Pulmonary Toxicities of Tyrosine Kinase Inhibitors Maajid Mumtaz Peerzada, MD, Timothy P. Spiro, MD, FACP, and Hamed A. Daw, MD Dr. Peerzada is a Resident in the Depart- Abstract: The incidence of pulmonary toxicities with the use of ment of Internal Medicine at Fairview tyrosine kinase inhibitors (TKIs) is not very high; however, various Hospital in Cleveland, Ohio. Dr. Spiro and case reports and studies continue to show significant variability in Dr. Daw are Staff Physicians at the Cleve- the incidence of these adverse events, ranging from 0.2% to 10.9%. land Clinic Foundation Cancer Center, in Cleveland, Ohio. Gefitinib and erlotinib are orally active, small-molecule inhibitors of the epidermal growth factor receptor tyrosine kinase that are mainly used to treat non-small cell lung cancer. Imatinib is an inhibitor of BCR-ABL tyrosine kinase that is used to treat various leukemias, gastrointestinal stromal tumors, and other cancers. In this article, we Address correspondence to: review data to identify the very rare but fatal pulmonary toxicities Maajid Mumtaz Peerzada, MD Medicor Associates of Chautauqua (mostly interstitial lung disease) caused by these drugs. Internal Medicine 12 Center Street Fredonia, NY 14063 Introduction Phone: 716-679-2233 E-mail: [email protected] Tyrosine kinases are enzymes that activate the phosphorylation of tyro- sine residues by transferring the terminal phosphate of ATP. Some of the tyrosine kinase inhibitors (TKIs) currently used in the treatment of various malignancies include imatinib (Gleevec, Novartis), erlotinib (Tarceva, Genentech/OSI), and gefitinib (Iressa, AstraZeneca). This article presents a basic introduction (mechanism of action and indi- cations of use) of these TKIs and summarizes the incidence, various clinical presentations, diagnosis, treatment options, and outcomes of patients around the world that presented with pulmonary toxicities caused by these drugs. Articles were searched on PubMed using the keywords pulmonary toxicities/lung toxicities/pulmonary side effects of imatinib/erlotinib/gefitinib. Imatinib Imatinib inhibits BCR-ABL tyrosine kinase, the constitutive abnor- mal gene product of the Philadelphia chromosome (Ph+) in chronic myeloid leukemia (CML). Inhibition of this enzyme blocks prolif- eration and induces apoptosis in BCR-ABL– positive cell lines as well as in fresh leukemic cells in Ph+ CML. It also inhibits tyrosine kinase for platelet-derived growth factor (PDGF), stem cell factor (SCF), c-Kit, and cellular events mediated by PDGF and SCF. The US Food and Drug Administration (FDA)-approved indications for Keywords imatinib are presented in Table 1. The following are case studies Pulmonary toxicities, tyrosine kinase inhibitors, and clinical reports describing various presentations of pulmonary interstitial lung disease, imatinib, erlotinib, gefitinib toxicities in patients treated with imatinib. 824 Clinical Advances in Hematology & Oncology Volume 9, Issue 11 November 2011 PULMONARY TOXICITIES OF TYROSINE KINASE INHIBITORS Table 1. FDA-Labeled Indications for Imatinib The skin biopsy revealed perivascular lymphocytic infiltration in the dermis and exocytosis in the epidermis • Acute lymphoid leukemia, relapsed/refractory due to lymphocytes. These findings strongly suggested Philadelphia chromosome-positive the diagnosis of a drug reaction. The features of increased • Chronic eosinophilic leukemia alveolar macrophages with lymphocyte infiltration and interstitial fibrosis found in the lung biopsy along • Chronic myeloid leukemia, Philadelphia chromosome- with the presence of spongiloid dermatitis suggested an positive, accelerated phase or blast crisis imatinib-induced toxicity in this patient, most likely via • Chronic phase chronic myeloid leukemia, the immune mechanism.2 Philadelphia chromosome-positive, after failure of Hypersensitivity pneumonitis was reported in a patient interferon-alpha therapy who was being treated with imatinib (600 mg/day) for 1 • Chronic phase chronic myeloid leukemia, Philadelphia year.3 A chest X-ray showed ground-glass opacity (GGO) chromosome-positive, newly diagnosed that was confirmed to be bilateral and diffuse by high-resolu- • Chronic phase chronic myeloid leukemia, Philadelphia tion lung computed tomography (CT) scan. The bronchial chromosome-positive, recurrence after stem cell transplant biopsies were negative on pathology. • Dermatofibrosarcoma protuberans, unresectable, Eleven days after discontinuing therapy, the lung CT recurrent and/or metastatic scan had normalized. This patient also developed diffuse lichenoid dermatosis 9 months after the use of imatinib; • Gastrointestinal stromal tumor treatment with steroids permitted the skin lesion to only • Hypereosinophilic syndrome partially