Crizotinib-Induced Interstitial Lung Disease

Abstract

The versatility of emerging cancer therapies is due to the advancements in gene focused strategies whereby the identification of key driver mutations has led to the development of selectively targeted drugs. Crizotinib is one such drug used for non-small cell lung cancer (NSCLC). A rare but serious adverse effect (AE) of interstitial lung disease (ILD) has been reported in about 2% of patients on Crizotinib. CASE PRESENTATION:A 63 year-old man with metastatic squamous cell carcinoma of head and neck, history of Hodgkin's lymphoma post radiation, tobacco use presented with dyspnea, cough, and fever. Physical exam revealed respiratory distress, SpO2 89% on room air and diffuse rhonchi bilaterally. He was placed on 6 liters of nasal cannula with improvement in hypoxia. White blood cell was 11000/uL, c-reactive protein (CRP) 14.23 mg/d, procalcitonin 4.72ng/ml and brain natriuretic peptide 309 pg/ml. Sputum culture, COVID real time polymerase chain reaction (PCR), respiratory viral panel and a methicillin resistant Staphylococcus aureus nasal PCR swab were all negative. Chest radiograph showed bilateral consolidations, concerning for multifocal community acquired pneumonia for which he received broad spectrum antibiotics. However, the patient's respiratory status worsened on day 2. He was requiring 40L and FiO2 60% on high-flow nasal cannula (HFNC) to keep SpO2 > 92%. The patient then reported starting Crizotinib 250 mg oral twice/day 9 days ago and developed dyspnea and cough shortly thereafter. A computer tomography (CT) scan of the chest showed a right lower lobe segmental pulmonary embolism (PE) and severe bilateral airspace disease, with diffuse consolidation and ground glass opacities. He received anticoagulation for the PE and methylprednisolone 500mg IV twice/day due to concern for Crizotinib induced ILD. There was marked improvement in his respiratory status with decreasing oxygen requirements after steroid initiation.DISCUSSION: Crizotinib is a tyrosine kinase inhibitor (TKI) that suppresses anaplastic lymphoma kinase (ALK) gene activity. ILD due to Crizotinib is thought to be related to direct cytotoxicity to the pneumocytes. Risk factors include male sex, smoking, history of pulmonary fibrosis, history of radiation and combination therapy with immunotherapy. Our patient had several risk factors, except history of pulmonary fibrosis. There is no established therapy for TKI induced ILD, but some case reports recommend using systemic corticosteroids. Other case reports have demonstrated that continuing therapy with another ALK inhibitor, such as Alectinib, did not result in recurrence of ILD.CONCLUSIONS: TKIs are generally well tolerated but can rarely cause severe ILD. It is important to consider risk factors for TKI induced ILD prior to their administration. Prompt discontinuation of the drug and treatment with corticosteroids can cause symptomatic resolution of TKI induced ILD.