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Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 6185943, 5 pages https://doi.org/10.1155/2019/6185943 Case Report Emerging Risk Profile of Lung Cancer Therapy: Diffuse Alveolar Hemorrhage from Osimertinib Michael J. Forte and Rahul G. Sangani West Virginia University, Department of Pulmonary and Critical Care Medicine, PO BOX 9166 1 Medical Center Drive, Morgantown, WV 26506, USA Correspondence should be addressed to Michael J. Forte; firstname.lastname@example.org Received 17 April 2019; Revised 20 June 2019; Accepted 10 July 2019; Published 30 July 2019 Academic Editor: Peter F. Lenehan Copyright © 2019 Michael J. Forte and Rahul G. Sangani. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Osimertinib is an oral epithelial growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used primarily in the treatment of metastatic non-small cell lung cancer. It is usually well tolerated with less than 5% of patients developing signiﬁcant pulmonary toxicity from the medication, typically within the ﬁrst few months after initiation. Previously reported pulmonary adverse reactions include pneumonitis (nonspeciﬁc interstitial pneumonia or other forms of acute interstitial process), ﬂeeting asymptomatic inﬁltrates on imaging, and eosinophilic pneumonia. We present an interesting case of a 65-year-old female with recurrent metastatic adenocarcinoma of the lung, treated with Osimertinib for 4 months, who developed a previously unreported toxicity of diﬀuse alveolar hemorrhage (DAH) requiring mechanical ventilatory support. complication was interstitial lung disease, which occurred 1. Introduction in about 4% of patients. In general, the drug is felt to have a Diﬀuse alveolar hemorrhage (DAH) is a potentially life- favorable side eﬀect proﬁle and tolerability. threatening disorder characterized by respiratory failure, We present an interesting case of a previously unreported hemoptysis, diﬀuse inﬁltrates on chest imaging, and blood toxicity with the use of Osimertinib. loss anemia. Prompt recognition and urgent evaluation with bron- 2. Case Presentation choscopy are necessary for diagnosis. DAH is caused by a wide range of clinical entities. Common etiologies include The patient is a 65-year-old female who was previously diag- capillaritis, vasculitis, and diﬀuse alveolar damage or from nosed with moderately diﬀerentiated, invasive adenocarci- an extensive list of medications and toxins such as amioda- noma after a right upper lobectomy in 2013. The tumor rone, nitrofurantoin, cocaine, and tumor necrosis factor- was positive for EGFR mutation, KRAS wild type, ALK neg- (TNF-) alpha inhibitors . To date, there have been no ative, CK7 positive, CK20 negative, and TTF negative. At that previously reported cases of Osimertinib causing DAH in time, no chemotherapy or radiation was required. In 2014, the literature. the patient had a recurrence of her disease with a metastasis Osimertinib is an oral epithelial growth factor receptor to mediastinal subcarinal lymph node. Over the next four tyrosine kinase inhibitor (EGFR-TKI) used primarily in the years due to disease progression or inability to tolerate agents treatment of metastatic non-small cell lung cancer (NSCLC). (e.g., development of acute pancreatitis from erlotinib), the It is routinely used in patients with metastatic T790M- patient was treated with multiple antineoplastic agents positive NSCLC who have disease progression during or after including bevacizumab, pemetrexed, durvalumab, tremeli- EGFR-TKI therapy . Osimertinib can now be prescribed mumab, erlotinib, and afatinib. These were all discontinued as a ﬁrst-line agent regardless of the presence of T790M. Dur- over 6 months prior to this admission to the hospital. She ing early clinical trials , the most common pulmonary also received palliative radiation to the right mediastinal 2 Case Reports in Oncological Medicine Figure 1: Representative axial CT for PE image of our patient upon Figure 2: Initial sequential lavages from the patient’s lingular admission to the intensive care unit showing dense airspace segment demonstrating obvious DAH. opacities involving predominantly