Drug-induced interstitial lung disease caused by olaparib: three case reports and review of the Japanese Adverse Drug Event Report database and literature

A 72-year-old Japanese woman had continued prednisolone 10 mg/day for myelodysplastic syndrome for 15 years. In addition, she had been receiving zolpidem tartrate, esomeprazole magnesium hydrate, and amlodipine besylate for more than 10 years. One year prior, she was diagnosed with ovarian cancer and received a total of six courses of chemotherapy with carboplatin, paclitaxel, and bevacizumab before and after surgery. Subsequently administration of olaparib in combination with bevacizumab was initiated. Olaparib administration was continued for four months, during which her performance status (PS) was scored as 1. Olaparib was administered at 600 mg/day. Subsequently, after two weeks of fever and fatigue, she was admitted to our hospital. And chest computed tomography (CT) revealed faint ground glass opacity (GGO) resembling hypersensitivity pneumonitis in both lungs (Fig. 1a-c). Oxygen saturation in room air was 95%, but the lung sounds were not abnormal. The results of blood tests are shown in Table 1.

There were no significant abnormalities in the blood cell counts, but C-reactive protein and Krebs von den Lungen-6 (KL-6) were elevated to 4.80 mg/dl and 754 U/ml. In addition to bronchoscopy, bronchoalveolar lavage was performed on the right middle lobe, specifically in the right B⁵ bronchus. There was an increase in the total cell count to 7.75 × 10⁵/mL, alveolar macrophages, lymphocytes, and neutrophils were 13%, 81%, and 6%, respectively, and the CD4/CD8 ratio was 3.1. No bacterial colonies were detected in the alveolar lavage fluid culture. Transbronchial lung biopsy revealed no specific findings, although there was an infiltration of inflammatory cells and aggregation of foamy macrophages in the alveolar space (Fig. 2). There were no findings suggestive of infection, and a diagnosis of DIILD was made. Olaparib and bevacizumab were discontinued. The disease severity was determined to be grade 2 based on the presence of accompanying symptoms. Therefore, olaparib was suspended and prednisolone was started at 35 mg as an equivalent of 0.6 mg per kg of body weight. As a result, the fever subsided and an improvement in their general condition was observed. Subsequently, prednisolone was gradually tapered off over a period of 3 months until it was completely discontinued. Follow-up imaging demonstrated resolution of the lung lesions (Fig. 1d-f), and no recurrence was observed.

A 51-year-old Japanese woman was started on olaparib 600 mg/day as a fourth-line treatment for postoperative recurrence of ovarian cancer. Her PS was scored as 1. Nine months after starting olaparib, she developed general malaise and persistent fever (38 °C). Her oxygen saturation was 99% in room air, with no hypoxia, and her lung sounds were normal. Blood tests revealed bicytopenia and elevated interstitial pneumonia marker levels (Table 2).

In addition to olaparib, she had been receiving flunitrazepam for over a year. Chest CT revealed the presence of diffuse GGO in both lungs, similar to the pattern observed in hypersensitivity pneumonitis (Fig. 3a–c). Although bronchoscopy was not performed, DIILD was also suspected. The patient's general condition was good, and after discontinuation of olaparib without steroids or antibacterial agents, the fever subsided, and an improvement in fatigue was observed. In addition, the GGO in the lung fields improved (Fig. 3d–f), and there were no recurrences. Based on the improvement of symptoms and imaging findings following the discontinuation of olaparib, the patient was diagnosed with DIILD attributed to olaparib. The disease severity was determined to be grade 2.

A 78-year-old Japanese woman started olaparib at 600 mg/day as the 6th line treatment for postoperative recurrence of ovarian cancer that had been operated on six years earlier. PS was scored as 2. She had been receiving amlodipine besilate for five years. Two weeks after starting olaparib, the patient developed cough and dyspnea on exertion. Three weeks after starting olaparib, the patient was hospitalized because of fever and dyspnea. The patient had a body temperature of 38.3 °C, respiratory rate of 28 breaths per minute, and severe hypoxemia with an oxygen saturation of 88%, even after nasal cannula inhalation of 4 L of oxygen per minute. Lung sounds were heard as coarse crackles on the left lung. Blood tests revealed marked myelosuppression and high levels of inflammation (Table 3).

High-flow nasal cannula therapy was initiated, and the arterial blood oxygen partial pressure was 74.7 torr at 50% inspired air oxygenation, resulting in a PaO2/FiO2 ratio of 149.4. Antigen testing for influenza was negative. Since the patient had sought treatment prior to the outbreak of the COVID-19 pandemic, testing for COVID-19 was not performed. Urinary antigen tests for Streptococcus pneumoniae and Legionella were negative as well. Chest radiography revealed the presence of consolidation with air bronchograms in the left lung. Chest CT revealed the presence of patchy GGO and consolidation, resembling the patterns observed in nonspecific interstitial pneumonia and organizing pneumonia, affecting the left upper lobe and bilateral lower lobes (Fig. 4a–c). Bronchoscopy was not performed because of the severity of the respiratory failure. Based on the patient's clinical course and laboratory findings, the diagnosis of DIILD was considered, olaparib was discontinued, and steroid pulse therapy with methylprednisolone at 1000 mg/body was initiated. Although there were no laboratory findings to suggest opportunistic infections, the patient also had a decreased white blood cell count, and it was decided to administer antimicrobial chemotherapy with tazobactam/piperacillin and azithromycin. After a 3-day steroid pulse therapy, treatment was continued with prednisolone 60 mg/day, which resulted in the resolution of fever, improvement of oxygenation, and gradual improvement of lung field shadows. Sputum culture did reveal the presence of any bacteria, and no test results were indicative of infection. Echocardiography did not reveal any abnormalities in cardiac function. Thus, based on the successful response to steroid therapy, the patient was diagnosed with DIILD. The disease severity was determined to be grade 4. Prednisolone was tapered off, and prednisolone was terminated after approximately six months, but there were no relapses of lung shadows (Fig. 4d–f).