Publique en esta revista
Información de la revista
Vol. 54. Núm. 6.Junio 2018
Páginas 301-354
Compartir
Compartir
Descargar PDF
Más opciones de artículo
Vol. 54. Núm. 6.Junio 2018
Páginas 301-354
Scientific letter
DOI: 10.1016/j.arbres.2018.01.026
Acceso a texto completo
Pembrolizumab-Induced Rhabdomyolysis With Myositis in a Patient With Lung Adenocarcinoma
Rabdomiolisis con miositis inducida por pembrolizumab en un paciente con adenocarcinoma pulmonar
Visitas
59
Satoshi Hamadaa, Yasuhiro Fuseyab, Mitsuhiro Tsukinoa
a Department of Respiratory Medicine, Hikone Municipal Hospital, Hassakacho, Hikone, Japan
b Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan
Este artículo ha recibido
59
Visitas
Información del artículo
Texto Completo
Bibliografía
Descargar PDF
Estadísticas
Figuras (1)
Dear Editor,
Texto Completo

Lung cancer is the leading cause of cancer mortality worldwide. Cytotoxic and platinum-based chemotherapy are the standard first-line treatment for metastatic non-small cell lung cancer (NSCLC) without activating epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) or cytoplasmic c-ros oncogene 1 translocation/re-arrangements.1 Recently, the development of immune checkpoint inhibitors (ICIs) against modulators including cytotoxic T-lymphocyte-associated protein 4 and programmed cell death protein 1 (PD-1) and its ligand (PD-L1) has created a major paradigm shift in the therapeutic management of metastatic NSCLC.1 The ICI, pembrolizumab, is a humanized monoclonal antibody against PD-1. The KEYNOTE-024 trial showed that pembrolizumab provided significantly longer progression-free survival and overall survival, with fewer adverse events, than cytotoxic and platinum-based chemotherapy.2 Compared with cytotoxic or targeted agents, however, ICIs can induce autoimmune-like toxicities known as immune-related adverse events (irAEs) by inducing the infiltration of immune cells in normal tissues3; in patients with advanced NSCLC, the common pembrolizumab-induced irAEs are thyroid dysfunction, pneumonitis, and skin reactions.3,4 Here, we describe a patient with lung adenocarcinoma with rhabdomyolysis and myositis triggered by pembrolizumab treatment, while pembrolizumab rapidly reduced lung tumor size.

The patient is an 83-year-old non-smoking man who was diagnosed with prostate cancer at age 80 years and treated with brachytherapy for 2 years. At age 83 years, he presented with an abnormal chest X-ray (CXR) during routine follow up (Fig. 1A). Chest computed tomography (CT) revealed a 30.5mm×30.5mm mass in the right lower portion of the lung that crossed over into the adjacent middle lobe and thickened interlobular septa in the right middle and lower lobes. 18F-fluorodeoxyglucose (FDG) positron emission tomography/CT showed intense FDG uptake on both sides of the hilar and mediastinal lymph nodes. Magnetic resonance imaging (MRI) with contrast did not reveal any brain metastases. Fiberoptic bronchoscopy revealed lung adenocarcinoma. The patient was clinically staged as T2aN3M1a, stage IVA. Although no sensitizing EGFR mutations or ALK translocations were detected, the PD-L1 tumor proportion score was 95%, and the patient's Eastern Cooperative Oncology Group performance-status score was 0. Thus, we selected pembrolizumab at a dose of 200mg every 3 weeks as the first-line treatment. CXR showed a decrease in pulmonary mass size 5 days after initial pembrolizumab administration (Fig. 1B); however, the patient presented with myalgia of both proximal femurs and lower back pain 1 week after the second cycle of pembrolizumab. Two days before admission, he developed right ptosis. At admission, he was unable to walk without assistance, because of myalgia. Physical examination revealed symmetric weakness of the deltoid (medical research council [MRC] 4) and iliopsoas (MRC 4+) with hoarseness and mild dysphagia. He was administered bethanechol 25mg twice daily, silodosin 4mg twice daily, benidipine 4mg once daily, rosuvastatin 2.5mg once daily, and alfacalcidol 1μg once daily. Initial laboratory test results revealed elevated levels of creatine kinase (CK) 6417IU/L (62–287IU/L), CK-MB 176IU/L (0–25IU/L), and aldolase 74.7IU/L (2.1–6.1IU/L). The levels of thyroid-stimulating hormone and free thyroxine were within normal ranges. Test results for anti-aminoacyl tRNA synthase antibody, anti-acetylcholine receptor (AChR) antibody, and anti-muscle-specific kinase (MuSK) antibody were negative. At admission, rosuvastatin was discontinued. Short-tau inversion recovery MRI of the femur revealed diffuse increased signal in the gluteal and thigh muscles (Fig. 1C). Repetitive nerve stimulation test did not reveal gradual amplitude reduction (waning) and increment (waxing) of compound muscle action potentials. Edrophonium test results were negative. Muscle biopsy from the left musculus quadriceps femoris revealed lymphohistiocytic infiltration with muscle atrophy. The patient was then diagnosed with rhabdomyolysis with myositis, a suspected immune-related toxicity. We discontinued pembrolizumab and initiated systemic prednisone (40mg/day) soon after the muscle biopsy. Serum CK level was normalized within 3 weeks after prednisone administration. Myalgia and ptosis improved within 4 weeks after prednisone administration. CXR showed continuous decrease in pulmonary mass size 2 months after initial pembrolizumab administration (Fig. 1D). However, his performance-status score decreased from 0 to 2.

