Long-Term Follow-Up of a Patient with GM-CSF Antibody-Negative Pulmonary Alveolar Proteinosis Following Exposure to Dust After the Great East Japan Earthquake

Abstract Background: Studies of Id/KLH immunotherapy in treatment naïve (TN) fNHL pts following first remission from chemotherapy have demonstrated a prolonged duration of remission. We expanded this approach in a PhII trial to include TN and relapsed/refractory (R/R) pts with stable disease (SD) or PR or CR/CRu following 4 wkly doses of rituximab. We report here long term follow up of RRI, defined as the % of pts who converted from SD to PR or PR to CR/CRu following initiation of Id/KLH treatment, and analysis of disease progression. Treatment: Pts received rituximab (375mg/m2 i.v. wkly x 4 during wk1–4) and those with stable or responsive disease received Id/KLH (1 mg s.q. mo x 6) starting on wk 12 along with GM-CSF (250 mcg, s.q.) on days 1–4. Pts continued to receive booster injections on a reduced schedule until disease progression. Radiological scans, performed every 3 mos, were reviewed centrally. Disease progression and response were assessed using modified Cheson criteria. This data analysis was performed 32 mo from end of enrollment. Results: 103 pts were enrolled and received rituximab; 89 pts had ≥SD and received Id/KLH + GM-CSF of whom, 54 were R/R, and 35 were TN. The overall response rate (ORR) was 47% (42/89) at mo 3. After the initiation of Id/KLH dosing, ORR improved to 63% (56/89). In RRI pts, median time to best response was 9.1 mos from start of rituximab treatment (5.2 – 29.6 mos). 12 of 39 PR pts (31%) converted to CR/Cru. 14 of 43 SD pts (33%) converted to PR. Pt Groups # of Pts % Prog Free Median TTP Est by K-M (mo) Pts w/RRI 26 69% 37.9 TN rituximab responders 23 70% Not Reached (NR) Rituximab responders (All) 42 60% NR Non Responders (All) 47 36% 14.9 All Pts 89 47% 18.2 TN Pts (All) 35 66% NR Relapsed Pts (All) 54 37% 16.8 Conclusion: RRI following FavId is seen in nearly one third of pts. The magnitude of this improvement, the number of conversions to CR/CRu and median time to best response (9 mo and as late as 29.6 mo) suggests this is likely to be a FavId effect rather than late response to rituximab. Responders and TN pts show more durable responses compared to previously published data for rituximab therapy. FavId may also confer a benefit for nonresponders and R/R pts relative to rituximab alone. To confirm benefit of FavId following rituximab induction, a placebo controlled PhIII study was initiated; it completed enrollment in Jan 06. RRI data from this study is expected to be available in Nov 06.

Download Full-text

Therapeutic effect of subcutaneous injection of low dose recombinant human granulocyte-macrophage colony-stimulating factor on pulmonary alveolar proteinosis

Respiratory Research ◽

10.1186/s12931-019-1261-1 ◽

2020 ◽

Vol 21 (1) ◽

Cited By ~ 11

Author(s):

Fen Zhang ◽

Dong Weng ◽

Yiliang Su ◽

Chengsheng Yin ◽

Li Shen ◽

...

Keyword(s):

Subcutaneous Injection ◽

Low Dose ◽

Pulmonary Alveolar Proteinosis ◽

Colony Stimulating Factor ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Alveolar Proteinosis ◽

