Sirolimus Linked to Lower Malignancy After Heart Transplant

Debra L Beck

May 30, 2019

Switching heart transplantation patients from calcineurin inhibitor (CNI)-based to sirolimus-based immunosuppression was associated with an almost doubling of the malignancy-free survival rate in a retrospective cohort analysis.

Over a median of 10 years, de novo (nonskin) malignancies were seen in 13% of patients converted early to sirolimus compared with 31% of patients maintained on CNI-based immunosuppression (P < .001).

In a Cox regression model, estimated survival at 10 years decreased to 36% from 70% among patients with and without malignancy, respectively.

"Long-term use of sirolimus after withdrawal of calcineurin inhibitor among heart transplantation recipients who tolerate this conversion is an effective immunosuppressive strategy for risk reduction of overall de novo malignancy and subsequent improvement in late survival," write Rabea Asleh, MD, PhD, MHA, Mayo Clinic, Rochester, Minnesota, and colleagues.

The researchers published their relatively large single-center cohort analysis in the June 4 issue of the Journal of the American College of Cardiology.

They included all 523 patients who underwent heart transplantation between January 1994 and December 2016 at the Mayo Clinic. Starting in July 2006, all post-transplant stable patients without evidence of rejection received gradually increasing doses of sirolimus. Prior to 2006, patients were switched to sirolimus only if there was a specific reason, such as to preserve renal function or as an adjunctive therapy for coronary vasculopathy.

When target sirolimus levels were reached, the CNI dose was gradually titrated down without changes to the antimetabolite or steroid regimens.

Both before and after July 2006, CNI was typically used for the first 6 months after heart transplantation to avoid issues of delayed wound healing that are seen with early introduction of sirolimus.

No significant difference was noted in the occurrence of first nonmelanoma skin cancers, but the adjusted risk for post-transplantation lymphoproliferative disorders and subsequent occurrences of nonmelanoma skin cancers were both reduced in sirolimus-treated patients, compared with CNI-treated patients.

In patients who developed malignancies, late mortality risk was almost fourfold higher than in those who did not.

Immunosuppression after solid organ transplantation is always a balancing act. Ideally, it should offer "selective or antigen-specific tolerance," wherein there is "both allo recognition of the graft by recipient T-cells and production of alloantibodies to the graft by recipient B-cells," Sharon A. Hunt, MD, Stanford University, California, writes in an accompanying editorial comment.

But until this "Holy Grail" of solid organ transplantation is achievable, the best to be hoped for is nonspecific immunosuppression that is the least toxic possible.

Sirolimus was approved in the United States for solid organ transplantation in 1999. In late 2018, Asleh et al published data in 402 transplant patients from the same cohort showing attenuated progression of cardiac allograft vasculopathy in patients who converted early to sirolimus.

Over a mean follow-up of 8.9 years from transplantation, all-cause mortality occurred in 25.6% of the patients, and was reduced by 53.0% during treatment with sirolimus compared with CNI (adjusted hazard ratio, 0.47; P = .0002). Outcomes favored early over late conversion to sirolimus, the researchers report.

Hunt pointed out that the Mayo investigators did not use sirolimus as a substitute for the antimetabolite in the regimen, but rather phased out the CNI, which was most often tacrolimus. Other transplant centers have opted to switch to an mTOR inhibitor, usually by switching from the antimetabolite in the regimen (usually mycophenolate) and lowering the CNI dose.

Whether the findings will lead to a "wholesale change" in how transplant centers approach immunosuppression is unclear, said Hunt, although she suggested that it's more "likely that a modified approach, with mTOR inhibitors being substituted for antimetabolite agents and lower doses of CNI, will be embraced sooner than the wholesale withdrawal of CNI used in this study," she writes.

A randomized trial on this topic would be helpful, said Hunt, but that is "clearly undoable" because of ethical concerns and the difficulty in enrolling a large enough sample to yield a definitive result.

Alseh and Hunt reported that have no relationships relevant to this paper to disclose.

J Am Coll Cardiol. 2019;73:2676-2688, 2689-2690. Abstract, Editorial

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