Fig. 1.
(0,27MB).

Chest X-ray images at a routine follow up (A) and 5 days after initial pembrolizumab administration (B). Short-tau inversion-recovery magnetic resonance image of the femur (C). Chest X-ray Image 2 months after initial pembrolizumab administration (D).

Previous trials reported that pembrolizumab-induced myositis occurred in 1–1.9% patients.2,4 The average onset of symptoms was 4.6 weeks after treatment initiation (range 1–7 weeks).5–7 Our patient presented with right ptosis in addition to myalgia and dysphagia 4 weeks after treatment initiation. Ptosis and diplopia are observed in the vast majority of myasthenia gravis (MG), whereas these symptoms are not typically observed in myositis.8 In this patient, anti-AChR antibody and anti-MuSK antibody test results were negative. Also, repetitive nerve stimulation tests did not reveal waning and waxing, and the edrophonium test result was negative. These results can make it difficult to diagnose MG. Vallet et al.5 and Haddox et al.6 reported that patients with advanced melanoma with pembrolizumab-induced myositis developed ptosis. The observations in these cases are similar to those in our case. ICIs, including pembrolizumab, can induce aberrant immune activation leading to undesired off-target inflammation and autoimmunity by blocking regulatory checkpoints9; therefore, irAE will not present with typical symptom of each disease as in our patient.

Pembrolizumab-induced rhabdomyolysis with myositis in our patient was administered systemic prednisolone. Vallet et al.5 and Haddox et al.6 used plasma exchange in addition to systemic corticosteroids. Zimmer et al. either used systemic corticosteroids or did not administer additional treatments.7 At present, there is no consensus regarding therapeutic options and treatment duration for pembrolizumab-induced myositis. Therefore, we must closely examine treatment in each case.

In several previous reports, irAEs, including skin reactions and thyroid dysfunction, were associated with a better therapy response.10–12 However, irAEs induce potentially long courses of corticosteroids and even anti-tumor necrosis factor therapy to mitigate effects.9 Furthermore, irAEs result in permanent discontinuation of treatment, long-term sequelae, and death.13 Our patient achieved good clinical response to pembrolizumab; however, pembrolizumab-induced irAE deteriorated performance-status. Therefore, it is critical to closely monitor patients treated with ICIs for early detection and appropriate management of irAE, which will not present with typical symptom of each disease as in our patient.