the left upper lobe and small pleural eﬀusion. mass as well as to several metastatic spine lesions in the cer- vical and thoracic spine during 2017. Follow-up staging imaging did not show any evidence of radiation pneumonitis or ﬁbrosis. In early 2018, she underwent biopsy of metastatic liver lesions, found to be adenocarcinoma of the lung pri- mary with EGFR exon 19 deletion and T790M mutations. In April 2018, she was started on Osimertinib 80 mg daily, Figure 3: Repeat sequential lavage after 3 days of methylprednisone which she tolerated well for approximately four months. from lingular segment demonstrating an improvement in her DAH. A staging CT was completed in June of 2018, which showed response to therapy as evidenced by a decrease in size of the right infrahilar mass, adenopathy, pulmonary nodules, and hepatic metastases. In addition, her previously noted brain metastasis was no longer seen on her brain MRI. In August 2018, she required an admission to an outside facil- ity due to symptoms suggestive of congestive heart failure. She was diuresed and diagnosed with nonischemic cardio- myopathy. Her heart failure remained well compensated on goal-directed medical therapy and diuretics. Other past medical history is notable for hypertension, acid reﬂux, emphysema, and iron deﬁciency anemia. She is not pre- scribed any antiplatelet or anticoagulation agents. She has several allergies to antibiotics and was previously intolerant Figure 4: Axial CT chest with contrast approximately 3 months to subcutaneous heparin. later in an outpatient follow-up, demonstrating a marked The patient was admitted to our facility in September improvement of her inﬁltrate. 2018 due to progressive dyspnea, fatigue, and weakness of several weeks of duration. She was initially managed as Due to the progressive respiratory failure, a bronchos- hospital-acquired pneumonia in an immunocompromised copy was performed. The bronchoscopy revealed inﬂamed host with broad-spectrum antimicrobials, aggressive bron- airways (left>right) and increasingly hemorrhagic return chodilators, and intravenous corticosteroids. Within 24 on sequential lavages (Figure 2) from the lingular segment hours of admission, transfer to the intensive care unit was of the left upper lobe. Bronchoalveolar lavage (BAL) RBC facilitated due to worsening respiratory distress requiring counts were increasing signiﬁcantly in sequential samples noninvasive positive pressure ventilation which eventually (42,000/μL, 190,000/μL, and 230,000/μL). She was diagnosed progressed to require mechanical ventilation. At this time, with DAH with predominant left-sided parenchymal involve- her exam was remarkable for predominant left-sided rhonchi ment. She was initiated with pulse dose methylprednisone and rales. Laboratory analysis was unremarkable except a 250 mg IV every 6 hours for 3 days. Her ventilator settings severe acute respiratory acidosis of pH 7.18 and PCO of improved signiﬁcantly after the initiation of pulse dose sys- 54 mmHg. Upon arrival, her WBC count was 7 6× 10 /μL, temic steroids. After three days of IV steroids, we decided to repeat the bronchoscopy due to continued small amount hemoglobin was 8.5 g/dL, and platelets were 305 × 10 /μL, and she had normal coagulation panel and B-type natri- of blood-tinged tracheal aspirates requiring in-line suction. uretic peptide (BNP). A CT chest with contrast demonstrated On repeat bronchoscopy, the airway inﬂammation had a consolidation in the left lung suspicious for pneumonia and diminished considerably. There was no visible bleeding. We small eﬀusions bilaterally with associated atelectasis (Figure 1). elected to repeat a sequential lavage in the lingular segment, which was dramatically less hemorrhagic (Figure 3). The Her antibiotics were continued. Case Reports in Oncological Medicine 3 Table 1: Summary of previously reported cases of pulmonary toxicities of Osimertinib. Onset of Article Patient age/sex Symptoms Diagnosis Treatment Outcome symptoms Resolution of Drug-induced Dyspnea and Withdrawal of ILD Mamesaya et al.  38 F 31 days interstitial lung low-grade fever medication but progression disease (ILD) of malignancy Methylprednisone Generalized 500 mg daily for Resolution of Drug-induced Matsumoto et al.  75 M 20 days weakness 3days, then ILD following ILD (NSIP) and dyspnea prednisone steroid taper 40 mg daily 3 patients resolved, 8 patients Average of ILD and one case 2 remained at end Yang et al.  