Patricia Julien-Williams

Sustained Effects of Sirolimus on Lung Function and Cystic Lung Lesions in Lymphangioleiomyomatosis

RATIONALE Sirolimus therapy stabilizes lung function and reduces the size of chylous effusions and lymphangioleiomyomas in patients with lymphangioleiomyomatosis. OBJECTIVES To determine whether sirolimus has beneficial effects on lung function, cystic areas, and adjacent lung parenchyma; whether these effects are sustained; and whether sirolimus is well tolerated by patients. METHODS Lung function decline over time, lung volume occupied by cysts (cyst score), and lung tissue texture in the vicinity of the cysts were quantified with a computer-aided diagnosis system in 38 patients. Then we compared cyst scores from the last study on sirolimus with studies done on sirolimus therapy. In 12 patients, we evaluated rates of change in lung function and cyst scores off and on sirolimus. MEASUREMENTS AND MAIN RESULTS Sirolimus reduced yearly declines in FEV1 (-2.3 ± 0.1 vs. 1.0 ± 0.3% predicted; P < 0.001) and diffusing capacity of carbon monoxide (-2.6 ± 0.1 vs. 0.9 ± 0.2% predicted; P < 0.001). Cyst scores 1.2 ± 0.8 years (30.5 ± 11.9%) and 2.5 ± 2 years (29.7 ± 12.1%) after initiating sirolimus were not significantly different from pretreatment values (28.4 ± 12.5%). In 12 patients followed for 5 years, a significant reduction in rates of yearly decline in FEV1 (-1.4 ± 0.2 vs. 0.3 ± 0.4% predicted; P = 0.025) was observed. Analyses of 104 computed tomography scans showed a nonsignificant (P = 0.23) reduction in yearly rates of change of cyst scores (1.8 ± 0.2 vs. 0.3 ± 0.3%; P = 0.23) and lung texture features. Despite adverse events, most patients were able to continue sirolimus therapy. CONCLUSIONS Sirolimus therapy slowed down lung function decline and increase in cystic lesions. Most patients were able to tolerate sirolimus therapy.

Severity and outcome of cystic lung disease in women with tuberous sclerosis complex

What are the clinical features, severity, and rate of progression of lung disease in women with tuberous sclerosis and lymphangioleiomyomatosis (LAM) and how do they differ from patients with sporadic LAM? Data from 94 tuberous sclerosis/LAM and 460 sporadic LAM women were compared. 40 tuberous sclerosis/LAM and 40 sporadic LAM patients were age- and lung function-matched, and changes in volume occupied by cysts (cyst score) and pulmonary function occurring over 6.5 years were evaluated. Tuberous sclerosis/LAM patients had better lung function than sporadic LAM patients, but no difference was observed from sporadic LAM patients in yearly rates of change in forced expiratory volume in 1 s (−1.9±2.7 versus −1.9±1.9% predicted; p=0.302), diffusing capacity of the lung for CO (−2.1±2.8 versus −1.9±2.7% predicted; p=0.282) or cyst scores (+1.0±1.3 versus +1.4±1.7%, p=0.213). However, the proportion of patients with abnormal lung function and higher rates of FEV1 decline was greater in sporadic LAM. Some young tuberous sclerosis/LAM patients (mean age 25.7±3 years) progressed rapidly from minimal to severe lung disease. Tuberous sclerosis/LAM patients may experience abrupt declines in lung function. Consequently, women with tuberous sclerosis found to have lung cysts should undergo periodic functional and radiological testing to follow disease progression and determine need for therapy. While the natural history is variable, some women with TSC and LAM may quickly progress to disabling respiratory disease http://ow.ly/Dywa7

Long-Term Effect of Sirolimus on Serum Vascular Endothelial Growth Factor D Levels in Patients With Lymphangioleiomyomatosis

Background Sirolimus reduces serum levels of vascular endothelial growth factor D (VEGF‐D); the size of chylous effusions, lymphangioleiomyomas, and angiomyolipomas; and stabilizes lung function in patients with lymphangioleiomyomatosis (LAM). Methods To determine whether reductions in VEGF‐D levels are sustained over time, as well as parallel changes in lung function and lymphatic disease, we evaluated 25 patients with LAM and measured VEGF‐D levels, lung function, and extent of lymphatic disease before and during sirolimus therapy. Results Treatment with sirolimus stabilized FEV1 and diffusion capacity for carbon monoxide (Dlco) over a period of 4.5 ± 1.6 years, caused resolution of lymphatic disease, and reduced the size of angiomyolipomas and VEGF‐D levels (3,720 ± 3,020 pg/mL to 945 ± 591 pg/mL; P < .0001). Yearly changes in FEV1 % predicted and Dlco % predicted were reduced from –7.4% ± 1.4% to –0.3% ± 0.5% (P < .001) and –6.4% ± 0.9% to –0.4% ± 0.5% (P < .001), respectively. Lower VEGF‐D levels correlated with sirolimus therapy (P < .001), but no significant relationship was observed between reduction in VEGF‐D levels and FEV1 and Dlco during sirolimus therapy. The magnitude of VEGF‐D decline was not related to the effect on lung function. Patients with lymphatic disease had higher serum VEGF‐D levels, a greater reduction in VEGF‐D levels, and better long‐term sustained improvement in lung function during sirolimus therapy than did those without lymphatic disease. Conclusions Sirolimus therapy stabilizes lung function over many years of therapy while producing a sustained reduction in VEGF‐D levels in patients with elevated levels preceding therapy. An association was not demonstrated between the magnitude of VEGF‐D decline and the beneficial effect of sirolimus on lung function. Persistent improvement in lung function was observed in patients with lymphatic disease.

