New Insights into Red Blood Cell Microcytosis upon mTOR Inhibitor Administration

Abstract

The aim of this study was to evaluate the effect of everolimus, a mammalian target of rapamycin (mTOR) inhibitor, on red blood cell parameters in the context of iron homeostasis in patients with tuberous sclerosis complex (TSC) and evaluate its effect on cell size in vitro. Everolimus has a significant impact on red blood cell parameters in patients with TSC. The most common alteration was microcytosis. The mean MCV value decreased by 9.2%, 12%, and 11.8% after 3, 6, and 12 months of everolimus treatment. The iron level declined during the first 3 months, and human soluble transferrin receptor concentration increased during 6 months of therapy. The size of K562 cells decreased when cultured in the presence of 5 μM everolimus by approximately 8%. The addition of hemin to the cell culture with 5 μM everolimus did not prevent any decrease in cell size. The stage of erythroid maturation did not affect the response to everolimus. Our results showed that the mTOR inhibitor everolimus caused red blood cell microcytosis in vivo and in vitro. This effect is not clearly related to a deficit of iron and erythroid maturation. This observation confirms that mTOR signaling plays a complex role in the control of cell size.

mTOR Inhibitors Induce Erythropoietin Resistance in Renal Transplant Recipients

“…In our study, the elevated EPO production was able to compensate and preserve hemopoiesis. Previous studies have demonstrated that microcytosis or anemia are induced in mTOR inhibitor-treated subjects (7,(13)(14)(15)(22)(23)(24). EPO is also known to inhibit hepcidin production (25)(26)(27)(28).…”

“…In vitro studies have demonstrated that mTOR inhibitors induce microcytosis, possibly due to inhibition of erythroid precursors (22,23) and that these effects are not overcome by increasing available iron in the culture environment (23). This microcytosis is reversed by withdrawal of mTOR inhibitors (7,13,15).…”

“…The presence of similar hepcidin levels in the mTOR and tacrolimus groups, despite the elevated EPO levels in the former, suggests that the effects of EPO are probably direct and not mediated via changes in hepcidin production. In vitro studies have demonstrated that mTOR inhibitors induce microcytosis, possibly due to inhibition of erythroid precursors ( 22 , 23 ) and that these effects are not overcome by increasing available iron in the culture environment ( 23 ). This microcytosis is reversed by withdrawal of mTOR inhibitors ( 7 , 13 , 15 ).…”

“…However, prohepcidin levels correlate poorly with total body iron status in comparison with mature hepcidin-25 ( 30 ). A 2021 pediatric case-control study found no difference in IL-6, hepcidin or ferritin levels in 17 children with tuberous sclerosis complex treated with everolimus compared to 47 controls ( 23 ). IL-6 levels were also measured in the patients prior to commencing everolimus and at 3, 6 and 12 months with no significant elevation with introduction of everolimus ( 23 ).…”

“…A 2021 pediatric case-control study found no difference in IL-6, hepcidin or ferritin levels in 17 children with tuberous sclerosis complex treated with everolimus compared to 47 controls ( 23 ). IL-6 levels were also measured in the patients prior to commencing everolimus and at 3, 6 and 12 months with no significant elevation with introduction of everolimus ( 23 ). IL-6 levels were similarly elevated in both our treatment groups, compared to data derived from healthy adults ( 31 ), indicating similar levels of inflammation and suggesting this pathway does not contribute to impaired hemopoiesis.…”