Adding cyclophosphamide to glucocorticoids confers no survival benefit in IPF
Adding cyclophosphamide to glucocorticoid treatment in patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) was associated with a numerically increased risk of mortality, according to results of the phase III EXAFIP trial.
“The addition of intravenous cyclophosphamide to high-dose glucocorticoids did not confer a survival benefit in patients with AE-IPF,” presented study author Dr Jean-Marc Naccache from the Groupe Hospitalier Paris Saint-Joseph, Paris, France, at ERS 2021.
The double-blind trial was conducted at 35 sites in France and included 120 adults with confirmed or suspected AE-IPF. They were randomized 1:1 to receive intravenous cyclophosphamide (600 mg/m2 [maximum 1.2 g]) plus uromitexan* (200 mg/m2; mean age 71 years, 81.7 percent male) or placebo (mean age 73.2 years, 76.3 percent male) on days 0, 15, 30, and 60. All patients also received high-dose glucocorticoids. Patients undergoing mechanical ventilation, those with active infection or cancer, and those on the lung transplantation waitlist were excluded.
Fifty-two percent of patients were diagnosed as having severe IPF, defined as forced vital capacity <50 percent or diffusing capacity for carbon monoxide <35 percent. About 36 percent were on antifibrotic therapy (nintedanib or pirfenidone).
At 3 months, all-cause mortality in the intention-to-treat population was numerically, but not significantly, increased among patients in the cyclophosphamide compared with placebo group (45 percent vs 31 percent; difference, 14.5 percent, 95 percent confidence interval [CI], -3.1 to 31.6; p=0.10). [ERS 2021, presentation ID 2903; Lancet Respir Med 2021;doi:10.1016/S2213-2600(21)00354-4]
The results were consistent in the per-protocol population (40 percent vs 30 percent; difference, 10.5 percent, 95 percent CI, -9.6 to 30.1; p=0.29) as well as after adjusting for IPF severity (odds ratio [OR], 1.89, 95 percent CI, 0.89–4.04).
Overall survival (OS) did not significantly differ between groups at any time point over 1 year, with 1-year OS rates of 40.5 and 49.5 percent in the cyclophosphamide and placebo arms, respectively.
Death was secondary to respiratory causes in almost all cases (96 percent [cyclophosphamide] vs 94 percent [placebo] at 3 months [25 vs 17 deaths] and 100 percent for both groups [four and five deaths, respectively] between months 3 and 6).
Regardless of treatment, mortality risk at 3 months was higher in patients with severe compared with non-severe IPF at baseline (OR, 2.62, 95 percent CI, 1.12–6.12; p=0.03), and lower among patients who were on antifibrotic therapy at baseline (OR, 0.33, 95 percent CI, 0.13–0.82; p=0.02).
Adverse event incidence at 6 months was comparable between the cyclophosphamide and placebo groups (42 percent vs 51 percent). Rates of infection, the most frequent adverse event, were also comparable between groups (33 percent vs 36 percent).
“Cyclophosphamide was not associated with more adverse events regarding haematological toxicity and there [were no incidents of] haemorrhagic cystitis,” said Naccache.
Should cyclophosphamide be avoided?
“AE-IPF is associated with a very poor prognosis,” said Naccache. “Overall 3-month mortality exceeds 50 percent and up to 46 percent of deaths in IPF patients are preceded by an acute exacerbation.”
There is currently no proven effective treatment for AE-IPF, with current guidelines recommending the use of high-dose glucocorticoids such as intravenous methylprednisolone pulses.
“The higher mortality with cyclophosphamide suggests a potential deleterious effect and provides evidence against its use in such patients,” Naccache pointed out.
Nonetheless, more research is warranted to assess the efficacy and safety of glucocorticoids in AE-IPF as well as to identify potential targets for innovative treatment in AE-IPF, he said.