Not described (no speciﬁcs) 5.1 months of pneumonitis of study, and 3 patients deceased Dose reduction to 80 mg every Improvement in Cough and Nie et al.  32 M 4.5 months Acute ILD other day and inﬁltrates and dyspnea dexamethasone symptoms 10 mg daily Asymptomatic No adverse Lee et al.  15 patients 24 weeks None pulmonary None events opacities reported 4males Asymptomatic (average age 57) 8 weeks pulmonary opacities, All patients had Noonan et al.  None None and 3 females mean onset mostly nodules and good outcomes (average age 43) ground glass opacities Eosinophilic Gradual Fever and Withdrawal of Tachi et al.  77 F 14 days pneumonia due improvement hypoxia medication to Osimertinib in her symptoms RBC counts from the sequential lavage were 5,250/μL, maintenance of tumor growth, have been identiﬁed. Among 6,750/μL, and 11,500/μL. Microbiology from BAL was unre- these mutations, EGFR alterations are the most common, markable. The patient was transitioned to oral prednisone present in about 10% to 15% of patients with NSCLC in 1 mg/kg daily. She was successfully weaned from mechanical the United States. EGFR belongs to the ERBb superfamily ventilation and eventually discharged from the hospital with- of tyrosine kinase receptors, which mediate tumor prolifera- out a need of any supplemental oxygen. tion, invasion, metastasis, resistance to apoptosis, and angio- A comprehensive standard etiological assessment for genesis. EGFR-TKI (ﬁrst generation: erlotinib and geﬁtinib; DAH was unremarkable including ANCA vasculitis panel second generation: afatinib; and most recent: Osimertinib) and anti-GBM antibodies. Despite her diagnosis of nonis- signiﬁcantly prolong progression-free survival in patients chemic cardiomyopathy, the patient was not clinically in with advanced NSCLC that contains an activating mutation decompensated heart failure at any point in her admission. in EGFR compared with platinum-based chemotherapy Upon medication review, Osimertinib 80 mg daily was the doublets . only new medication the patient had initiated in the prior Osimertinib is usually well tolerated with less than 5% four months. Osimertinib was discontinued in consultation of patients developing toxicity from the medication, usu- with medical oncology and was held at her discharge from ally within the ﬁrst few months. Previously reported pul- the hospital. She was discharged on a prolonged prednisone monary adverse reactions include pneumonitis including taper. A follow-up CT of the chest demonstrated resolution nonspeciﬁc interstitial pneumonia [3–6] or other acute of the opacities in the left upper lobe (Figure 4). interstitial processes [3, 6], ﬂeeting asymptomatic inﬁl- trates on imaging [7, 8], and eosinophilic pneumonia . Previously reported pulmonary toxicities are summarized 3. Discussion in Table 1. All of the patients had improvement in their In recent years, several molecularly deﬁned subsets of non- pulmonary complaints after discontinuation of the medica- small cell lung cancer (NSCLC) with speciﬁc somatic “driver” tion. There seemed to be no typical time frame or age/sex mutations, thought to be responsible for the initiation and predilection in the previous case reports. Pneumonitis 4 Case Reports in Oncological Medicine Table 2: Summary of previously reported cases of cardiac toxicities of Osimertinib. Patient Onset of Article Symptoms Diagnosis Treatment Outcome age/sex symptoms Facial and Withdrawal of No recurrence of Congestive heart Watanabe et al.  78 F 21 days lower extremity medication and CHF after drug failure (CHF) edema, dyspnea diuretics discontinuation Withdrawal of Dilated medication, Improved edema, Oyakawa et al.  84 F 34 weeks Facial edema cardiomyopathy/myocarditis diuretics, and persistently low EF GDMT Normalization of QT 5 days after Withdrawal of discontinuation, Schiefer et al.  62 F 11 months Asymptomatic QTc prolongation medication