Everolimus Versus Azathioprine in Maintenance Lung Transplant Recipients: An International, Randomized, Double-Blind Clinical Trial

Abstract

Everolimus is a proliferation signal inhibitor with immunosuppressive activity that may reduce the rate of progression of chronic rejection, bronchiolitis obliterans syndrome (BOS), after lung transplantation. In a randomized, double-blind clinical trial, 213 BOS-free maintenance patients received everolimus (3 mg/day) or azathioprine (AZA, 1-3 mg/kg/day) in combination with cyclosporine and corticosteroids. The prospectively defined primary endpoint was the incidence of efficacy failure (decline in FEV 1 >15% [∆FEV 1 >15%], graft loss, death or loss to follow-up) at 12 months. Incidence of efficacy failure at 12 months was significantly lower in the everolimus group than AZA (21.8% vs. 33.9%; p = 0.046); at 24 months, rates of efficacy failure became similar between the groups. At 12 months, the everolimus group had significantly reduced incidences of ∆FEV 1 >15%, ∆FEV 1 >15% with BOS, and acute rejection. At 24 months, only incidence of acute rejection remained significantly less in the everolimus group. Treatment discontinuations (particularly due to adverse events), serious adverse events and high serum creatinine values were more common with everolimus. For the first time, a drug has demonstrated significant slowing of loss in lung function, suggesting that patients kept on prolonged maintenance treatment with everolimus may benefit from replacing AZA with everolimus 3 months after lung transplantation.

Technology and Outcomes Assessment in Lung Transplantation

“…Studies of bronchiolitis obliterans syndrome (BOS) in lung transplantation provide a common example of this analytic approach, where the main outcome is chronic rejection-free survival (50, 51) ( Figure 2). As another example, a recent randomized controlled trial of maintenance immunosuppression in lung transplantation evaluated a primary composite endpoint of lung function worsening (FEV 1 change .15%), graft loss, or death (52). As with all analytic approaches, the pros must be weighed against the cons for the use of combined endpoints.…”

Current status of lung transplantation

“…109 A randomised multicenter study showed that BOS-free lung transplant recipients had significantly smaller decline in FEV1 and experienced fewer acute rejections when treated with everolimus compared with azathoprine. 110 Everolimus has been shown to give a significant survival benefit compared to those treated with MMF. 111 Cyclosporine and tacrolimus inhibit calcineurin, thereby decreasing IL-2 production and reducing T-cell activation/proliferation.…”

Monitoring of Nonsteroidal Immunosuppressive Drugs in Patients With Lung Disease and Lung Transplant Recipients

“…Table 36 summarizes the two studies in which everolimus administration was studied in lung transplant patients. 316,516 3.6.1.1 Toxicity-Leukopenia, thrombocytopenia, and anemia occur commonly with everolimus. Other common adverse effects include hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, and hypertension.…”

“…325 A summary of 11 studies supporting recommendations for the monitoring of AZA in patients with lung disease and organ transplant recipients is provided in Table 28 . [310][311][312]314,316,317,320,[322][323][324]326 3.5.1.1 Toxicity-Common adverse reactions associated with azathioprine include leukopenia, 327 pancreatitis, 328 and hepatitis. 329 Other effects of bone marrow toxicity include thrombocytopenia, anemia, megaloblastic anemia, aplastic anemia, eosinophilia, myelodysplastic syndrome, and fatal acute myeloid leukemia.…”

“…308 It has also been used for prophylactic treatment of heart, liver, pancreas, and lung transplantation. [309][310][311][312][313][314][315][316][317] Additionally, azathioprine has been used to treat pulmonary and extrapulmonary sarcoidosis, [318][319][320] cryptogenic organizing pneumonia, 321 idiopathic pulmonary fi brosis, 322 interstitial lung disease (ILD) associated with systemic sclerosis, 323,324 and radiation pneumonitis. 325 A summary of 11 studies supporting recommendations for the monitoring of AZA in patients with lung disease and organ transplant recipients is provided in Table 28 .…”