LETTERS Masaharu Kataoka, M.D. Ryoji Yanagisawa, M.D. Hideaki Yoshino, M.D. Toru Satoh, M.D. Kyorin University School of Medicine Tokyo, Japan
References 1 Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004;351:1425–1436. 2 McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation 2006;114:1417–1431.
Everolimus-induced Severe Pulmonary Toxicity with Diffuse Alveolar Hemorrhage To the Editor: We report a case of severe diffuse alveolar hemorrhage (DAH) attributed to treatment of breast cancer with everolimus. Lung injury resolved after the drug was discontinued. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, is approved for use as an immunosuppressant agent and an anti-neoplastic drug (1). The U.S. Food and Drug Administration (FDA) approved indications include treatment of postmenopausal women with advanced hormone-receptor positive, HER2-negative breast cancer (2, 3). Commonly reported adverse effects of everolimus include stomatitis (40%), rash (25%), and fatigue (20%) (1). Potentially life-threatening complications of everolimus and other mTOR inhibitors include pulmonary toxicity. A recently published meta-analysis reported incidence rates of 10.4% and 2.4% for everolimus-induced all-grade and high-grade pulmonary toxicity, respectively (4) The pathogenesis of the pulmonary toxicity remains unclear. A recent in vivo study suggested that mTOR inhibitors can interact with the STAT1 gene, causing amplification of cellular apoptosis and augmenting lung injury (5). Although diffuse alveolar hemorrhage (DAH) is a well-recognized
3 Akagi S, Nakamura K, Miyaji K, Ogawa A, Kusano KF, Ito H, Matsubara H. Marked hemodynamic improvements by high-dose epoprostenol therapy in patients with idiopathic pulmonary arterial hypertension. Circ J 2010;74:2200–2205. 4 Rich S, McLaughlin VV. The effects of chronic prostacyclin therapy on cardiac output and symptoms in primary pulmonary hypertension. J Am Coll Cardiol 1999;34:1184–1187. 5 Jones DK, Higenbottam TW, Wallwork J. Treatment of primary pulmonary hypertension intravenous epoprostenol (prostacyclin). Br Heart J 1987;57:270–278. Copyright © 2013 by the American Thoracic Society
manifestation of sirolimus-induced pulmonary toxicity, this complication has been reported only rarely for everolimus. Our patient, a 65-year-old woman with a history of stage 4 breast cancer (ER-positive/HER2-negative) was initiated on treatment with everolimus and anastrozole for a relapse of breast cancer. Four months later, she presented with a 2-week history of progressive shortness of breath and dry cough. These symptoms did not respond to an empiric course of levofloxacin. Physical examination revealed rhonchi and crackles in both lower lungs. The hemoglobin was10.9 gm/dl, the white blood count was 5.8 3 103/ml, and the platelet count was 193 3 103/ml. Prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR) were 10.8, 23.9, and 1.0, respectively. Sputum and blood cultures were negative. A chest radiograph showed bilateral interstitial pulmonary infiltration. Computed tomography (CT) chest imaging demonstrated diffuse ground glass opacities with alveolar septal thickening in both lower lobes (Figure 1). Subsequent bronchoscopy with bronchoalveolar lavage (BAL) recovered hemorrhagic fluid in all of several serially obtained samples. The white blood cell count on the fluid was 725/ml (polymorphonuclear cells 11%, lymphocytes 58%, monocytes 25%, and eosinophils 4%). The red blood cell count was 16,250/ml. Many hemosiderinladen macrophages were present. BAL fluid cultures grew no
Figure 1. Computed tomography (CT) chest imaging performed after intravenous administration of contrast material (A, cross-sectional view; B, coronal view) demonstrated diffuse interstitial abnormality in the lungs, characterized by ground glass opacities with septal thickening at the bases.
