Osimertinib-Associated Severe Aplastic Anemia: A Case Report

Abstract Background Osimertinib is a third-generation, oral EGFR tyrosine kinase inhibitor designed to irreversibly inhibit EGFR-activating mutations as well as the T790M mutation responsible for resistance to earlier-generation EGFR-TKIs. While its safety profile is generally favorable, severe hematologic toxicities are extremely uncommon. Aplastic anemia associated with Osimertinib has been reported only rarely, and the underlying mechanisms, clinical course, and outcomes remain insufficiently described. Case Presentation We report the case of a 65-year-old non-smoking woman diagnosed with metastatic NSCLC, adenocarcinoma histology. Initial molecular testing revealed PD-L1 <1% and wild-type EGFR and ALK, and she was treated with carboplatin–pemetrexed induction followed by pemetrexed maintenance. After disease progression, the re-biopsy with histology was done with the subsequent next-generation sequencing identified an activating EGFR exon 18 mutation (c.2156G>C; p.Gly719Ala) with concurrent TP53 mutation and EGFR amplification. Osimertinib (80 mg daily) was initiated. Twelve weeks later, the patient developed Grade 1 radiologic pneumonitis followed by acute-onset profound pancytopenia complicated by febrile neutropenia and hemorrhagic manifestations. Despite aggressive supportive care, including transfusions, broad-spectrum antimicrobials, G-CSF, and immunosuppressive therapy with cyclosporine, the patient developed subarachnoid hemorrhage and died. Conclusion This case highlights a rare but fatal complication of osimertinib-associated aplastic anemia with immune-mediated bone marrow failure. Clinicians should maintain a high index of suspicion for severe hematologic toxicity in patients receiving EGFR-TKIs, particularly when unexplained cytopenias develop. Early recognition and prompt multidisciplinary management are critical.