Efficacy and Safety of Sirolimus in Lymphangioleiomyomatosis

McCormack, Francis X.; Inoue, Yoshikazu; Moss, Joel; Singer, Lianne G.; Strange, Charlie; Nakata, Koh; Barker, Alan F.; Chapman, Jeffrey T.; Brantly, Mark; Stocks, James M.; Brown, Kevin K.; Lynch, Joseph P.; Goldberg, Hilary J.; Young, Lisa R.; Kinder, Brent W.; Downey, Gregory P.; Sullivan, Eugene J.; Colby, Thomas V.; McKay, Roy T.; Cohen, Marsha M.; Korbee, Leslie; Taveira-DaSilva, Angelo M.; Lee, Hye Seung; Krischer, Jeffrey P.; Trapnell, Bruce C.

doi:10.1056/nejmoa1100391

Cited by 905 publications

(787 citation statements)

References 26 publications

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“…Patients with TSC typically have comorbidities that reflect the involvement of multiple organs. Unlike a neurosurgical procedure, mTOR inhibitor therapy may cause regression of other lesions, such as angiomyolipomas (kidney), angiofibromas (skin), and lymphangioleiomyomatosis (lung) 12, 22, 23, 24, 25…”

Section: Discussionmentioning

confidence: 99%

Everolimus for subependymal giant cell astrocytoma: 5‐year final analysis

Franz

Agricola

Mays

et al. 2015

Annals of Neurology

132

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ObjectiveTo analyze the cumulative efficacy and safety of everolimus in treating subependymal giant cell astrocytomas (SEGA) associated with tuberous sclerosis complex (TSC) from an open‐label phase II study (NCT00411619). Updated data became available from the conclusion of the extension phase and are presented in this ≥5‐year analysis.MethodsPatients aged ≥ 3 years with a definite diagnosis of TSC and increasing SEGA lesion size (≥2 magnetic resonance imaging scans) received everolimus starting at 3mg/m2/day (titrated to target blood trough levels of 5–15ng/ml). The primary efficacy endpoint was reduction from baseline in primary SEGA volume.ResultsAs of the study completion date (January 28, 2014), 22 of 28 (78.6%) initially enrolled patients finished the study per protocol. Median (range) duration of exposure to everolimus was 67.8 (4.7–83.2) months; 12 (52.2%) and 14 (60.9%) of 23 patients experienced SEGA volume reductions of ≥50% and ≥30% relative to baseline, respectively, after 60 months of treatment. The proportion of patients experiencing daily seizures was reduced from 7 of 26 (26.9%) patients at baseline to 2 of 18 (11.1%) patients at month 60. Most commonly reported adverse events (AEs) were upper respiratory tract infection and stomatitis of mostly grade 1 or 2 severity. No patient discontinued treatment due to AEs. The frequency of emergence of most AEs decreased over the course of the study.InterpretationEverolimus continues to demonstrate a sustained effect on SEGA tumor reduction over ≥5 years of treatment. Everolimus remained well‐tolerated, and no new safety concerns were noted. Ann Neurol 2015;78:929–938

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Section: Discussionmentioning

confidence: 99%

Everolimus for subependymal giant cell astrocytoma: 5‐year final analysis

Franz

Agricola

Mays

et al. 2015

Annals of Neurology

132

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“…A recent randomized, double-blind clinical trial of rapamycin, an inhibitor of the mammalian target of rapamycin, demonstrated stabilization of pulmonary function and improvement in quality of life in LAM patients. (27) The establishment of national and international registries is also key to enabling access to patients for participation in studies. (28) The results obtained in our study support the development of a prospective randomized protocol to assess the functional effects of doxycycline and survival in LAM patients treated with this drug.…”

Section: Discussionmentioning

confidence: 99%

Doxiciclina em pacientes com linfangioleiomiomatose: segurança e eficácia no bloqueio de metaloproteinases