Letters
727
LETTERS
Figure 2. Repeat CT chest imaging performed 2 weeks later (A, cross-sectional view; B, coronal view) revealed worsening bilateral airspace disease, increased size of the bilateral pleural effusions, and pericardial effusion. No evidence of pulmonary embolism.
pathogenic organisms. No malignant cells were found in the lavage fluid. Because no other cause was identified for the patient’s lung injury, everolimus was discontinued and patient was started on methylprednisolone 240 mg/d. Shortly thereafter, she developed acute respiratory failure and was intubated for mechanical ventilation. After extubation 1 week later, methylprednisolone was replaced with prednisone administered at a dose of 60 mg/d. A few days thereafter, the patient became hypoxemic again and required reintubation. The hemoglobin level dropped from 9.8 to 7.5 mg/dl. The platelet was 235 3 103/mcL, PT was 12, and PTT was 54.6. Repeat chest CT imaging revealed worsening diffuse ground glass alveolar opacities (Figure 2). These radiographic findings and
the hemorrhagic appearance of fluid in the ventilator tubing affirmed a diagnosis of diffuse alveolar hemorrhage. The methylprednisolone dose was increased to 240 mg/d. The patient gradually improved and was successfully extubated. She returned home several weeks later. A chest CT scan obtained 1 month after hospital discharge revealed residual reticulation of the lungs bilaterally (Figure 3). In summary, our patient developed diffuse lung injury that progressed to life-threatening diffuse alveolar hemorrhage after the drug was discontinued and high-dose methylprednisolone therapy was begun. We have found two previously published case reports of everolimus-induced DAH (6, 7). One of these patients died of respiratory failure 5 weeks after initiation of everolimus therapy for heart transplantation
Figure 3. CT chest imaging obtained 1 month after hospital discharge (A, cross-sectional view; B, coronal view) showed residual reticulation of the lungs bilaterally.
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AnnalsATS Volume 10 Number 6 | December 2013
LETTERS despite prompt despite treatment with methylprednisolone 120 mg daily (7). The primary treatment of everolimus-induced pneumonitis remains early discontinuation of the offending drug. Although corticosteroids have been widely used to treat patients with severe medication-induced pneumonitis, there is still lack of evidence supporting this practice in the setting of mTOR inhibitor lung toxicity. There is no published evidence-based guidance on the optimal dose of corticosteroid therapy or the appropriate duration of treatment.
2
3
4
Author disclosures are available with the text of this letter at www.atsjournals.org. 5 Parichart Junpaparp, M.D. Bhavna Sharma, M.D. Ambiga Samiappan, M.D. Ji Hyun Rhee, M.D. K. Randall Young, M.D. Albert Einstein Medical Center Philadelphia, Pennsylvania
References 1 Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald ¨ V, Thompson JA, Figlin RA, Hollaender N, et al.; RECORD-
Letters
6
7
1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372:449–456. Baselga J, Campone M, Piccart M, Burris HA III, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366:520–529. Noguchi S, Masuda N, Iwata H, Mukai H, Horiguchi J, Puttawibul P, Srimuninnimit V, Tokuda Y, Kuroi K, Iwase H, et al. Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone-receptor-positive breast cancer in BOLERO-2. Breast Cancer (In press) Iacovelli R, Palazzo A, Mezi S, Morano F, Naso G, Cortesi E. Incidence and risk of pulmonary toxicity in patients treated with mTOR inhibitors for malignancy: a meta-analysis of published trials. Acta Oncol 2012;51:873–879. Fielhaber JA, Carroll SF, Dydensborg AB, Shourian M, Triantafillopoulos A, Harel S, Hussain SN, Bouchard M, Qureshi ST, Kristof AS. Inhibition of mammalian target of rapamycin augments lipopolysaccharide-induced lung injury and apoptosis. J Immunol 2012;188:4535–4542. Vandewiele B, Vandecasteele SJ, Vanwalleghem L, De Vriese AS. Diffuse alveolar hemorrhage induced by everolimus. Chest 2010; 137:456–459. Depuydt P, Nollet J, Benoit D, Praet M, Caes F. Fatal acute pulmonary injury associated with everolimus. Ann Pharmacother 2012;46:e7.
