high-dose induction therapy period (weeks 1, 12, and 24; n = 39) and 35 patients completed subsequent low-dose maintenance therapy period (week 36; n = 35). (B) Change in A–aDO₂ in patients who responded to inhaled GM-CSF during each trial period (n = 24). A responder was defined as a participant who had improvement in A–aDO₂ of at least 10 mm Hg during the treatment period (weeks 12–36). Each bar represents the mean (± SE) for the improvement of A–aDO₂ during the designated period. *P < 0.05; **P < 0.01.

Figure 3.

Changes in computed tomography of the chest in response to inhaled granulocyte/macrophage–colony stimulating factor (GM-CSF) in patients with pulmonary alveolar proteinosis (PAP). (A) High-resolution computed tomography (HRCT) of the chest of a representative patient before (left) and after (right) treatment with inhaled GM-CSF therapy for 24 weeks. (B) Effect of inhaled GM-CSF therapy on the severity of PAP lung disease measured by the zonal HRCT score (21) as described in the Methods. Shown are pre (open boxes) and post (shaded boxes) regional HRCT score values for upper, middle, and lower lung regions in 35 patients with PAP before and after completing both high- and low-dose GM-CSF treatment periods. Box plots show the median (dashed line), 25th (box bottom), and 75th (box top) percentiles, 10th percentile (lower T bars), 90th percentile (upper T bars). *P < 0.05; **P < 0.01; calculated by the contingency-table analysis for ordered variables using the χ² test on the platform of the JMP software.

Figure 4.

Serum concentration of granulocyte/macrophage–colony stimulating factor (GM-CSF) autoantibody in patients with autoimmune pulmonary alveolar proteinosis (PAP) before and after GM-CSF inhalation therapy. The line shows the GM-CSF autoantibody titer for each patient.

Figure 5.

Durability of the response to inhaled granulocyte/macrophage–colony stimulating factor (GM-CSF) in patients with pulmonary alveolar proteinosis (PAP). (A) Kaplan-Meier plot showing individuals free of additional specific therapy of PAP. (B) Disease severity scores of patients (*P < 0.05) who completed high- and low-dose inhalation treatment (n = 35) and 1-year observation with no additional treatment (n = 29).