Use of sirolimus associated with a reduction in mortality risk after late post-heart transplantation

Sept. 27, 2019

Analysis of a single-center cohort of patients who received heart transplantation has provided evidence that conversion from calcineurin inhibitor therapy to a sirolimus-based regimen is an effective approach for mitigation of malignancy risk related to long-term immunosuppression therapy.

Survival after heart transplantation has improved since the introduction of improved immunosuppression therapy: Approximately 50% of patients who receive heart transplantation now survive more than 13 years and the number of patients who survive more than 20 years post-heart transplantation continues to rise.

However, the resulting longer exposure to immunosuppression therapy, coupled with an increasing population of patients who undergo heart transplantation at an older age and with a higher risk profile, has blunted further improvement in late survival due to a greater risk of de novo malignancy after heart transplantation. Long-term immunosuppression therapy has also been associated with a fivefold increase in the incidence of post-transplantation nonmelanoma skin cancer (NMSC) and the development of post-heart-transplantation lymphoproliferative disorders and other solid cancers.

In a retrospective study published in the Journal of the American College of Cardiology in 2019, Sudhir S. Kushwaha, M.D., Cardiovascular Medicine, and a research team at Mayo Clinic in Rochester, Minnesota, examined whether conversion from calcineurin inhibitor therapy to sirolimus-based immunosuppression was associated with decreased risk of malignancy post-heart transplantation.

Less risky immunosuppression

"The use of calcineurin inhibitors has been implicated in a dose-dependent increase in risk of different types of cancers that might be attributed to increased levels of transforming growth factor B and pro-angiogenic factors," says Dr. Kushwaha. "Although recipient-related risk factors such as sun exposure, viral infections and local immune reactions against the graft have emerged as risk factors for malignancy after heart transplantation, the type and duration of immunosuppression remain important determinants of malignancy risk.

"Sirolimus exerts anti-proliferative properties. The mammalian target of rapamycin (mTOR) pathway is a key regulator of cell growth and survival that is frequently dysregulated in various types of malignancies. Sirolimus and its derivative, everolimus, are mTOR inhibitors that suppress tumor growth in animal models and have been successfully used in treating selective types of cancers."

A prior study, also published in the Journal of the American College of Cardiology in 2019, showed that early conversion to a maintenance sirolimus-based immunosuppression regimen with complete withdrawal of calcineurin inhibitor therapy was associated with attenuation of cardiac allograft vasculopathy progression and improvement in cardiac outcomes and late survival after heart transplantation compared with continued use of calcineurin inhibitors from time of heart transplantation.

"This improved late survival with long-term use of sirolimus, however, is not fully explained by attenuated cardiac allograft vasculopathy progression and a reduction in associated events," says Dr. Kushwaha. "In the most recent study, we examined in recipients of heart transplantation with prevalent use of sirolimus for primary immunosuppression whether conversion from calcineurin inhibitor therapy to sirolimus-based immunosuppression was associated with decreased rates of overall de novo malignancies ― thus providing an additional explanation for the survival benefit seen with long-term sirolimus maintenance therapy. We also examined the effects of conversion to sirolimus on the incidence and rates of primary and subsequent primary occurrences of NMSC, which are common in this population."

The research team retrospectively analyzed a cohort of 523 patients who received heart transplantation between January 1994 and December 2016 at Mayo Clinic in Rochester, Minnesota and were treated either with a calcineurin inhibitor therapy (216 patients) or were converted to a sirolimus-based regimen without calcineurin inhibitor as the primary immunosuppression therapy (307 patients).

Dr. Kushwaha notes: "A routine conversion protocol from calcineurin inhibitor to sirolimus was introduced at Mayo Clinic in July 2006 in which calcineurin inhibitor therapy was typically used for the first six months after heart transplantation to avoid delayed wound healing that could occur with earlier introduction of sirolimus. Biopsies were generally performed two weeks after the conversion process, and a reduced dose of calcineurin inhibitor was reintroduced if the biopsy was positive for rejection, with a second attempt to withdraw calcineurin inhibitor therapy later if rejection subsided."

Median 10-year follow-up results

Over a median follow-up of 10 years after heart transplantation, overall de novo malignancies (non-NMSC skin cancer) occurred in 31% of patients receiving calcineurin inhibitor and in 13% of patients receiving sirolimus.

The incidence of first NMSC was similar in the calcineurin inhibitor and sirolimus groups. However, conversion to sirolimus was associated with a decreased risk of subsequent primary occurrences of NMSC.

The adjusted risk of post-transplantation lymphoproliferative disorders decreased in the group receiving sirolimus. Late survival post-heart transplantation decreased in patients who developed non-NMSC or post-transplantation lymphoproliferative disorders compared with patients who did not develop these malignancies.

NMSC had no significant effect on survival.

"This study provides evidence of reduced incidence of de novo non-NMSC malignancies, post-transplantation lymphoproliferative disorders and lower subsequent primary occurrences of NMSC in recipients of heart transplantation who were converted to a sirolimus-based immunosuppression regimen with complete calcineurin inhibitor withdrawal post-heart transplantation," says Dr. Kushwaha. "The findings also provide further explanation of the late survival benefit with long-term sirolimus use."

For more information

Hunt SA. Less risky immunosuppression in heart transplantation? Journal of the American College of Cardiology. 2019;73:2689.

Asleh R, et al. Incidence of malignancies in patients treated with sirolimus following heart transplantation. Journal of the American College of Cardiology. 2019;73:2676.