Copyright © 2013 by the American Thoracic Society
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References 1 Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004;351:1425–1436. 2 McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation 2006;114:1417–1431.
Everolimus-induced Severe Pulmonary Toxicity with Diffuse Alveolar Hemorrhage To the Editor: We report a case of severe diffuse alveolar hemorrhage (DAH) attributed to treatment of breast cancer with everolimus. Lung injury resolved after the drug was discontinued. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, is approved for use as an immunosuppressant agent and an anti-neoplastic drug (1). The U.S. Food and Drug Administration (FDA) approved indications include treatment of postmenopausal women with advanced hormone-receptor positive, HER2-negative breast cancer (2, 3). Commonly reported adverse effects of everolimus include stomatitis (40%), rash (25%), and fatigue (20%) (1). Potentially life-threatening complications of everolimus and other mTOR inhibitors include pulmonary toxicity. A recently published meta-analysis reported incidence rates of 10.4% and 2.4% for everolimus-induced all-grade and high-grade pulmonary toxicity, respectively (4) The pathogenesis of the pulmonary toxicity remains unclear. A recent in vivo study suggested that mTOR inhibitors can interact with the STAT1 gene, causing amplification of cellular apoptosis and augmenting lung injury (5). Although diffuse alveolar hemorrhage (DAH) is a well-recognized
3 Akagi S, Nakamura K, Miyaji K, Ogawa A, Kusano KF, Ito H, Matsubara H. Marked hemodynamic improvements by high-dose epoprostenol therapy in patients with idiopathic pulmonary arterial hypertension. Circ J 2010;74:2200–2205. 4 Rich S, McLaughlin VV. The effects of chronic prostacyclin therapy on cardiac output and symptoms in primary pulmonary hypertension. J Am Coll Cardiol 1999;34:1184–1187. 5 Jones DK, Higenbottam TW, Wallwork J. Treatment of primary pulmonary hypertension intravenous epoprostenol (prostacyclin). Br Heart J 1987;57:270–278. Copyright © 2013 by the American Thoracic Society
manifestation of sirolimus-induced pulmonary toxicity, this complication has been reported only rarely for everolimus. Our patient, a 65-year-old woman with a history of stage 4 breast cancer (ER-positive/HER2-negative) was initiated on treatment with everolimus and anastrozole for a relapse of breast cancer. Four months later, she presented with a 2-week history of progressive shortness of breath and dry cough. These symptoms did not respond to an empiric course of levofloxacin. Physical examination revealed rhonchi and crackles in both lower lungs. The hemoglobin was10.9 gm/dl, the white blood count was 5.8 3 103/ml, and the platelet count was 193 3 103/ml. Prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR) were 10.8, 23.9, and 1.0, respectively. Sputum and blood cultures were negative. A chest radiograph showed bilateral interstitial pulmonary infiltration. Computed tomography (CT) chest imaging demonstrated diffuse ground glass opacities with alveolar septal thickening in both lower lobes (Figure 1). Subsequent bronchoscopy with bronchoalveolar lavage (BAL) recovered hemorrhagic fluid in all of several serially obtained samples. The white blood cell count on the fluid was 725/ml (polymorphonuclear cells 11%, lymphocytes 58%, monocytes 25%, and eosinophils 4%). The red blood cell count was 16,250/ml. Many hemosiderinladen macrophages were present. BAL fluid cultures grew no
Figure 1. Computed tomography (CT) chest imaging performed after intravenous administration of contrast material (A, cross-sectional view; B, coronal view) demonstrated diffuse interstitial abnormality in the lungs, characterized by ground glass opacities with septal thickening at the bases.
