Dataset Information

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).

SUBMITTER: Tazawa R

PROVIDER: S-EPMC2894410 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Publications

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

Tazawa Ryushi R Trapnell Bruce C BC Inoue Yoshikazu Y Arai Toru T Takada Toshinori T Nasuhara Yasuyuki Y Hizawa Nobuyuki N Kasahara Yasunori Y Tatsumi Koichiro K Hojo Masayuki M Ishii Haruyuki H Yokoba Masanori M Tanaka Naohiko N Yamaguchi Etsuro E Eda Ryosuke R Tsuchihashi Yoshiko Y Morimoto Konosuke K Akira Masanori M Terada Masaki M Otsuka Junji J Ebina Masahito M Kaneko Chinatsu C Nukiwa Toshihiro T Krischer Jeffrey P JP Akazawa Kohei K Nakata Koh K

American journal of respiratory and critical care medicine 20100218 12

<h4>Rationale</h4>Inhaled granulocyte/macrophage-colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied.<h4>Objectives</h4>To evaluate safety and efficacy of inhaled GM-CSF in patients with unremitting or progressive PAP.<h4>Methods</h4>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, ...[more]

PMID: 20167854

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Project description:BACKGROUND:Treatment of autoimmune pulmonary alveolar proteinosis (aPAP) by inhaled granulocyte-macrophage colony stimulating factor (GM-CSF) is considered safe and effective. Evidence of benefit from GM-CSG inhalation for mild to moderate aPAP patients is limited. METHODS:In this multicenter, randomized, open-labeled clinical trial, 36 aPAP patients with mild to moderate disease severity were randomized into either the GM-CSF treatment group or control group. Inhaled GM-CSF was prescribed for 6?months, and patients received follow-up for another 18?months without treatment. Physiological features of the patients were analyzed. RESULTS:There were 36 patients (19 in the treatment group, 17 in the control group) included. There were no significant differences in the primary endpoints as measured by the change of alveolar arterial oxygen gradient (A-aDO2) from the baseline values to the values obtained during treatment or during the following 18-month non-treatment observation period [control group vs. treatment group: 0.51?±?12.09?mmHg vs. -0.35?±?13.76?mmHg, p?=?0.848 (3?month); 1.85?±?11.21?mmHg vs. 7.31?±?8.81?mmHg, p?=?0.146 (6?months); 6.05?±?11.14?mmHg vs. 6.61?±?10.64?mmHg, p?=?0.899 (24?months)]). Percentage of diffusion capacity predicted (DLCO%) and percentage of total lung capacity predicted (TLC%), however, were significantly improved in the treatment group by the end of the study (P =?0.010 and 0.027). St. George Respiratory questionnaire (SGRQ) scores were better after 6?months treatment with GM-CSF compared to the control group, and the benefits of treatment were maintained throughout the observation period. No severe side effects were observed during the study. CONCLUSION:Six months of inhaled GM-CSF treatment had no effect on the alveolar-arterial oxygen gradient in patients with mild to moderate pulmonary alveolar proteinosis. There were changes in some clinical or laboratory measures, but no clinically important changes were noted at the end of study. (Clinical Trial Registry: NCT02243228, Registered on September 17, 2014, https://www.clinicaltrials.gov/ct2/show/NCT02243228?term=NCT02243228&draw=2&rank=1 ).

Project description:BackgroundAutoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia. It is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which pulmonary alveolar macrophages require to clear surfactant. Recently, inhaled GM-CSF was shown to improve the partial pressure of arterial oxygen in patients with aPAP.MethodsIn a double-blind, placebo-controlled, three-group trial, we randomly assigned patients with aPAP to receive the recombinant GM-CSF molgramostim (300 μg once daily by inhalation), either continuously or intermittently (every other week), or matching placebo. The 24-week intervention period was followed by an open-label treatment-extension period. The primary end point was the change from baseline in the alveolar-arterial difference in oxygen concentration (A-aDo2) at week 24.ResultsIn total, 138 patients underwent randomization; 46 were assigned to receive continuous molgramostim, 45 to receive intermittent molgramostim, and 47 to receive placebo. Invalid A-aDo2 data for 4 patients (1 in each molgramostim group and 2 in the placebo group) who received nasal oxygen therapy during arterial blood gas measurement were replaced by means of imputation. For the primary end point - the change from baseline in the A-aDo2 at week 24 - improvement was greater among patients receiving continuous molgramostim than among those receiving placebo (-12.8 mm Hg vs. -6.6 mm Hg; estimated treatment difference, -6.2 mm Hg; P = 0.03 by comparison of least-squares means). Patients receiving continuous molgramostim also had greater improvement than those receiving placebo for secondary end points, including the change from baseline in the St. George's Respiratory Questionnaire total score at week 24 (-12.4 points vs. -5.1 points; estimated treatment difference, -7.4 points; P = 0.01 by comparison of least-squares means). For multiple end points, improvement was greater with continuous molgramostim than with intermittent molgramostim. The percentages of patients with adverse events and serious adverse events were similar in the three groups, except for the percentage of patients with chest pain, which was higher in the continuous-molgramostim group.ConclusionsIn patients with aPAP, daily administration of inhaled molgramostim resulted in greater improvements in pulmonary gas transfer and functional health status than placebo, with similar rates of adverse events. (Funded by Savara Pharmaceuticals; IMPALA ClinicalTrials.gov number, NCT02702180.).

Project description:Pulmonary Alveolar Proteinosis (PAP) patients exhibit an acquired deficiency of biologically active granulocyte-macrophage colony stimulating factor (GM-CSF) attributable to GM-CSF specific autoantibodies. PAP alveolar macrophages are foamy, lipid-filled cells with impaired surfactant clearance and markedly reduced expression of the transcription factor peroxisome proliferator-activated receptor gamma (PPAR?) and the PPAR?-regulated ATP binding cassette (ABC) lipid transporter, ABCG1. An open label proof of concept Phase II clinical trial was conducted in PAP patients using rituximab, a chimeric murine-human monoclonal antibody directed against B lymphocyte specific antigen CD20. Rituximab treatment decreased anti-GM-CSF antibody levels in bronchoalveolar lavage (BAL) fluid, and 7/9 patients completing the trial demonstrated clinical improvement as measured by arterial blood oxygenation.This study sought to determine whether rituximab therapy would restore lipid metabolism in PAP alveolar macrophages.BAL samples were collected from patients pre- and 6-months post-rituximab infusion for evaluation of mRNA and lipid changes.Mean PPAR? and ABCG1 mRNA expression increased 2.8 and 5.3-fold respectively (p???0.05) after treatment. Lysosomal phospholipase A2 (LPLA2) (a key enzyme in surfactant degradation) mRNA expression was severely deficient in PAP patients pre-treatment but increased 2.8-fold post-treatment. In supplemental animal studies, LPLA2 deficiency was verified in GM-CSF KO mice but was not present in macrophage-specific PPAR? KO mice compared to wild-type controls. Oil Red O intensity of PAP alveolar macrophages decreased after treatment, indicating reduced intracellular lipid while extracellular free cholesterol increased in BAL fluid. Furthermore, total protein and Surfactant protein A were significantly decreased in the BAL fluid post therapy.Reduction in GM-CSF autoantibodies by rituximab therapy improves alveolar macrophage lipid metabolism by increasing lipid transport and surfactant catabolism. Mechanisms may involve GM-CSF stimulation of alveolar macrophage ABCG1 and LPLA2 activities by distinct pathways.

Dataset Information

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

Rationale

Objectives

Methods

Measurements and main results

Conclusions

Publications

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

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