patient died of disease progression in 2 months Dose reduction in Yang et al.  6 patients Unknown Asymptomatic QTc prolongation Not described 2 patients generally appeared sooner than the ILD, within the ﬁrst targets speciﬁc genetic mutations. Considering more preva- month of therapy [4, 5]. ILD, including acute ILD, was a lent use of EGFR-TKI, particularly Osimertinib as front- later complication at about 4 months of therapy in the line therapy for NSCLC, it is highly signiﬁcant to recognize previous case reports [3, 6]. The asymptomatic pulmonary uncommon adverse reactions. Our case represents the opacities occurred at approximately 8-24 weeks of therapy unique side eﬀect of diﬀuse alveolar hemorrhage leading to [7, 8], whereas the eosinophilic pneumonia occurred at severe respiratory failure needing mechanical ventilation 2 weeks of therapy . Some patients were also given steroids with the use of Osimertinib. This paper provides the review which seemed to be an eﬀective adjunct to medication dis- of previously reported pulmonary adverse reactions from Osimertinib and highlights the ongoing need for prompt continuation in the improvement in respiratory symptoms. In addition to respiratory adverse reactions, a very small recognition and appropriate management measures to be number of patients seem to have developed cardiac adverse undertaken during the course of therapy. drug reactions to Osimertinib (Table 2). Watanabe et al. and Oyakawa et al. described two females, aged 78 and 84, Disclosure respectively, who developed symptoms of congestive heart An earlier version of this work was presented as a poster failure and dilated cardiomyopathy with no other obvious at the American Thoracic Society International Conference cause during their course of treatment with Osimertinib 2019. Reference: Am J Respir Crit Care Med 2019; 199 [10, 11]. One was 21 days and the other was 34 weeks A 1508. https://www.atsjournals.org/doi/pdf/10.1164/ajrccm- into treatment [10, 11]. These patients also improved with conference.2019.199.1_MeetingAbstracts.A1508. drug discontinuation and goal-directed medical therapy as well as diuretics. One patient described by Schiefer et al., who was a 61-year-old female, developed a signiﬁcant QT Conflicts of Interest prolongation after 11 months of treatment with Osimerti- The authors declare that there is no conﬂict of interest nib, which quickly normalized after discontinuation of the regarding the publication of this article. medication . To our knowledge, this is the ﬁrst known case reporting References diﬀuse alveolar hemorrhage associated with Osimertinib. Cli- nicians should be cognizant of this new potential adverse  M. S. Park, “Diﬀuse alveolar hemorrhage,” Tuberculosis Respi- reaction in addition to the already recognized pulmonary ratory Disease, vol. 74, no. 4, pp. 151–162, 2013. and cardiac toxicities of the medication. Urgent evaluation  D. Planchard, M. J. Boyer, J. S. Lee et al., “Postprogression out- with bronchoscopy and serial bronchoalveolar lavage is comes for osimertinib versus standard-of-care egfr-tki in critical for quick recognition and diagnosis. Our patient patients with previously untreated egfr-mutated advanced responded very well to discontinuation of the medication non–small cell lung cancer,” Clinical Cancer Research, and pulse dose steroids with subsequent slow taper. The vol. 25, no. 7, pp. 2058–2063, 2019. optimal treatment algorithm is not known but high-dose  J. C. Yang, M. J. Ahn, D. W. Kim et al., “Osimertinib in pre- corticosteroids are likely very eﬀective in bringing prompt treated T790M-positive advanced nonsmall cell lung cancer: resolution to the syndrome. Further investigations into the AURA study phase II extension component,” Journal of Clin- management of this subset of patients could be undertaken. ical Oncology, vol. 35, no. 12, pp. 1288–1296, 2017. With advent of genetic analysis and targeted therapy  N. Mamesaya, H. Kenmotsu, M. Katsumata, T. Nakajima, for lung cancers, there is an increased use of therapy which M. Endo, and T. 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Published: Jul 30, 2019
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