Rapalogs are drugs that inhibit the mTOR pathway and include sirolimus (rapamycin), temsirolimus, everolimus, and deforolimus. All are immunosuppressive and have antineoplastic/antiproliferative effects. The mTOR protein is a serine-threonine kinase involved in complex intracellular signaling pathways affecting the key processes of cell growth, cell proliferation, angiogenesis, cellular metabolism, autophagy and apoptosis. Vascular endothelial growth factor (VEGF) is a vital regulator in lymphangiogenesis and angiogenesis acting both as a potential upstream stimulator of, and downstream effector in, the mTOR-signaling pathway. The mTOR inhibitors decrease VEGF secretion by tumors and reduce the sensitivity of endothelial cells to VEGF, thereby preventing neovascularization (1).
Of the rapalogs, sirolimus has been used most frequently for managing vascular malformations and tumors. Examples of recent reports include the diminution of life-threatening bleeding in the Klippel-Trenaunay syndrome, by decreasing the tumefaction and hemorrhage of the malformation (2); improvement of lesional size, bleeding, pain, and quality of life in patients with the Blue Rubber Bleb syndrome (3); and shrinkage of Kaposiform hemangioendotheliomas, with or without the Kasabach-Merritt syndrome (4).
In their combined study of 84 patients, Nadal et al , 35.7% (n = 30) had vascular tumors, and 64.3% (n = 54) had malformations. Sirolimus was the most frequent mTOR inhibitor used (98.8%, n = 83). It was efficient in all cases, at a median time of 2 weeks (95% confidence interval1–10 weeks). Sirolimus was well tolerated, the main side-effect being mouth sores, which led to treatment withdrawal in one case. (1).
Caveat emptor: When prescribing siroliumus remember there are potentially serious adverse reactions. According to Nadal, et al:
Classically described adverse effects of sirolimus include mucositis, headaches, asthenia, gastrointestinal effects, peripheral oedema, hypertension and defect
healing. Renal dysfunction, especially proteinuria, has also been reported in transplant and non-transplant patients exposed to mTOR inhibitors. The most
common biological effects are haematological (thrombocytopaenia,
leucopaenia, anaemia, microcytosis) and metabolic effects (hyperlipidaemia,
hyperglycaemia, hypokaliemia, hypophosphataemia and increased level of liver enzymes). A very rare and potentially serious side effect is interstitial pneumonitis. Finally, given the potential risk of immunosuppression, some authors systematically prescribe co-trimoxazole, or pentamisine for Pneumocystis prophylaxis.
I am always fearful of the rare risk of progressive multifocal leukoencephalopathy (PML), whenever I prescribe immunosuppressants. There is some evidence to suggest that the risk of PML with sirolimus is less that seen with other immunosuppressive drugs. In a study of 1,978,706 patients eligible for analysis., 21 out of 36 analyzed immunosuppressants were reported at least once with PML – the risk appears to be lower with sirolimus, leflunomide and methotrexate (5).
In conclusion, for vascular malformations and tumors, think mTOR inhibition in those circumstances where pharmacologic intervention may be preferable to surgery, laser, embolization, or other drugs.
- Nadal M, et al. Efficacy and safety of mammalian target of rapamycin inhibitors in vascular anomalies: A systematic review. Acta Derm Venereol 2016; 96: 448-52.
- Bessis D, et al. Life-threatening cutaneous bleeding in childhood Klippel-Trenaunay syndrome. JAMA Dermatol 2016; 152: 1058-9.
- Salloum R, et al. Response of blue rubber bleb nevus syndrome to sirolimus treatment. Pediatr Blood Cancer 2016; June 8 [Epub ahead of print].
- Oza VS, et al. Role of sirolimus in advanced Kaposiform hemangioendothelioma. Pediatr Dermatol 2016; 33: e88-92.
- Schmedt N, et al. Signals of progressive multifocal leukoencephalopathy for immunosuppressants: A disproportionality analysis of spontaneous reports within the US Adverse Event Reporting System (AERS). Pharmacoepidemiol Drug Saf 2012; 21: 1216-20.