间变性淋巴瘤激酶阳性非小细胞肺癌患者阿来替尼诱发间质性肺病后劳拉替尼的疗效：病例报告
抽象的
间变性淋巴瘤激酶酪氨酸激酶抑制剂是治疗间变性淋巴瘤激酶阳性非小细胞肺癌的标准药物，并且已证实使用这些药物治疗可提高患者的长期生存率。然而，对于间变性淋巴瘤激酶酪氨酸激酶抑制剂相关药物引起的间质性肺疾病发作后的治疗过程尚无共识。
这里我们介绍了一例在阿来替尼引起药物性间质性肺病后，劳拉替尼治疗成功的病例。
一名57岁的日本男性经支气管镜检查确诊为IVB期非小细胞肺癌，但因标本量少而无法进行基因突变检测。确诊后，开始使用顺铂/培美曲塞进行一线治疗，但患者出现肾功能不全。再次进行支气管镜检查以指导进一步治疗，发现非小细胞肺癌为间变性淋巴瘤激酶阳性。病情出现进展后开始使用艾乐替尼，但导致药物性间质性肺疾病，需要替代治疗。他随后接受纳米颗粒白蛋白结合紫杉醇治疗，鉴于肾功能不全而停止治疗。此后，给予劳拉替尼治疗，继续用药，未出现药物性间质性肺疾病复发。
由于阿来替尼偶尔会导致药物性间质性肺病，如本病例，因此对于没有其他治疗方案的患者，劳拉替尼可能是一种继续治疗的选择。
背景
随着间变性淋巴瘤激酶 (ALK) 阳性非小细胞肺癌 (NSCLC) 基因异常的发现，已开发出有效的 ALK 酪氨酸激酶抑制剂 (ALK-TKI) 用于治疗。ALK-TKI 比细胞毒性化疗更有效，长期使用 TKI 治疗已被证明可以延长患者的总体生存期。劳拉替尼是一种新型第三代 ALK TKI，生化和细胞测定结果表明其比第二代 TKI 更有效，并且对已发现的 ALK 耐药突变的覆盖范围最广。此外，该药物旨在穿过血脑屏障，从而在中枢神经系统 (CNS) 中达到高暴露水平 [1]。由于其疗效，劳拉替尼是 ALK 阳性 NSCLC 患者（对于一种或多种 ALK-TKI 治疗失败）的标准治疗选择。
然而，尚不清楚在因不良事件（例如药物引起的间质性肺病 (DILD) 病例）停用另一种 ALK-TKI 后是否可以继续使用劳拉替尼。在这里，我们介绍了一个罕见病例，显示在阿来替尼引起 DILD 后继续使用劳拉替尼的可行性。
病例介绍
A 57-year-old Japanese man with a chief complaint of hoarseness visited the Otolaryngology Department at our hospital. A contrast-enhanced computed tomography (CT) scan showed a tumor, with its major axis measuring approximately 40 mm in the left upper lobe of the lung. The hilar and mediastinal lymph nodes were also swollen (Fig.1a). Primary lung cancer was suspected, and the patient was directed to the Department of Respiratory Medicine on the same day that he was admitted to the Otolaryngology Department. He was diagnosed with lung adenocarcinoma, which was confirmed by bronchoscopy. We performed transbronchial lung biopsy (TBLB) for the primary lesion in the left upper lobe and endobronchial ultrasonography-guided transbronchial needle aspiration in the mediastinal lymph nodes 1 week after the first visit. Genetic mutation testing was not performed because the sample was insufficient. Subsequently,18F-fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) was performed, and abnormal accumulation was observed in the longitudinal hilar lymph nodes (#4L, #5, #10L), vertebral body, and left pleura. The results of the18F-FDG PET/CT and other findings led to the diagnosis of lung adenocarcinoma [cT2bN2M1c (PUL, OSS); stage IVB]. We recommended rebiopsy considering the possibility of a genetic mutation, but the patient refused the examination because of strong coughing during the first bronchoscopy and progressive symptoms of hoarseness. The patient strongly desired an early treatment, so we initiated first-line therapy with cisplatin (75 mg/m2) and pemetrexed (500 mg/m2) 3 weeks after the first visit. However, the patient developed grade 2 renal dysfunction [creatinine, 1.83 mg/dL; estimated glomerular filtration rate (eGFR), 31.23 mL/min/1.73 m2], making it difficult to continue the therapy (Fig.1b). We informed the patient about the need for a second bronchoscopy for consideration of further treatment and obtained his consent. Bronchoscopy was performed again, and the patient was diagnosed with ALK-positive NSCLC (immunohistochemistry, 3+; fluorescencein situhybridization, 56%). In addition, progressive disease was noted (Fig.1c). Development of progressive disease required approximately 9 months, and cisplatin and pemetrexed were administered over four cycles, after which pemetrexed alone was administered over five cycles. Thereafter, second-line therapy with alectinib (300 mg/day) was initiated. Three months after starting alectinib, chest CT showed that the primary lesion had shrunk, and we judged it to be a partial response, but the ground-glass opacities and infiltration continued to spread on both sides (Figs.1d,2). At this time, the patient complained of dyspnea on exertion, and his saturation of percutaneous oxygen was approximately 82% in room air. Blood gas analysis showed that the partial pressure of arterial oxygen was 58.2 torr, indicating respiratory failure. A pulmonary function test revealed restrictive ventilatory impairment, with a vital capacity (VC) of 2.11 L and a %VC of 57.1%. A diffuse lung capacity for carbon monoxide (DLCO) of 4.84 mL/min/mmHg and a %DLCO of 22.8% indicated diffusion disorder. Bronchoalveolar lavage fluid (BALF) (Fig.3a) and TBLB samples (Fig.3b) were obtained at this time. The BALF showed an increased lymphocyte ratio (34.4%), and pathological analysis of the TBLB specimen revealed an organizing pneumonia (OP)/nonspecific interstitial pneumonia (NSIP) overlapping pattern. On the basis of the chest CT results, we suspected alectinib-induced DILD. However, we also considered respiratory infection or cancerous lymphangiopathy with cancer progression in the differential diagnoses. Laboratory testing revealed a white blood cell count of 9300/µL and a C-reactive protein level of 1.41 mg/dL. The BALF culture results were negative. The BALF was lymphocyte dominant, and no findings suggestive of cancer infiltration were observed in the TBLB specimen. On the basis of these results, we excluded the other conditions evaluated in the differential diagnosis. Our final diagnosis was alect

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