Sirolimus and Autophagy Inhibition in Lymphangioleiomyomatosis: Results of a Phase I Clinical Trial

BACKGROUND: Animal and cellular studies support the importance of autophagy inhibition in lymphangioleiomyomatosis (LAM). In a cohort of subjects with LAM, we tested the hypothesis that treatment with sirolimus and hydroxychloroquine (an autophagy inhibitor) at two different dose levels is safe and well tolerated. Secondary end points included changes in lung function. METHODS: This 48‐week, two‐center phase I trial evaluated the safety of escalating oral hydroxychloroquine doses (100‐200 mg) given twice a day in combination with sirolimus to eligible patients ≥ 18 years old with LAM. Subjects received combination therapy for 24 weeks followed by an observation phase without taking study drugs for an additional 24 weeks. RESULTS: Fourteen patients provided written informed consent. Thirteen were treated in cohorts of three patients each with escalating hydroxychloroquine doses (200 and 400 mg) and an extension phase at the 400‐mg dose. The most common adverse events were mucositis, headache, and diarrhea. No drug‐related serious adverse events were reported. Secondary end points showed improvement in lung function at 24 weeks, with a decrease in lung function at the 48‐week time point. When the higher dose of hydroxychloroquine was analyzed separately, FEV1 and FVC remained stable at 48 weeks, but the 6‐min walk distance showed a decrease toward baseline. CONCLUSIONS: The combination of sirolimus and hydroxychloroquine is well tolerated, with no dose‐limiting adverse events observed at 200 mg twice a day. Potential effects on lung function should be explored in larger trials. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01687179; URL: www.clinicaltrials.gov

Retrospective Review of Combined Sirolimus and Simvastatin Therapy in Lymphangioleiomyomatosis

BACKGROUND Combined simvastatin and sirolimus therapy reduces tuberous sclerosis complex 2-null lesions and alveolar destruction in a mouse model of lymphangioleiomyomatosis (LAM), suggesting that therapy with both drugs may benefit patients with LAM. METHODS To determine whether simvastatin changed the prevalence of adverse events or altered the therapeutic effects of sirolimus, we recorded adverse events and changes in lung function in patients with LAM treated with simvastatin plus sirolimus (n = 14), sirolimus alone (n = 44), or simvastatin alone (n = 20). RESULTS Sirolimus-related adverse events in the simvastatin plus sirolimus and sirolimus-only groups were 64% and 66% for stomatitis, 50% and 52% for diarrhea, 50% and 45% for peripheral edema, 36% and 61% for acne, 36% and 30% for hypertension, 29% and 27% for proteinuria, 29% and 27% for leukopenia, and 21% and 27% for hypercholesterolemia. The frequency of simvastatin-related adverse events in the simvastatin-only and simvastatin plus sirolimus groups were 60% and 50% for arthralgias and 35% and 36% for myopathy. Before simvastatin plus sirolimus therapy, FEV1 and diffusing capacity of the lung for carbon monoxide (Dlco) yearly rates of change were, respectively, -1.4 ± 0.2 and -1.8 ± 0.2% predicted. After simvastatin plus sirolimus therapy, these rates changed to +1.2 ± 0.5 (P = .635) and +0.3 ± 0.4% predicted (P = .412), respectively. In 44 patients treated with sirolimus alone, FEV1 and Dlco rates of change were -1.7 ± 0.1 and -2.2 ± 0.1% predicted before treatment and +1.7 ± 0.3 and +0.7 ± 0.3% predicted after treatment (P < .001). CONCLUSIONS Therapy with sirolimus and simvastatin does not increase the prevalence of drug adverse events or alter the therapeutic effects of sirolimus.

CA-125 in Disease Progression and Treatment of Lymphangioleiomyomatosis

Background Lymphangioleiomyomatosis (LAM) is a destructive lung disease of women caused by proliferation of neoplastic‐like LAM cells, with mutations in the TSC1/2 tumor suppressor genes. Based on case reports, levels of cancer antigen 125 (CA‐125), an ovarian cancer biomarker, can be elevated in patients with LAM. We hypothesized that elevated serum CA‐125 levels seen in some patients with LAM were due to LAM, not other malignancies, and might respond to sirolimus treatment. Methods Serum CA‐125 levels were measured for 241 patients at each visit. Medical records were reviewed for co‐morbidities, disease progression, and response to sirolimus treatment. CA‐125 expression in LAM cells was determined by using immunohistochemical analysis. Results Almost 25% of patients with LAM had at least one elevated serum CA‐125 measurement. Higher serum CA‐125 levels correlated with lower FEV1, premenopausal status, and pleural effusion in a multivariate model (each P < .001). Serum CA‐125 levels decreased following sirolimus treatment (P = .002). CA‐125 and &agr;‐smooth muscle actin were co‐expressed in LAM lung nodules. Conclusions Higher serum CA‐125 levels were associated with pleural effusions and reduced pulmonary function and were decreased with sirolimus therapy. LAM cells express CA‐125. Some elevated serum CA‐125 levels may reflect serosal membrane involvement.

