For how long should GM-CSF be administered, and at what dose?
As mentioned above, inhaled GM-CSF is said to be effective because a portion of it reaches the alveoli and restores weakened alveolar macrophage function.1 How many weeks does it then take for weakened alveolar macrophages to recover? Based on the experience of administering this treatment to severely ill patients, 12 cycles (1 vial) of 250 μg (1 vial) per day of inhalation for 1 week followed by 1 week off the drug are recommended. When repeated (for 24 weeks), approximately 50% or more of patients respond to inhalation therapy, with improvement in arterial oxygen partial pressure. Over 50% of patients respond to inhalation therapy with improvement in arterial oxygen partial pressure of more than 10 mmHg. For patients with insufficient improvement (improvement in arterial oxygen partial pressure under 10 mmHg), 500 μg (2 vials) per day every other week is administered by inhalation for 12 weeks. In such cases, approximately 30% of these patients respond to the inhalation treatment and their arterial blood oxygen partial pressure improves (J. Jap. Resp. Soc., 13(4), 2024). However, increasing the dose to 500 μg (2 vials) is now not covered by general health insurance in Japan.
Since GM-CSF is expensive, it is best to start by inhaling 250 μg every other week and then extending the duration if the effect is insufficient.
- The development of a novel treatment for autoimmune pulmonary alveolar proteinosis designated as an intractable disease was based on “Understanding of the cause: cytokine inhalation therapy for the first time in Japan,” Japan for Medical Research and Development. https://www.amed.go.jp/en/news/release_20190905.html ↩︎
Inhalation treatment schedule
Inhalation therapy begins to work at different times, varying from patient to patient. It is a patient-specific treatment, with some people showing signs of recovery within 12 weeks, and others seeing results within 12 to 24 weeks. As a patient, you should never panic, and if you find that the effect is poor after 24 weeks of inhalation, discuss it with your doctor and decide whether to choose other treatments, such as whole lung lavage, or continue GM-CSF inhalation therapy for a longer time period.
Treatment flow
The package insert (attached documents) for Sargmalin, sold by Nobel Pharma, describes the following:
Usage and dosage:
For adults, 125μg of sargramostim are usually inhaled twice a day for 7 days using a nebulizer. The drug is then discontinued for 7 days. This is considered as one course, and the administration is repeated.
Precautions related to usage and administration:
Efficacy and safety will be evaluated after 12 courses, and additional administration should be judged accordingly. If the administration is continued, the effectiveness and safety should be checked periodically to decide whether to continue administration.
Doctors performing GM-CSF inhalation therapy for the first time may not be confident in treating a patient, even after reading this. Therefore, as an example, we propose the following treatment flow:
（Figure Source: Created by Medical Tribune based on the Japanese Respiratory Society Symposium on April 5, 2024)
About maintenance therapy
Even if the patient enters remission after 12 courses of inhalation treatment, A-aDO2 worsens again in many cases when followed up for another 24 weeks (Journal of the Japanese Respiratory Society 13(4), 2024). In such cases, repeat 12 to 24 courses of inhalation therapy and increase the level of 10 mmHg or more compared to baseline A-aDO2. If improvement is seen, you may consider continuing the inhaled treatment at a lower dose than usual to maintain remission. For example, on day 1 at 6 pm, dissolve one vial of Sargmalin in normal saline and inhale 125 μg. Store the rest in the refrigerator and inhale the remaining 125 μg by noon on the second day. Do this twice a month for 12 months. If remission is maintained, the same 2-day inhalation treatment is repeated once a month for 12 months, and if remission is maintained, the same treatment is repeated once every two months for one year.
We recommend periodically checking whether remission is maintained (improvement in A-aDO2 from baseline by 10 mmHg or more). If remission cannot be achieved, there are options to repeat 12 courses of 250 μg inhaled for 7 days and 7 days off, or to perform maintenance therapy after whole lung lavage.