Use of sirolimus in the treatment of lymphangioleiomyomatosis: favorable responses in patients with different extrapulmonary manifestations

Case Series Use of sirolimus in the treatment of lymphangioleiomyomatosis: favorable responses in patients with different extrapulmonary manifestations* Uso de sirolimo no tratamento de linfangioleiomiomatose: resposta favorável em pacientes com diferentes manifestações extrapulmonares Carolina Salim Gonçalves Freitas1, Bruno Guedes Baldi2, Mariana Sponholz Araújo1, Glaucia Itamaro Heiden1, Ronaldo Adib Kairalla3, Carlos Roberto Ribeiro Carvalho4 Abstract Objective: Lymphangioleiomyomatosis (LAM) is a rare disease that is currently considered a low-grade neoplasm with metastatic potential and variable progression. Mammalian target of rapamycin (mTOR) inhibitors, such as sirolimus and everolimus, have recently become a treatment option for LAM patients, especially those with extrapulmonary manifestations. The objective of the present study was to describe a case series of four patients with LAM in Brazil who showed significant improvement, particularly in their extrapulmonary manifestations, after treatment with sirolimus (at 1-4 mg/day). Methods: We describe four cases of LAM patients with different extrapulmonary manifestations who were treated with sirolimus. Results: After treatment with sirolimus for 12 months, one patient presented resolution of severe chylothorax; one had a significant reduction in renal angiomyolipoma volume; and one showed significant regression of retroperitoneal lymphangioleiomyomas and abdominal lymph node enlargement. After treatment with sirolimus for 6 months, the remaining patient had a significant reduction in the volume of a massive retroperitoneal lymphangioleiomyoma. Conclusions: Our findings confirm that mTOR inhibitors are beneficial for patients with LAM, especially those with extrapulmonary manifestations, such as renal angiomyolipoma, lymphangioleiomyomas, and chylous effusions. However, certain aspects, such as the optimal dose, duration of treatment, and long-term adverse effects, have yet to be sufficiently clarified for mTOR inhibitors to be incorporated into LAM management protocols. Keywords: Neoplasms; Lymphangioleiomyomatosis/therapy; TOR serine-threonine kinases; Sirolimus. Introduction Lymphangioleiomyomatosis (LAM) is a rare disease of unknown etiology. It primarily affects women of childbearing age, and the prevalence of LAM is approximately 1/1,000,000 population. It can occur in isolation or in association with tuberous sclerosis complex (TSC).(1-3) The disease is characterized by proliferation of atypical cells (LAM cells) with characteristics of low-grade neoplasm and metastatic potential, leading to vascular and bronchial obstruction and cyst formation.(4-8) Major clinical manifestations of LAM include progressive dyspnea on exertion, dry cough, recurrent spontaneous pneumothorax, chylothorax, 1. Collaborating Physician. Department of Pulmonology, Instituto do Coração – InCor, Heart Institute – University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil. 2. Attending Physician. Department of Pulmonology, Instituto do Coração – InCor, Heart Institute – University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil. 3. Associate Professor. Department of Pulmonology, Instituto do Coração – InCor, Heart Institute – University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil. 4. Full Professor. Department of Pulmonology, Instituto do Coração – InCor, Heart Institute – University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil. *Study carried out in the Department of Pulmonology, Instituto do Coração – InCor, Heart Institute – University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil. Correspondence to: Carolina Salim Gonçalves Freitas. Divisão de Pneumologia, Instituto do Coração – InCor – Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Avenida Dr. Enéas de Carvalho Aguiar, 44, 8o andar, bloco 2, CEP 05403-900, São Paulo, SP, Brasil. Tel. 55 11 2661-5191. Fax: 55 11 2661-5695. E-mail: Financial support: None. Submitted: 13 January 2015. Accepted, after review: 8 April 2015. http://dx.doi.org/10.1590/S1806-37132015000004553 J Bras Pneumol. 2015;41(3):275-280 276 Freitas CSG, Baldi BG, Araújo MS, Heiden GI, Kairalla RA, Carvalho CRR and hemoptysis.(1,3,9) Renal angiomyolipomas and lymphangioleiomyomas can occur. A CT scan of the chest typically shows the presence of diffuse, well-defined, thin-walled lung cysts. Although pulmonary function test results can be normal, variable and progressive lung function decline can occur over time. Reduced DLCO is the most common change, and spirometry most commonly reveals airflow obstruction and air trapping; bronchodilator test results can be positive in up to 25% of cases.(10-12) A definitive diagnosis of LAM is based on the following(3,6): • typical chest HRCT findings, i.e., diffuse, well-defined lung cysts, in association with renal angiomyolipoma, pleural effusion/ chylous ascites, lymphangioleiomyoma/ lymph node involvement, or a definite or probable diagnosis of TSC • presence of lung cysts consistent with LAM on chest HRCT scans and pathological findings of LAM in a lung tissue sample preferably obtained by surgical biopsy Determination of serum levels of VEGF-D, which is a marker of lymphangiogenesis, has been increasingly used in order to aid in the diagnosis of LAM and to evaluate disease progression. Chest CT findings consistent with LAM associated with elevated VEGF-D levels are currently considered to be sufficient for the diagnosis of LAM.(13,14) The progression of LAM is highly variable, ranging from asymptomatic patients to patients with progressive respiratory failure requiring lung transplantation. Survival has been shown to be better in recent studies than in previous studies; a recent study conducted in Brazil showed a five-year survival of 90%.(15) Various drugs have been used in an attempt to control LAM. Matrix metalloproteinase inhibitors, such as doxycycline, and hormonal blockade have yielded controversial results and are not recommended for the treatment of LAM.(16-19) Mammalian target of rapamycin (mTOR) inhibitors, such as sirolimus and everolimus, are promising in the treatment of LAM, particularly in improving extrapulmonary manifestations and stabilizing or even improving lung function.(20,21) The objective of the present study was to describe a case series of patients with LAM in Brazil treated with sirolimus, which had positive effects, particularly on extrapulmonary manifestations. J Bras Pneumol. 2015;41(3):275-280 Case series Of a total of 10 patients with LAM treated with sirolimus at our center during the study period, we describe four cases of patients in whom the drug was primarily used because of extrapulmonary involvement. Case 1 A 48-year-old smoker (with a smoking history of 15 pack-years) was admitted with a two-year history of dyspnea, which had worsened one week prior. Sh (...truncated)