References
[1]
J. Malhotra, S.K. Jabbour, J. Aisner
Current state of immunotherapy for non-small cell lung cancer
Transl Lung Cancer Res, 6 (2017), pp. 196-211 http://dx.doi.org/10.21037/tlcr.2017.03.01
[2]
M. Reck, D. Rodríguez-Abreu, A.G. Robinson, R. Hui, T. Csőszi, A. Fülöp
Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell-lung cancer
N Engl J Med, 375 (2016), pp. 1823-1833 http://dx.doi.org/10.1056/NEJMoa1606774
[3]
G. De Velasco, Y. Je, D. Bossé, M.M. Awad, P.A. Ott, R.B. Moreira
Comprehensive meta-analysis of key immune-related adverse events from CTLA-4 and PD-1/PD-L1 inhibitors in cancer patients
Cancer Immunol Res, 5 (2017), pp. 312-318 http://dx.doi.org/10.1158/2326-6066.CIR-16-0237
[4]
R.S. Herbst, P. Baas, D.W. Kim, E. Felip, J.L. Pérez-Gracia, J.Y. Han
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial
[5]
H. Vallet, A. Gaillet, N. Weiss, C. Vanhaecke, S. Saheb, V. Touitou
Pembrolizumab-induced necrotic myositis in a patient with metastatic melanoma
Ann Oncol, 27 (2016), pp. 1352-1353 http://dx.doi.org/10.1093/annonc/mdw126
[6]
C.L. Haddox, N. Shenoy, K.K. Shah, J.C. Kao, S. Jain, T.R. Halfdanarson
Pembrolizumab induced bulbar myopathy and respiratory failure with necrotizing myositis of the diaphragm
Ann Oncol, 28 (2017), pp. 673-675 http://dx.doi.org/10.1093/annonc/mdw655
[7]
L. Zimmer, S.M. Goldinger, L. Hofmann, C. Loquai, S. Ugurel, I. Thomas
Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy
Eur J Cancer, 60 (2016), pp. 210-225 http://dx.doi.org/10.1016/j.ejca.2016.02.024
[8]
J.J. Paik, A.M. Corse, A.L. Mammen
The co-existence of myasthenia gravis in patients with myositis: a case series
Semin Arthritis Rheum, 43 (2014), pp. 792-796 http://dx.doi.org/10.1016/j.semarthrit.2013.12.005
[9]
J.S. Weber, J.C. Yang, M.B. Atkins, M.L. Disis
Toxicities of immunotherapy for the practitioner
J Clin Oncol, 33 (2015), pp. 2092-2099 http://dx.doi.org/10.1200/JCO.2014.60.0379
[10]
O. Hasan Ali, S. Diem, E. Markert, W. Jochum, K. Kerl, L.E. French
Characterization of nivolumab-associated skin reactions in patients with metastatic non-small cell lung cancer
Oncoimmunology, 5 (2016), pp. e1231292 http://dx.doi.org/10.1080/2162402X.2016.1231292
[11]
J.C. Osorio, A. Ni, J.E. Chaft, R. Pollina, M.K. Kasler, D. Stephens
Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer
Ann Oncol, 28 (2017), pp. 583-589 http://dx.doi.org/10.1093/annonc/mdw640
[12]
S. Teraoka, D. Fujimoto, T. Morimoto, H. Kawachi, M. Ito, Y. Sato
Early immune-related adverse events and association with outcome in advanced non-small cell lung cancer patients treated with nivolumab: a prospective cohort study
J Thorac Oncol, 12 (2017), pp. 1798-1805 http://dx.doi.org/10.1016/j.jtho.2017.08.022
[13]
N. Abdel-Wahab, M. Shah, M.E. Suarez-Almazor
Adverse events associated with immune checkpoint blockade in patients with cancer: a systematic review of case reports
Copyright © 2018. SEPAR
Idiomas
Archivos de Bronconeumología

Suscríbase al Newsletter

Opciones de artículo
Herramientas
es en
Política de cookies Cookies policy
Utilizamos cookies propias y de terceros para mejorar nuestros servicios y mostrarle publicidad relacionada con sus preferencias mediante el análisis de sus hábitos de navegación. Si continua navegando, consideramos que acepta su uso. Puede cambiar la configuración u obtener más información aquí. To improve our services and products, we use "cookies" (own or third parties authorized) to show advertising related to client preferences through the analyses of navigation customer behavior. Continuing navigation will be considered as acceptance of this use. You can change the settings or obtain more information by clicking here.
es en

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?