Macrophage Colony ◽

Stimulating Factor

Abstract Objective To observe the efficacy of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) for pulmonary alveolar proteinosis (PAP). Materials and methods A total of 55 patients with PAP were screened at Shanghai Pulmonary Hospital between May 2014 and May 2018. Among these, 42 were diagnosed with idiopathic PAP, 24 were included in this study, 20 were treated for 6 months, and 17 were followed up for additional 6 months. All patients received a subcutaneous injection of 75μg/d GM-CSF qd for 1 month. The therapeutic dose was adjusted according to the changes in the lesions of chest CT. If the lesions were absorbed, subcutaneous injections of 75μg/d GM- CSF qd and 75μg/d GM-CSF qod were given for 2 and 3 months, otherwise, the dose was increased to 150μg/d GM-CSF qd and 150μg/d qod for 2 and 3 months, respectively. All cases were treated once a day in the first 3 months and once every other day in the last 3 months. The total course of treatment was 6 months. After withdrawal, the patients were followed up for another 6 months. The deadline of follow up was September 30, 2019. Results Twenty patients completed the treatment and efficacy evaluation. One patient was completely cured, 16 cases improved, three cases were noneffective. After 1-month evaluation, 12 patients received an increased dose (150μg) from the second month of treatment. Seventeen patients completed the 12-month follow-up, among which fourteen improved. CT showed the lesions were slightly increased in three cases. Economic burden was the following: RMB 7324–15,190 Yuan were required for the 6-month treatment course, which is significantly lower compared to other treatment methods. Conclusion Subcutaneous injection of rhGM-CSF at low dose (75μg-150μg /d) is effective treatment for patients with idiopathic PAP. Trial registration NCT01983657. Registered 16 April 2013.

Download Full-text

Long-term follow-up and treatment of congenital alveolar proteinosis

BMC Pediatrics ◽

10.1186/1471-2431-11-72 ◽

2011 ◽

Vol 11 (1) ◽

Cited By ~ 22

Author(s):

Matthias Griese ◽

Jan Ripper ◽

Anke Sibbersen ◽

Pia Lohse ◽

Peter Lohse ◽

...

Keyword(s):

Long Term Follow Up ◽

Alveolar Proteinosis

Download Full-text

SERUM LEVELS OF ANTI-GM-CSF AUTOANTIBODY REFLECTED DISEASE SEVERITY OF AUTOIMMUNE PULMONARY ALVEOLAR PROTEINOSIS FOLLOWED UP FOR LONG-TERM

Respirology ◽

10.1111/resp.13206_205 ◽

2017 ◽

Vol 22 ◽

pp. 84-85

Keyword(s):

Disease Severity ◽

Pulmonary Alveolar Proteinosis ◽

Serum Levels ◽

Gm Csf ◽

Alveolar Proteinosis

Download Full-text

Inhaled granulocyte-macrophage colony stimulating factor for mild-to-moderate autoimmune pulmonary alveolar proteinosis - a six month phase II randomized study with 24 months of follow-up

10.21203/rs.3.rs-18107/v2 ◽

2020 ◽

Author(s):

Xinlun Tian ◽

Yanli Yang ◽

Lulu Chen ◽

Xin Sui ◽

Wenshuai Xu ◽

...

Keyword(s):

Treatment Group ◽

Pulmonary Alveolar Proteinosis ◽

Arterial Oxygen ◽

Control Group ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Alveolar Proteinosis ◽

Macrophage Colony ◽

Observation Period

Abstract 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±10.64mmHg, 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)

Download Full-text

Long-term follow-up and successful treatment of pulmonary alveolar proteinosis without hypercholesterolemia with statin therapy: a case report

Journal of International Medical Research ◽

10.1177/03000605211010046 ◽

2021 ◽

Vol 49 (4) ◽

pp. 030006052110100

Author(s):

Shenyun Shi ◽

Rujia Wang ◽

Ling Chen ◽

Yan Li ◽

Yingwei Zhang ◽

...

Keyword(s):

Statin Therapy ◽

Successful Treatment ◽

Pulmonary Alveolar Proteinosis ◽

Lung Lavage ◽

Long Term Follow Up ◽

Macrophage Colony Stimulating Factor ◽

Alveolar Proteinosis ◽

Macrophage Colony ◽

Present Case Study

Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by the accumulation of excessive surfactant lipids and proteins in alveolar macrophages and alveoli. Oral statin therapy is a novel treatment for PAP with hypercholesterolemia. However, this treatment has never been described in a patient without hypercholesterolemia. Here, we present a case of successful treatment with atorvastatin for a patient with possibly unclassified PAP without hypercholesterolemia who responded poorly to whole lung lavage therapy and inhaled granulocyte-macrophage colony-stimulating factor. After 18 months of atorvastatin treatment, the patient experienced improvements in dyspnea, radiographic abnormalities and pulmonary function. The present case study supports the feasibility of statin therapy for PAP regardless of the level of cholesterol.

Download Full-text