- © 2012 by American Society of Clinical Oncology
Severe Acute interstitial lung disease After Crizotinib Therapy in a Patient With EML4-ALK–Positive Non–Small-Cell Lung Cancer
- Corresponding author: Isamu Okamoto, Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan; e-mail: chi-okamoto{at}dotd.med.kindai.ac.jp.
Introduction
The development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib, and, more recently, that of the anaplastic lymphoma kinase (ALK) TKI crizotinib, has had a profound impact on the treatment of advanced non–small-cell lung cancer (NSCLC).1–3 The occurrence of EGFR-TKI–associated interstitial lung disease (ILD) in patients with NSCLC has been found to be more frequent among Japanese patients than among white patients.4,5
Case Report
A 39-year-old male current-smoker (30 pack years) of Japanese descent was diagnosed with poorly differentiated stage IV lung adenocarcinoma (T4N3M1b) with multiple pleural dissemination as well as intra-abdominal lymph node and brain metastasis. Mutation analysis of biopsied tumor tissue showed that the tumor was wild type for the EGFR gene. Fluorescence in situ hybridization analysis with break-apart probes for the ALK gene revealed the presence of an ALK rearrangement, and subsequent reverse transcription and polymerase chain reaction analysis confirmed the presence of transcripts for variant 1 of the echinoderm microtubule-associated-like protein-4 gene (EML4) –ALK fusion gene. The patient received one cycle of chemotherapy with paclitaxel and carboplatin, but treatment was then withdrawn because of disease progression. As a second-line treatment, crizotinib was administered orally at a dose of 250 mg twice daily. After 9 days of crizotinib, the patient developed acutely deteriorating dyspnea without demonstrable infection. With the patient breathing oxygen via a mask at a flow rate of 10 L/min, arterial blood gas determination revealed a PaO2 of 61.5 mmHg, a PaCO2 of 36.0 mmHg, and a pH of 7.46. A computed tomography scan of the chest showed extensive bilateral ground-glass opacities throughout both lungs, despite obvious shrinkage of the primary tumor lesions in his left lobes (Fig 1A, before crizotinib; Fig 1B, after crizotinib [day 9]). Crizotinib treatment was immediately discontinued, and methylprednisolone pulse therapy (1 g once per day for 3 days) was initiated. Empirical treatment with meropenem, ciprofloxacin hydrochloride, and trimethoprim-sulfamethoxazole was also administered. The patient nevertheless developed acute lung injury in accordance with the Lung Injury Score definitions,6 and he died 21 days after his first administration of crizotinib. Postmortem analysis of a specimen of the right lung by hematoxylin-eosin (HE) staining revealed juvenile fibroblast hyperplasia (black arrow), nuclear swelling of aberrant alveolar cells (white arrow), and mild infiltration of inflammatory small round cells and neutrophils (Fig 2). The patient was thus diagnosed with diffuse alveolar damage, as previously described for individuals with severe EGFR-TKI–associated ILD.7,8 No evidence of infection or of other specific etiologies was found. It can be difficult to make a diagnosis of pulmonary toxicity in lung cancer patients because of the high incidence of preexisting lung disease, respiratory tract infections, and progressive malignancy. Despite his smoking history, our patient did not have any preexisting pulmonary fibrosis or chronic obstructive lung disease. He developed rapidly progressive dyspnea with severe hypoxemia and diffuse interstitial infiltrates, which were detected radiographically 9 days after the onset of treatment with crizotinib. The histologic characteristics of his lung tissue were consistent with diffuse alveolar damage, thus opening up the possibility of various potential etiologies. An infectious etiology was ruled out by extensive microbiologic analysis of sputum and blood cultures and by the postmortem examination of the lungs. The pathologic analysis of lung tissue did not reveal any lymphangitic spread of the cancer. The patient's history and clinical examination did not provide any evidence of a toxic origin, prior radiotherapy, collagen vascular disorders, or other usual causes of adult respiratory distress syndrome. The exclusion of these other causes indicated that the severe ILD was most likely attributable to crizotinib treatment. Written informed consent was obtained from the patient's family for publication of this case report and accompanying images.
Discussion
EML4-ALK was recently identified as a transforming fusion gene in NSCLC.9,10 Preclinical and clinical studies have shown that cancer cells harboring EML4-ALK are highly sensitive to ALK inhibition.3,11 Crizotinib is the first clinically available ALK-TKI and competes with ATP for binding to the tyrosine kinase pocket of the enzyme, inhibiting tyrosine phosphorylation of activated ALK at nanomolar concentrations. On the basis of its pronounced clinical activity and tolerability profile, crizotinib was approved by the US Food and Drug Administration to treat ALK rearrangement–positive NSCLC in August 2011. As far as we are aware, our patient is the first reported example of histologically documented crizotinib-associated ILD. Although crizotinib is generally well tolerated, physicians should thus be aware of the possibility of such a severe adverse reaction and full informed consent for treatment should be obtained. We have previously identified male sex, a history of smoking, and coincidence of interstitial pneumonia as independent risk factors for EGFR-TKI–associated ILD12; however, it remains unclear whether these risk factors also apply to crizotinib-associated ILD. Given that drug-induced ILD has a high associated mortality, a systematic survey allowing direct determination of the prevalence of and identification of risk factors for crizotinib-induced ILD is warranted.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
Acknowledgment
The patient described in this report was treated in a crizotinib clinical trial (A8081007, NCT00932893) that was sponsored by Pfizer.
