This study demonstrates that mTOR inhibition through the use of rapamycin is effective in reducing AML volume in TS patients and has an acceptable safety profile.
The drug is marketed and indicated for prophylaxis of acute rejection in adult kidney transplant recipients with low immunological risk.
Preliminary clinical data suggest that rapamycin could play a beneficial role in the treatment of TS [15, 16]. There are case reports in which the size of astrocytomas or angiomyolipomas decreased in patients with TS and good tolerability was reported [17–21]. Also some clinical trials showed beneficial effect of mTOR inhibitors in lymphangioleiomyomatosis  and astrocytomas . Moreover, 3 clinical trials show evidence of AML response to mTOR inhibition [24–26]. In a non-controlled, phase II trial, Bissler JJ et al. showed a reduction in the size of renal angiomyolipomas (53.2% ± 26.6%) in 14 TSC patients with AML larger than 1 centimetre in size treated over 1 year  . Davies DM et al. also carried out a non-controlled trial with 16 patients with AML and TSC or LAM. Seven patients with TSC and AML reached 2 years of treatment with sirolimus and the results showed a significant reduction of AML burden . The response rate, by RECIST criteria, was 50%, being all partial responses Very recently Dabora SL et al. reported their experience in treating 36 patients with TSC or LAM with Sirolimus for one year and had a 44.4% response rate (partial responses in all cases) according to RECIST criteria . We also reported the preliminary results at one year observing an excellent response to treatment . An explanation for the higher success rates in our trial compared to others may be that we focused the evaluation of AML volume decrease in the largest AML while others analyzed the AML in general. Perhaps, the greater AML have a better response to treatment than smaller ones, based on its hypothetically higher mitotic rate.
The hypothesis of this trial is that inhibitors of the Akt signalling cascade, such as rapamycin, can block the inadequate proliferation observed in TS in the form of AML . The drug reduces vascular endothelial growth factor (VEGF) plasma levels and, taking into account the considerable tumour vascularisation in TS caused by up-regulation of VEGF, its anti-angiogenic action could prove very beneficial .
This study is the largest and longest carried out to date focused on AML in patients with TSC without LAM. The results show that AML shrank faster early on in the trial and persist with approximately the same volume while on treatment. There is a significant decrease in volume after six months of treatment, which continues at a slower rate up to one year, but remains stable from 1 to 2 years (RECIST partial response rate: 100% at one year). This evidence suggests that the shrinkage power of the drug is at its maximum at the beginning, probably due to its anti-angiogenic effect. And, although there does not seem to be any beneficial effect after one year, there is indeed, as some authors demonstrated by withdrawing the treatment and then showing an increase in AML volume [24, 26]. Therefore, it seems reasonable to assume that TSC patients with large AML should be kept under mTOR inhibition for life. This suggestion may raise two concerns: what the optimal dose is and whether we can accept the side effects of the drug for a lifetime. In this study, we experienced a great deal of trouble achieving the desired target plasma levels of sirolimus in patients on antiepileptic treatment, which is very common among TSC patients. Moreover, all patients in general needed higher doses than transplanted patients to achieve the same target plasma levels. Larger studies and a long follow-up period should address whether low doses of mTOR inhibitors are enough to prevent AML growth after the initial reduction. The most frequent adverse reactions we recorded were stomatitis (27.7%), which was observed at the start of treatment. The reaction was dose-dependent and easily managed with topical corticosteroids and dose adjustment. The next most frequent reaction was hypertriglyceridaemia (22.2%) mainly in patients who already had high triglyceride levels prior to inclusion. Medical treatment was provided in most cases. Given the anti-proliferative effect of rapamycin, we also observed microcytosis and hypochromia (16.6%), with normal results for iron metabolism and stable haemoglobin values. A total of 41% of patients developed microalbuminuria but no patients developed impaired renal function. However, the development of microalbuminuria raises the concern on the long term effects on renal function of mTOR inhibition. Two patients were withdrawn because of serious adverse events, one due to reactivation of erythema nodosum and the other due to nephrotic-range proteinuria, which fully resolved after discontinuation of the treatment.
There are efficacy reports on topical and oral rapamycin for facial angiofibromas in TSC patients [30, 31], however this clinical feature has not been analyzed in previous trials using systemic rapamycin. In this study, we noticed an improvement in facial angiofibromas and a subjective improvement of periungual fibromas.