Letters
727
LETTERS
Figure 2. Repeat CT chest imaging performed 2 weeks later (A, cross-sectional view; B, coronal view) revealed worsening bilateral airspace disease, increased size of the bilateral pleural effusions, and pericardial effusion. No evidence of pulmonary embolism.
pathogenic organisms. No malignant cells were found in the lavage fluid. Because no other cause was identified for the patient’s lung injury, everolimus was discontinued and patient was started on methylprednisolone 240 mg/d. Shortly thereafter, she developed acute respiratory failure and was intubated for mechanical ventilation. After extubation 1 week later, methylprednisolone was replaced with prednisone administered at a dose of 60 mg/d. A few days thereafter, the patient became hypoxemic again and required reintubation. The hemoglobin level dropped from 9.8 to 7.5 mg/dl. The platelet was 235 3 103/mcL, PT was 12, and PTT was 54.6. Repeat chest CT imaging revealed worsening diffuse ground glass alveolar opacities (Figure 2). These radiographic findings and
the hemorrhagic appearance of fluid in the ventilator tubing affirmed a diagnosis of diffuse alveolar hemorrhage. The methylprednisolone dose was increased to 240 mg/d. The patient gradually improved and was successfully extubated. She returned home several weeks later. A chest CT scan obtained 1 month after hospital discharge revealed residual reticulation of the lungs bilaterally (Figure 3). In summary, our patient developed diffuse lung injury that progressed to life-threatening diffuse alveolar hemorrhage after the drug was discontinued and high-dose methylprednisolone therapy was begun. We have found two previously published case reports of everolimus-induced DAH (6, 7). One of these patients died of respiratory failure 5 weeks after initiation of everolimus therapy for heart transplantation
Figure 3. CT chest imaging obtained 1 month after hospital discharge (A, cross-sectional view; B, coronal view) showed residual reticulation of the lungs bilaterally.
728
AnnalsATS Volume 10 Number 6 | December 2013
LETTERS despite prompt despite treatment with methylprednisolone 120 mg daily (7). The primary treatment of everolimus-induced pneumonitis remains early discontinuation of the offending drug. Although corticosteroids have been widely used to treat patients with severe medication-induced pneumonitis, there is still lack of evidence supporting this practice in the setting of mTOR inhibitor lung toxicity. There is no published evidence-based guidance on the optimal dose of corticosteroid therapy or the appropriate duration of treatment.
2
3
4
Author disclosures are available with the text of this letter at www.atsjournals.org. 5 Parichart Junpaparp, M.D. Bhavna Sharma, M.D. Ambiga Samiappan, M.D. Ji Hyun Rhee, M.D. K. Randall Young, M.D. Albert Einstein Medical Center Philadelphia, Pennsylvania
References 1 Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald ¨ V, Thompson JA, Figlin RA, Hollaender N, et al.; RECORD-
Letters
6
7
1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372:449–456. Baselga J, Campone M, Piccart M, Burris HA III, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366:520–529. Noguchi S, Masuda N, Iwata H, Mukai H, Horiguchi J, Puttawibul P, Srimuninnimit V, Tokuda Y, Kuroi K, Iwase H, et al. Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone-receptor-positive breast cancer in BOLERO-2. Breast Cancer (In press) Iacovelli R, Palazzo A, Mezi S, Morano F, Naso G, Cortesi E. Incidence and risk of pulmonary toxicity in patients treated with mTOR inhibitors for malignancy: a meta-analysis of published trials. Acta Oncol 2012;51:873–879. Fielhaber JA, Carroll SF, Dydensborg AB, Shourian M, Triantafillopoulos A, Harel S, Hussain SN, Bouchard M, Qureshi ST, Kristof AS. Inhibition of mammalian target of rapamycin augments lipopolysaccharide-induced lung injury and apoptosis. J Immunol 2012;188:4535–4542. Vandewiele B, Vandecasteele SJ, Vanwalleghem L, De Vriese AS. Diffuse alveolar hemorrhage induced by everolimus. Chest 2010; 137:456–459. Depuydt P, Nollet J, Benoit D, Praet M, Caes F. Fatal acute pulmonary injury associated with everolimus. Ann Pharmacother 2012;46:e7.
Copyright © 2013 by the American Thoracic Society
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