regress. The skin lesion had greatly improved • Myelodysplastic syndrome, with platelet-derived growth after imatinib was discontinued. factor receptor (PDGFR) gene rearrangement In a report, a 77-year-old woman received imatinib (400 mg/day) for CML.4 Four weeks after imatinib ther- • Myeloproliferative disorder, chronic, with PDGFR gene rearrangement apy, she developed progressive dyspnea on exertion after 4 weeks. Her oxygen saturation was 85% on room air, • Systemic mast cell disease, aggressive and auscultation of her lungs revealed scattered rhonchi. A chest radiograph revealed bilateral patchy infiltrates, and blood culture showed no growth. The patient did not improve even 16 days after discontinuing imatinib, at which point the prednisone dose was increased from Case Studies Reporting Pulmonary Toxicities 6 mg/day to 30 mg/day (patient was already on a taper- In 1 report, a 58-year-old man developed fulminant ing dose of prednisone for her polymyalgia rheumatica interstitial pneumonitis and severe skin rash 3 days after even before imatinib was started). Over the next 4 days, the use of low-dose imatinib (100 mg/day).1 His symp- the dyspnea began to improve. A chest radiograph done toms included fever, dry cough, dyspnea, and extremely approximately 2 weeks later showed improvement in pruriginous skin lesions on the upper extremity. A chest pulmonary infiltrates. There was gradual resolution of X-ray showed a bilateral interstitial reticular/nodular dyspnea and oxygen requirement over the next 2 months. pattern throughout both lung fields. The lung biopsies The patient had a predominance of macrophages rather demonstrated chronic interstitial pneumonitis and than lymphocytes, with a large number of eosinophils pulmonary hypertension, with mild interstitial fibrosis in the bronchoalveolar lavage fluid. This report widened and lymphocytic infiltration with marked pulmonary the spectrum of pulmonary hypersensitivity that can be vascular mural thickening. associated with imatinib therapy. The patient’s condition rapidly evolved into acute Interstitial pneumonitis (clinical diagnosis) was also respiratory failure, and he was intubated. He was receiv- observed in a patient with gastrointestinal stromal tumor ing steroids with low-dose imatinib, which was discontin- (GIST) after 4 weeks of imatinib (400 mg/day).5 The ued at this time. The patient’s condition improved after 3 patient developed hypoxia, and bilateral ground-glass days of treatment, and antibiotics were discontinued. He infiltrates were seen on a high-resolution lung CT scan. was extubated after 1 week. No steroids were given after Two weeks after the administration of steroids, the he developed respiratory failure. The skin lesion regressed lung scan had normalized. In another case6 a CML patient after his condition improved. A follow-up chest X-ray who received imatinib 400 mg/day developed interstitial performed 3 weeks later showed improvement, with pneumonitis (clinical diagnosis, no pathology done) with residual infiltrates in the right lower lobe of the lung. The bilateral interstitial infiltrates on chest X-ray 1 month after follow up chest X-ray after 1 month was normal. treatment. No hypoxia was present. Steroids were given and Clinical Advances in Hematology & Oncology Volume 9, Issue 11 November 2011 825 P eer z A d A E T A L the abnormalities improved, but they were not completely an immunoallergic reaction. This case and the others resolved after 1 year. In another report,7 non-specific inter- noted above suggest that imatinib-induced interstitial stitial pneumonitis (transbronchial biopsy done) developed pneumonitis may be heterogeneous, and some of these in a patient 2 months after imatinib therapy (400 mg/day). cases may likely involve an immunoallergic mechanism. Hypoxia was present, and after the discontinuation of ima- A case of lymphomatoid granulomatosis (LYG) tinib and use of steroids, the patient’s condition improved, induced by imatinib has also been reported.11 In this case, but GGO remained 2 months later. an 89-year-old woman with liver metastasis from GIST In another report,8 the result of re-administration was treated with imatinib at an initial dose of 400 mg/day. of imatinib for long-term use was noted. In this case, a Three months later, the size of the liver tumors decreased. 70-year-old man with metastatic GIST was treated with Three months after that, a CT scan revealed 3 intrapul- imatininb. After 3 months, he developed dyspnea on monary lesions that radiologically resembled an infectious exertion. His chest radiography and CT scan revealed dif- complication or metastases of the GIST. Owing to the fuse interstitial changes with peribronchovascular bundle age of the patient and continuous decline of her physical