Angiomyolipoma rebound tumor growth after discontinuation of everolimus in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis

Abstract

IntroductionThe EXIST-2 (NCT00790400) study demonstrated the superiority of everolimus over placebo for the treatment of renal angiomyolipomas associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (LAM). This post hoc analysis of EXIST-2 study aimed to assess angiomyolipoma tumor behavior among patients who submitted to continued radiographic examination following discontinuation of everolimus in the noninterventional follow-up phase.MethodsFor patients who discontinued everolimus at the completion of extension phase for reasons other than angiomyolipoma progression, a single CT/MRI scan of the kidney was collected after 1 year of treatment discontinuation. Changes from baseline and from the time of everolimus discontinuation in the sum of volumes of target angiomyolipoma lesions were assessed in the non-interventional follow-up phase (data cutoff date, November 6, 2015).ResultsOf the 112 patients who received ≥1 dose of everolimus and discontinued treatment by the end of extension phase, 34 (30.4%) were eligible for participation in the non-interventional follow-up phase. Sixteen of 34 patients were evaluable for angiomyolipoma tumor behavior as they had at least one valid efficacy assessment (i.e. kidney CT/MRI scan) after everolimus discontinuation. During the non-interventional follow-up phase, compared with baseline, two patients (12.5%) experienced angiomyolipoma progression (angiomyolipoma-related bleeding [n = 1], increased kidney volume [n = 1]). Five patients out of 16 (31.3%) experienced angiomyolipoma progression when compared with the angiomyolipoma tumor assessment at everolimus discontinuation. The median (range) percentage change in angiomyolipoma tumor volume (cm3) from baseline was −70.56 (−88.30; −49.64) at time of everolimus discontinuation (n = 11), and −50.55 (−79.40; −23.16) at week 48 (n = 7) after discontinuation of everolimus. One patient death was reported due to angiomyolipoma hemorrhage.ConclusionsAngiomyolipoma lesions displayed an increase in volume following discontinuation of everolimus in patients with renal angiomyolipoma or sporadic LAM associated with TSC, but there was no evidence of rapid regrowth.Trial registrationClinicalTrials.gov NCT00790400

Mutational analysis of renal angiomyolipoma associated with tuberous sclerosis complex and the outcome of short-term everolimus therapy

“…However, our research shows that 7 patients (7/25; 28.00%) who were primarily sensitive to everolimus treatment, experienced an increase in renal AML tumor volume after the treatment stopped. Although similar results have been reported in other studies 48–50 , the AML progression rate was much higher in this study than in other long-term everolimus treatment studies. This may be due to a number of reasons, but the main reason is that the treatment time is short and possibly related to the sensitivity of the Chinese race to everolimus treatment.…”

Experience of a Single Center in Treating Multiple Manifestations of Tuberous Sclerosis Complex with Everolimus

“…In cardiac RHM, rebound growth of tumors was also observed in the three patients (Patients #17, #18, and #19) who discontinued everolimus treatment due to a reduction in tumor size, but the tumors of these patients did not exceed the original size and did not cause hemodynamic instability or arrhythmia. This is consistent with previous studies in which renal AML or cardiac RHM rebound growth occurred following withdrawal of mTOR inhibitors [12,19,20]. The regrowth of tumors after the cessation of an mTOR inhibitor suggests that continued treatment with everolimus in TSC patients may be required to sustain significant tumor volume reduction.…”

“…TSC-related tumors shrink and stabilize with mTOR inhibitor treatment, but after treatment is stopped, tumor volume tends to increase again [18,19]. For this reason, it is often difficult to determine how long a patient should be maintained on a maintenance dose of everolimus to treat TSC-related tumors.…”

Deceased Donor Renal Transplantation Combined with Bilateral Nephrectomy in a Patient with Tuberous Sclerosis and Renal Failure

“…The main reason is to avoid an increased risk of renal insufficiency and end-stage renal failure and to avoid two-stage procedure [14]. If the mTOR inhibitors as a “first-line” therapy fail to control the AML size, selective embolisation or kidney-sparing resections are acceptable “second-line” treatments for asymptomatic angiomyolipoma [13–15]. However, in patients with life-threatening retroperitoneal haemorrhage caused by ruptured aneurysms from angiolipomas, renal nephrectomy represents a lifesaving procedure despite the accompanying complications that may arise.…”