Sirolimus Therapy for Angiomyolipoma in Tuberous Sclerosis and Sporadic Lymphangioleiomyomatosis: A Phase 2 Trial

Abstract

Purpose: Renal angiomyolipomas are a frequent manifestation of tuberous sclerosis and sporadic lymphangioleiomyomatosis (LAM). These disorders are associated with mutations of TSC1 or TSC2 that lead to overactivation of mTOR complex 1 (mTORC1), suggesting an opportunity for targeted therapy by using mTORC1 inhibitors. This study investigated the efficacy and safety of the mTORC1 inhibitor sirolimus for treatment of renal angiomyolipomas in patients with these disorders.Experimental Design: In this multicenter phase 2 nonrandomized open label trial, 16 patients with tuberous sclerosis or sporadic LAM and renal angiomyolipoma(s) were treated with oral sirolimus for up to 2 years. Steady-state blood levels were 3 to 10 ng/mL. The primary outcome was change in size of renal angiomyolipomas measured by MRI and assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary outcomes included safety, neurocognitive function, and pulmonary function.Results: The response rate, by RECIST criteria, was 50%. Summated angiomyolipoma diameters were reduced in all 16 patients and by 30% or more in eight (all from the per protocol group of 10). Forty-one of 48 angiomyolipomas were smaller at the last measurement than at baseline. Most shrinkage occurred during the first year of treatment. There was little change in pulmonary function. Recall memory improved in seven of eight patients with tuberous sclerosis. Adverse events were consistent with the known toxicities of sirolimus.Conclusions: This study showed sustained regression of renal angiomyolipomas in patients with tuberous sclerosis or sporadic LAM receiving 2 years of sirolimus treatment. Possible effects on pulmonary function and neurocognition require further investigation.

O caminho à frente da linfangioleiomiomatose: um ensaio para cada paciente, cada paciente em um ensaio

“…However, lung function was found to resume its decline when the drug was discontinued. On the basis of these results and those of previous trials involving LAM patients, (12,13) we can conclude that sirolimus has more of a suppressive effect than a remission-inducing effect. Pilot studies recruiting candidates for future combination therapies that might complement or potentiate sirolimus effects are best conducted in areas of the world where large numbers of LAM patients have assembled in support groups, such as Brazil, the United States, Canada, Japan, Korea, China, Australia, Germany, France, Italy, Spain, and England.…”

Recommendations for extralicence application of rapamycin in tu berous sclerosis

“…wykazali zmniejszenie guzów AML na leczeniu sirolimusem u wszystkich 16 chorych, w tym u 8, o co najmniej 30% [5].…”

LAM cells biology and lymphangioleiomyomatosis

“…TORC1 is the rapamycin-sensitive mTOR complex responsible for the regulation of protein translation initiation and efficiency [8]. Clinical trials with rapamycin as a therapeutic solution for lymphangioleiomyomatosis are in an advanced phase [9]. Rapamycin is a macrolide antibiotic isolated from a strain of Streptomyces higroscopicus.…”

“…Rapamycin binds to the cytosolic protein FKPB-12 thereby inactivating the mTOR kinase. Treatment with rapamycin resulted in the reduction of tumor volume and improved lung function in LAM patients [9][10][11]. However, rapamycin only partially inhibits cell growth, proliferation and disease progression.…”