Abstract

Objective: Lymphangioleiomyomatosis (LAM) is a rare systemic disease of young women arising from mutations in the tuberous sclerosis complex (TSC) genes, TSC1 or TSC2. This disrupts the mammalian target of rapamycin (mTOR) pathway, affecting cellular proliferation and growth. mTOR inhibitors are a promising novel therapy in LAM. The mTOR inhibitor sirolimus is reported to produce resolution of lymphatic abnormalities in LAM, but the efficiacy of the mTOR inhibitor everolimus has not been assessed. We aimed to examine the efficacy of everolimus on lymphatic abnormalities in LAM.

Design, setting and participants: Open-label treatment of five patients with sporadic LAM (sLAM) and abdominopelvic and lung involvement at the outpatient LAM clinic of a tertiary city teaching hospital. Clinical data were collected during treatment of the women and included regular clinical reviews, everolimus levels, lung function and computed tomography assessment before and after 6 months of everolimus treatment.

Main outcome measures: Symptoms and level of resolution of lymphangioleiomyomas.

Results: All five women experienced significant shrinkage or complete resolution of the lymphangioleiomyomas during treatment. In one woman, cessation of everolimus resulted in recurrence of symptoms. Adverse events were compatible with the known side-effect profile of everolimus, but overall the drug was well tolerated.

Conclusions: This is the first report to suggest that everolimus has efficacy in the treatment of lymphangioleiomyoma and chylous ascites in sLAM.

Discussion

Although LAM frequently presents with respiratory symptoms, abdominal involvement occurs in up to 70% of cases,14 with abdominal lymphangioleiomyomas in 16% of cases.2 Women may present with abdominal pain and swelling, and refractory chylous ascites, or with non-specific signs such as infertility or perimenstrual abdominal discomfort.4Treatment is generally unsatisfactory, with medical therapies ineffective, and repeated abdominocentesis resulting in fluid reaccumulation, protein loss and potential infection.

The use of mTOR therapy in LAM is a targeted approach to an abnormality arising from a genetic mutation affecting multiple systems. The 2011 MILES trial showed that treatment with sirolimus in LAM was associated with a slower decline in lung function, improvement in quality of life and shrinkage of renal AMLs, but abdominal LAM was not the focus of that trial.3 To date, single-case reports and one observational series have documented regression of abdominal lymphangioleiomyomas with sirolimus or temsirolimus treatment,6–9,11 but there are no reports on everolimus. Our case series suggests that the efficacy of mTOR inhibitors extends to everolimus, and that this has good effect on abdominal LAM, which has been very difficult to treat in the past. Previous studies have shown that mTOR inhibitor treatment needs to be continued in TSC, but longitudinal data in LAM are limited.3,7 This is the first study to report everolimus treatment for LAM for several years, with all five women continuing on everolimus therapy. This is significant because the efficacy of mTOR inhibitors appears to rely on sustained therapy.3,11

Everolimus is a derivative of sirolimus and has a very similar side-effect profile. It has a shorter elimination half-life (about 30 hours) and greater relative bioavailability, compared with sirolimus.15 We used a lower dose of everolimus than the dose of sirolimus that was used in the MILES trial. The everolimus dose we used was consistent with the lower range of doses used in lung transplantation in our centre, with the aim of producing fewer side effects. Overall, everolimus was well tolerated and side effects, although significant, were within its described profile.

In summary, all women with sLAM showed a good response to treatment, with disappearance or shrinkage of abdominal lymphangioleiomyomas in four of five of cases, and clinical resolution of the lymphangioleiomyoma in the fifth. Abdominal symptoms resolved. Cessation of the therapy in one patient resulted in recurrence of ascites, and reinstitution of treatment resulted in resolution again. This is similar to the MILES trial, in which continued treatment was required.3 We suggest that everolimus treatment may be an effective long-term therapy for lymphangioleiomyomas and chylous ascites, which requires further evaluation in an appropriately designed controlled trial.

Source: MJA