et al. 2011

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Objective: Lymphangioleiomyomatosis (LAM) is characterized by lung cysts, whose development is associated with matrix metalloproteinase (MMP) hyperactivity, principally that of MMP-2 and MMP-9. Our objective was to compare LAM patients and controls in terms of the levels of these MMPs, as well as to determine the safety and efficacy of treatment with doxycycline, a potent MMP inhibitor. Methods: Prospective clinical study involving female LAM patients who received doxycycline (100 mg/day) for six months. Urine and blood samples were collected for the quantification of MMP-2 and MMP-9 before and after the treatment period. Samples from 10 healthy women were also collected. Results: Of the 41 LAM patients who started the treatment, 34 completed the protocol. Serum and urinary MMP-9 levels were significantly lower in the controls than in the LAM patients (p < 0.0001). Comparing pre-and post-treatment values, we found that the median level of MMP-9 in serum decreased from 919 ng/mL to 871 ng/mL (p = 0.05), whereas that of MMP-9 in urine decreased from 11,558 pg/mL to 7,315 pg/mL (p = 0.10). After treatment, the median level of MMP-2 in serum was significantly lower (p = 0.04) and urinary MMP-2 levels were undetectable. Nausea, diarrhea, and epigastric pain were the most prevalent adverse affects and were often self-limiting. There was only one case in which the patient discontinued the treatment because of side effects. Conclusions: We have demonstrated, for the first time, a decrease in serum and urine levels of MMPs in LAM patients treated with doxycycline, which proved to be a safe medication, with mild and well-tolerated side effects.Keywords: Lymphangioleiomyomatosis; Matrix metalloproteinases; Doxycycline. ResumoObjetivo: A linfangioleiomiomatose (LAM) é caracterizada pela presença de cistos pulmonares, cuja formação está associada à hiperreatividade de metaloproteinases de matriz (MMP), principalmente MMP-2 e MMP-9. Objetivamos comparar os níveis dessas MMPs entre pacientes com LAM e controles saudáveis, assim como avaliar, nas pacientes com LAM, a segurança e a eficácia do tratamento com doxiciclina, um potente inibidor de MMPs. Métodos: Estudo clínico prospectivo no qual as pacientes com LAM receberam doxiciclina (100 mg/dia) por seis meses, coletando-se amostras de urina e sangue para a dosagem de MMP-2 e MMP-9 antes e ao final do período. Foram ainda obtidas amostras de 10 mulheres saudáveis. Resultados: De 41 pacientes com LAM que iniciaram o tratamento, 34 concluíram o protocolo. Os níveis de MMP-9 sérica e urinária foram significativamente inferiores no grupo controle (p < 0,0001). Comparando-se os valores antes e após o tratamento, a mediana do nível sérico da MMP-9 reduziu de 919 ng/mL para 871 ng/mL (p = 0,05), enquanto a mediana da dosagem urinária de MMP-9 diminui de 11.558 pg/mL para 7.315 pg/mL (p = 0,10). A mediana da MMP-2 sérica apresentou um decréscimo significativo após o tratamento (p = 0,04). Não foram detectados níveis de MMP-2 urinária. Epigastralgia, náuseas e diarreia foram os...

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“…Clinical trials with the mTORC1 inhibitor rapamycin, the only US Food and Drug Administrationeapproved drug for the treatment of LAM and AML, have revealed only partial efficacy in the treatment of both conditions 22,37,81,82 ; therefore, combined therapies with rapamycin followed by surgery, 83 in the case of AML, or including an adjuvant drug in addition to rapamycin, particularly in the case of LAM, are currently the focus of much attention. 25,84,85 On the basis of the results obtained with NCTD in the treatment of TSC2…”

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confidence: 99%

Evidence Supporting a Lymphatic Endothelium Origin for Angiomyolipoma, a TSC2− Tumor Related to Lymphangioleiomyomatosis

Yue

Pacheco

Cheng

et al. 2016

The American Journal of Pathology

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Angiomyolipoma (AML) is a tumor closely related to lymphangioleiomyomatosis (LAM). Both entities are characterized by the proliferation of smooth muscle actin and melanocytic glycoprotein 100 (recognized by antibody HMB-45)epositive spindle-shaped and epithelioid cells. AML and LAM are etiologically linked to mutations in the tsc2 and tsc1 genes in the case of LAM. These genes encode the proteins tuberous sclerosis complex (TSC)-1 and TSC2, which are directly involved in suppressing the mechanistic target of rapamycin cell growth signaling pathway. Although significant progress has been made in characterizing and pharmacologically slowing the progression of AML and LAM with rapamycin, our understanding of their pathogenesis lacks an identified cell of origin. We used an AML-derived cell line to determine whether TSC2 restitution brings about the cell type from which AML arises. We found that AML cells express lymphatic endothelial cell markers consistent with lymphatic endothelial cell precursors in vivo and in vitro. Moreover, on TSC2 correction, AML cells mature into adult lymphatic endothelial cells and have functional attributes characteristic of this cell lineage, suggesting a lymphatic endothelial cell of origin for AML. These effects are dependent on TSC2-mediated mechanistic target of rapamycin inactivation. Finally, we demonstrate the in vitro effectiveness of norcantharidin, a lymphangiogenesis inhibitor, as a potential co-adjuvant therapy in the treatment of AML. (Am J Pathol 2016 http://dx

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Efficacy and Safety of Sirolimus in Lymphangioleiomyomatosis

Cited by 905 publications

References 26 publications

Everolimus for subependymal giant cell astrocytoma: 5‐year final analysis

Everolimus for subependymal giant cell astrocytoma: 5‐year final analysis

Doxiciclina em pacientes com linfangioleiomiomatose: segurança e eficácia no bloqueio de metaloproteinases

Evidence Supporting a Lymphatic Endothelium Origin for Angiomyolipoma, a TSC2− Tumor Related to Lymphangioleiomyomatosis

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