Vascular malformations include a heterogenous group of developmental anomalies of the vascular system, capillaries, veins, arteries, lymphatics or any combination of these vessels may be involved. The International Society for the Study of Vascular Anomalies (ISSVA) classified vascular malformations into the following categories(1): simple (low-flow vascular malformation: capillary (CM), lymphatic (LM), venous (VM) arteriovenous (AVM), combined, vascular malformation of major named vessels, and vascular malformation associated with other anomalies.
Vascular malformations are congenital, however, they can be discovered at any life stage, depending on their size and associated symptoms.
Current treatment options for low-flow vascular malformation may be conservative, with compression bandages, analgesics, anti-inflammatory or anti-coagulation drugs, or more invasive with intralesional sclerotherapy or embolization, and surgery(2). Unfortunately, treatment is challenging and not always successful, and can leave patients with a high clinical burden and subsequently a reduced Quality of Life (QoL)(3). Clinical symptoms that reduce the QoL in patients with low-flow vascular malformations include pain, functional impairment, bleeding, thrombophlebitis, ulceration, infections, and leakage (in LM)(4).
The PI3/AKT/mTOR pathway plays a pivotal role in low-flow vascular malformation(5). The activation of mammalian Target of Rapamycin (mTOR), stimulates angiogenesis, cell proliferation, and glucose metabolism. Some activating somatic mutations in genes in a target of the mTOR pathway, such as PIK3CA, AKT-1, TEK/TIE-2 and PTEN, in patients with low-flow vascular malformation resulted in the increased activation of mTOR(6–10). Therefore, the inhibition of this pathway in these patients seems a logical approach to treatment.
In cells, sirolimus binds to the immunophilin FK Binding Protein-12 (FKBP-12), which in turn binds to and inhibits the activation of mTOR. This inhibition results in the obstruction of several signal transduction pathways, thereby inhibiting downstream protein biosynthesis, cell proliferation, and angiogenesis(11, 12). In theory, this should decrease the size of the low-flow vascular malformation or at least inhibit activity and stop further growth. Unfortunaly, the inhibition of lymphocyte activation also results in immunosuppression and might therefore be associated with the susceptibility to infections(13).
Several studies have been performed to explore the use of sirolimus as a treatment option in low-flow vascular malformations(14–17). These prospective open-label trials used - high target sirolimus levels of 10–15 ng/ml leading to (partial) response in 85–100% patients(14–17). As these trials were open label trials, the question remains what is the true efficacy of sirolimus and what is natural behavior of the vascular malformation. Ideally, a placebo controlled randomized trial should be performed, however, in respect to the severe clinical burden of the patients and the rarity of the disease, it is difficult to execute. Recently, it has been postulated that a different design can be used in rare diseases to identify true efficacy of a drug(18). This design is based on the concept of Challenge, Dechallenge and Rechallenge (CDR) to proof the efficacy (or adverse events) caused by a single drug. Ideally, a future study should use this design to investigate true efficacy more in detail. Furthermore, more insight in the adverse events of sirolimus used as a single drug can be gained, as most information available so far, is based on adverse events observed in patients using a combination of drugs (e.g. renal transplant patients)(13, 19–23).
The side effects of sirolimus described include oral ulceration, mucositis and stomatitis, interstitial lung disease, diabetes mellitus, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, gastro-intestinal side effects, angioedema, thrombo-embolic disease, anemia, leucopenia, thrombocytopenia, proteinuria, glomerulonephritis, and lymphedema(13).
Our knowledge regarding long term toxicities of sirolimus is still expanding and makes it necessary to minimalize the risk for these long term toxicities. For example, it has been observed that in patients with long-term sirolimus impaired insulin receptor substrate signaling and Akt activation can be found indicating a deterioration of glucose metabolism leading to an increase of development of diabetes(24).
As in most drugs observed, one can imagine that higher levels of a drug increase the risk of developing adverse events of which the most serious and sometimes even fatal complication is sirolimus-associated interstitial pneumonitis(19, 23, 25, 26).
Bee et al. showed that low sirolimus serum levels (< 3 and 6.9 ng/ml) are related to less side effects without compromising efficacy of treatment in patients with diffuse lymphangioleiomyomatosis(27). Additionally, Kahan et al. showed a significant relation between the occurrence of adverse events (hypertriglyceridemia, hypercholesterolemia, leukopenia and thrombocytopenia) and the steady state concentration value of sirolimus(28). A Css below 10 ng/L showed no toxic values.
In the pilot study described here, we hypothesized that sirolimus used in low dosages with lower target levels (4–10 ng/ml) than previously described, is equally effective in the treatment of low flow vascular malformations however will lead to less serious adverse events as observed in those treated with high target levels. Treatment with low target levels (4–10 ng/ml) may require longer treatment than with high target levels (> 10 ng/ml), however low dose sirolimus will be more tolerable if less (serious) adverse events occur. This is especially important, as our knowledge regarding long term toxicities of sirolimus is still growing and makes it necessary to reduce the risk for these long term toxicities.