Sirolimus use in allogeneic hematopoietic cell transplant recipients: assessing its senotherapeutic role in a high risk population

TL;DR

This study explores whether sirolimus, used to prevent GVHD in bone marrow transplants, can also reduce aging-related cell damage in high-risk patients.

Contribution

The study investigates sirolimus's potential senotherapeutic effects in allogeneic hematopoietic cell transplant recipients.

Findings

Sirolimus use at GVHD prophylaxis doses did not significantly reduce senescent cell burden compared to cyclosporine.

A non-significant trend of lower p16 INK4a and p21 CIP1 expression was observed in the sirolimus-treated group.

Results suggest sirolimus's benefits may depend on a specific therapeutic window.

Abstract

Allogeneic hematopoietic cell transplantation (HCT) is often the only curative therapy for hematologic malignancies. Immune suppression is necessary for the engraftment of donor cells and prevention of graft-versus-host disease (GVHD). mTOR inhibitors like sirolimus are commonly used for GVHD prophylaxis. Low doses of sirolimus have demonstrated a gerotherapeutic effect, extending lifespan in animals, reducing senescent cell burden, and improving immune function in animals and humans. We hypothesized that the use of sirolimus in GVHD prophylaxis platforms, even at high doses, could have a senotherapeutic effect. We compared senescent cell burden in double umbilical cord blood HCT recipients with available baseline, day 100 and 365 post-HCT samples. All patients received an identical conditioning regimen with different GVHD prophylaxis: sirolimus + mycophenolate mofetil (MMF) or cyclosporine + MMF. At target doses to reduce GVHD risk, neither expression of senescence markers nor the abundance of SASP factors differed significantly in the sirolimus treated cohort compared to cyclosporine control cohort. However, we note a non-significant but perhaps biologically relevant trend of lower relative expression of p16

INK4a
and p21

CIP1
post-HCT in the sirolimus cohort. Further longitudinal analysis including a larger cohort would be useful to determine the true magnitude of differences in senescent cell burden. Our results suggest that the daily administration and dosing used for GVHD prevention are less likely to confer clinical benefits, possibly indicating that the beneficial effects of sirolimus occur within a specific therapeutic window. These findings highlight the need to further investigate senotherapeutic approaches in this setting of accelerated aging.

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