Inhaled recombinant GM-CSF reduces the need for whole lung lavage and improves gas exchange in autoimmune pulmonary alveolar proteinosis patients

Abstract

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 pathological accumulation of surfactant. In contrast, inhaled recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) is a promising pharmacological approach that restores alveolar macrophage functions including surfactant clearance. Here, we evaluate WLL followed by inhaled rGM-CSF (sargramostim) as therapy of aPAP.

Methods: 18 patients with moderate-to-severe aPAP were enrolled, received baseline WLL, were randomised into either the rGM-CSF group (receiving inhaled sargramostim) or control group (no scheduled therapy) and followed for 30 months after the baseline 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 of time to first rescue WLL was longer in rGM-CSF-treated patients than controls (30 versus 18 months, n=9 per group, p=0.0078). Seven control patients (78%) and only one rGM-CSF-treated patient (11%) required rescue WLL, demonstrating a 7-fold increase in relative risk (p=0.015). Compared to controls, rGM-CSF-treated patients also had greater improvement in peripheral arterial oxygen tension, alveolar-arterial oxygen tension difference, diffusing capacity of the lungs for carbon monoxide and aPAP biomarkers. One patient from each group withdrew for personal reasons. No serious adverse events were reported.

Conclusions: This long-term, prospective, randomised 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.

Overview of the study. aPAP: autoimmune pulmonary alveolar proteinosis; rGM-CSF: recombinant granulocyte–macrophage colony-stimulating factor; WLL: whole lung lavage; AE: adverse event; SAE: serious adverse event.

FIGURE 1

Screening, randomisation, treatment and follow-up of the study participants with moderate-to-severe autoimmune pulmonary alveolar proteinosis. rGM-CSF: recombinant granulocyte–macrophage colony-stimulating factor; WLL: whole lung lavage.

FIGURE 2

Effect of inhaled recombinant granulocyte–macrophage colony-stimulating factor (rGM-CSF) on the requirement for unscheduled rescue whole lung lavage (WLL) therapy. Kaplan–Meier analysis shows the percentage of study participants in each group (indicated) who required an unscheduled rescue WLL as a function of time during the 30 months following the scheduled baseline WLL at month 0. The number of participants who had not received an unscheduled rescue WLL at each visit is shown below (number at risk). Significance values (p-values) were determined with the log-rank Mantel–Cox test. ^#: participants who withdrew from the study for personal reasons.

FIGURE 3

Effects of inhaled recombinant granulocyte–macrophage colony-stimulating factor (rGM-CSF) on pulmonary gas transfer. a) Schematic showing for each study group the administration of the baseline whole lung lavage (WLL) (grey arrows) and unscheduled rescue WLL (black arrows), and inhaled rGM-CSF administered as induction therapy (thick vertical black lines) or maintenance therapy (thin vertical black lines). Open boxes indicate follow-up periods without scheduled intervention. The number of participants who have not yet required an unscheduled rescue WLL at each study visit is shown (number at risk). The times at which two study subjects withdrew (WD) from trial participation for personal reasons is indicated. b) Mean peripheral arterial oxygen tension (P_aO2) at each visit for each group (indicated). c) Mean alveolar–arterial oxygen tension difference (P_A–aO2) at each visit for each group. d) Mean diffusing capacity of the lungs for carbon monoxide (D­_LCO) % predicted at each visit for each group. T-bars represent the standard deviation. The timing of administration of inhaled rGM-CSF as induction therapy (thick vertical black lines) or maintenance therapy (thin vertical black lines) to participants in the rGM-CSF group as well as periods with no scheduled intervention are shown above b for b–d. The dashed vertical lines in panels b–d indicate the beginning and end of inhaled rGM-CSF therapy (months 0 and 10, respectively). Tx: therapy; ns: nonsignificant; *: p<0.05; **: p<0.01; ***: p<0.001, for between-group comparison at each visit.