Cyclophosphamide Not Recommended for Acute Exacerbation of Pulmonary Fibrosis

pulmonary embolism on CT scan
pulmonary embolism on CT scan
A clinical trial disproved the notion that adding cyclophosphamide pulses to glucocorticoids was effective for acute exacerbation of IPF.

In patients with acute exacerbation of idiopathic pulmonary fibrosis (IPF), adding intravenous cyclophosphamide pulses to glucocorticoids may increase mortality, according to a phase 3, double-blind, placebo-controlled trial published in The Lancet Respiratory Medicine.

To date, there are no effective treatments for acute exacerbation of IPF and its cause is unknown. Current guidelines support the use of high-dose glucocorticoids. When these medications do not work, it has been suggested to administer other immunosuppressants, such as cyclophosphamide, as either first-line or rescue therapy.

Therefore, researchers in France conducted the EXAFIP study ( Identifier: NCT02460588) to evaluate the efficacy and safety of administering 4 intravenous cyclophosphamide pulses in addition to standard treatment with high-dose methylprednisolone. In the trial, 119 patients received at least 1 dose of cyclophosphamide (n=60) or placebo (n=59).

The researchers determined that the 3-month all-cause mortality was 45% (27/60) in patients who received cyclophosphamide compared with 31% (18/59) in the placebo group (difference 14.5%; P =.10); similar results were found even after adjustment by IPF severity. The risk of death at 3 months, independent of the treatment received, was also found to be higher in patients with severe IPF compared with non-severe IPF and was also lower with use of antifibrotic therapy. By 6 months, the number of adverse events were similar between groups: 25 (42%) in the cyclophosphamide group vs 30 (51%) in the placebo group.

“In conclusion, the results of this EXAFIP trial showed that the addition of intravenous pulses of cyclophosphamide to high-dose glucocorticoids did not confer a survival benefit in patients with acute exacerbation of IPF,” stated the authors. They added, “The higher mortality with cyclophosphamide than with placebo suggests a potential deleterious effect, and the findings of this study provide evidence against its use in such patients.”

Disclosure: This research was supported by Roche Pharmaceuticals. Please see the original reference for a full list of disclosures.


Naccache J-M, Jouneau S, Didier M, et al; EXAFIP investigators and the OrphaLung network. Cyclophosphamide added to glucocorticoids in acute exacerbation of idiopathic pulmonary fibrosis (EXAFIP): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. Published online September 7, 2021. doi:10.1016/S2213-2600(21)00354-4