Rates of change in FEV1 and DLCO as potential indicators for mTOR inhibitor therapy in premenopausal lymphangioleiomyomatosis patients

The value of rates of change in forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO) to predict disease progression, and initiation of mTOR (mechanistic target of rapamycin) inhibitor therapy has not been evaluated. In 84 premenopausal lymphangioleiomyomatosis patients, individual rates of change in FEV1 and DLCO and their 95% confidence intervals were used to derive subsequent lowest values of FEV1 and DLCO that would prompt initiation of sirolimus therapy. These treatment criteria were compared with a criterion based on FEV1 or DLCO ≤70% predicted. In 12 patients undergoing sirolimus therapy both methods for determining the optimal point for initiation of therapy were evaluated. 27 and 35 patients who experienced greater than expected rates of change in FEV1 and DLCO, respectively, would have been excluded from therapy based on an FEV1 or DLCO >70% pred. 25 of the 84 patients were eventually treated, but only when FEV1 or DLCO were ≤70% pred. Applying such treatment criteria to 12 patients undergoing sirolimus therapy would have delayed treatment for many years. Premenopausal females in whom FEV1 or DLCO are declining at rates above the expected based on their individual rates of decline, should be considered for sirolimus therapy before the FEV1 or DLCO falls to ≤70% pred. Past rates of FEV1 or DLCO decline are indicators of future lung function loss and initiation of sirolimus therapy http://ow.ly/rnAe30iWEsn

Pseudoneutropenia in lymphangioleiomyomatosis (LAM) patients receiving sirolimus: evaluation in a 100 patient cohort

Diurnal variation in white blood cells (WBC), particularly neutrophils, is well-described [1]. WBC levels are lower in the morning and increase through the day [1, 2]. Drugs with immunosuppressive effects, such as sirolimus, may further lower WBC counts. This phenomenon has been observed in clozapine and related atypical antipsychotic medications, drugs with known immunosuppressive effects [3, 4]. For patients receiving these drugs, blood counts measured in the early morning may lead to a false impression of low WBC/neutrophil counts (“pseudoleukopenia/pseudoneutropenia”) [4–8] that may result in discontinuation or a reduction in dose and suboptimal treatment. Of importance, isolated morning neutropenia is not known to increase the risk of infection [6, 9]. In lymphangioleiomyomatosis patients receiving sirolimus treatment, transient leukopenia in the morning may be due to circadian rhythm, with leukocyte counts recovering later in the day, indicating that a decrease in drug dose may not be warranted http://ow.ly/jPFz30iysgV

Chest CT Scan at Radiation Dose of a Posteroanterior and Lateral Chest Radiograph Series

BACKGROUND: Given the rising utilization of medical imaging and the risks of radiation, there is increased interest in reducing radiation exposure. The objective of this study was to evaluate, as a proof of principle, CT scans performed at radiation doses equivalent to that of a posteroanterior and lateral chest radiograph series in the cystic lung disease lymphangioleiomyomatosis (LAM). METHODS: From November 2016 to May 2018, 105 consecutive subjects with LAM received chest CT scans at standard and ultra‐low radiation doses. Standard and ultra‐low‐dose images, respectively, were reconstructed with routine iterative and newer model‐based iterative reconstruction. LAM severity can be quantified as cyst score (percentage of lung occupied by cysts), an ideal benchmark for validating CT scans performed at a reduced dose compared with a standard dose. Cyst scores were quantified using semi‐automated software and evaluated by linear correlation and Bland‐Altman analysis. RESULTS: Overall, ultra‐low‐dose CT scans represented a 96% dose reduction, with a median dose equivalent to 1 vs 22 posteroanterior and lateral chest radiograph series (0.14 mSv; 5th‐95th percentile, 0.10‐0.20 vs standard dose 3.4 mSv; 5th‐95th percentile, 1.5‐7.4; P < .0001). The mean difference in cyst scores between ultra‐low‐ and standard‐dose CT scans was 1.1% ± 2.0%, with a relative difference in cyst score of 11%. Linear correlation coefficient was excellent at 0.97 (P < .0001). CONCLUSIONS: In LAM chest CT scan at substantial radiation reduction to doses equivalent to that of a posteroanterior and lateral chest radiograph series provides cyst score quantification similar to that of standard‐dose CT scan. TRIAL REGISTRY: ClinicalTrials.gov; Nos.: NCT00001465 and NCT00001532; URL: www.clinicaltrials.gov.