Immunosuppressive Drug Regimens that May Help Improve Survival and Reduce the Risks of Rejection, Infection, and Malignancy after a Lung Transplant

Abstract

Background: Median survival among lung transplant recipients is below 6 years, and there is minimal knowledge regarding modifiable factors that may help improve long-term survival. Identifying induction and maintenance immunosuppressive regimens associated with optimal survival can potentially improve outcomes.

Methods: We classified lung transplant recipients in the United States from 2003-2016 according to their induction and prophylactic cell cycle inhibitor maintenance therapies, within a tacrolimus-based regimen. We compared the different therapies via multivariable Cox Proportional Hazards models, generating adjusted hazard ratios for death, rejection, infection, and malignancy, the latter three of which utilized semi-competing risks methods. Since prophylactic sirolimus initiation is delayed by up to 1 year post-transplant, adjustments were made to avoid immortal time bias. Multiple imputation was utilized to handle missing data.

Results: Sirolimus had the best survival among cell cycle inhibitor maintenance therapies: adjusted Hazard Ratio (HR)=0.71, p=0.003, compared to mycophenolate mofetil [MMF]; chronic rejection incidence was also reduced with sirolimus (HR=0.75, p=0.005). Azathioprine also had slightly better survival than MMF (HR=0.92, p=0.05), and reduced infection incidence (HR=0.62, p<0.0001). Among induction therapies, equine ATG had the best survival: HR=0.79, p=0.003, compared to no induction, as well as reduced rejection (HR=0.75, p=0.02) and infection (HR=0.57, p=0.008) incidence. The combination of induction and maintenance therapies associated with the most favorable survival was sirolimus + tacrolimus maintenance with no induction; HR=0.48, p=0.002 compared to MMF + tacrolimus with induction, and HR=0.41, p<0.0001 compared to MMF + tacrolimus with no induction.

Conclusions: Sirolimus initiated in the first year within a tacrolimus-based regimen may significantly improve long-term survival compared to MMF in lung transplant recipients. Out of all combinations of maintenance and induction therapies studied, sirolimus + tacrolimus maintenance with no induction therapy was associated with the best survival. In patients whom sirolimus cannot be utilized for any reason, azathioprine may modestly improve survival compared to MMF. Additional long-term studies in lung transplantation are needed to confirm these findings.