Severe Aplastic Anemia during Osimertinib Therapy in a Patient with EGFR Tyrosine Kinase Inhibitor–Resistant Non–Small Cell Lung Cancer
Authors: Hiroaki Ogata, Yuzo Yamamoto, Taishi Harada, Yoichi Nakanishi, Isamu Okamoto, Eiji Iwama, Koji Kato, Yoshinao Oda
Journal: Journal of Thoracic Oncology (2017)

Osimertinib (Tagrisso [AstraZeneca, Wilmington, DE]) is a third-generation, irreversible tyrosine kinase inhibitor (TKI) of the EGFR with selectivity for mutant forms of the receptor harboring both an activating mutation and the T790M resistance mutation.1Cross D.A. Ashton S.E. Ghiorghiu S. et al.AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.Cancer Discov. 2014; 4: 1046-1061Crossref PubMed Scopus (1436) Google Scholar It has shown marked antitumor activity with tolerable toxicity in patients with NSCLC positive for the T790M mutation of EGFR in whom resistance to EGFR TKIs such as gefitinib, erlotinib, and afatinib has developed.2Jänne P.A. Yang J.C. Kim D.W. et al.AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.N Engl J Med. 2015; 372: 1689-1699Crossref PubMed Scopus (1625) Google Scholar We now report a case of severe aplastic anemia in a patient with advanced NSCLC treated with osimertinib. Stage IV lung adenocarcinoma (T2aN2M1a) harboring the activating L858R mutation of EGFR was diagnosed in a 78-year-old Japanese woman with no history of smoking. She was treated with the first-generation EGFR TKI gefitinib for 14 months and then with docetaxel for 2 months. At the time of disease progression during gefitinib treatment, a repeat tumor biopsy revealed the T790M mutation of EGFR in addition to the L858R mutation. Osimertinib was subsequently administered orally at a dose of 80 mg daily. A computed tomography scan of the chest revealed marked tumor shrinkage after treatment for 29 weeks. After 31 weeks of osimertinib treatment, however, profound pancytopenia developed (Table 1). Although osimertinib was immediately discontinued, the pancytopenia worsened 3 weeks later (see Table 1). All drugs were reviewed. Agents administered before and during treatment with osimertinib included Lactobacillus bifidus, ethyl icosapentate, eldecalcitol, lansoprazole, amlodipine, and sitagliptin phosphate hydrate, all of which had been initiated at least 16 months before the start of osimertinib treatment. On the basis of concern that the pancytopenia was secondary to drug effects, all current drugs were discontinued, prophylactic antibiotics and filgrastim were initiated, and red blood cell and platelet transfusions were administered. A biopsy showed bone marrow to be severely hypocellular with few erythroid and myeloid cells at any stage of differentiation as well as hardly any identifiable primitive progenitor stem cells (Fig. 1). A diagnosis of osimertinib-induced severe aplastic anemia was therefore established.3Camitta B.M. Thomas E.D. Nathan D.G. et al.Severe aplastic anemia: a prospective study of the effect of early marrow transplantation on acute mortality.Blood. 1976; 48: 63-70Crossref PubMed Google Scholar The patient received immunosuppressive therapy (cyclosporine A at 250 mg daily) for 1 month with no benefit. Although she continued to require red blood cell and platelet transfusions every 1 to 2 weeks (see Table 1), her clinical condition remained stable for 12 months after discontinuation of osimertinib. The patient provided written informed consent to publication of this case report.Table 1Hematologic Parameters of the Patient before, during, and after Osimertinib TreatmentTime after Initiation of Osimertinib Treatment, wkWhite Blood Count, 109 Cells/LAbsolute Neutrophil Count, 106 Cells/LPlatelets, 109 Cells/LHemoglobin Level, g/L0 (baseline)4.0174628411.1245.2363618610.4312.0899408.4342.2495117.9851.7425126.8Note: Treatment was discontinued at 31 weeks. Open table in a new tab Note: Treatment was discontinued at 31 weeks. Osimertinib has been shown to have an acceptable safety profile at a dose of 80 mg daily, with severe hematologic adverse events being infrequent (pancytopenia occurred in a single patient at the 80-mg dose).2Jänne P.A. Yang J.C. Kim D.W. et al.AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.N Engl J Med. 2015; 372: 1689-1699Crossref PubMed Scopus (1625) Google Scholar In the present patient, profound and persistent pancytopenia developed 31 weeks after the onset of osimertinib administration, with a bone marrow biopsy yielding a diagnosis of severe aplastic anemia. Symptoms of drug-induced aplastic anemia have been found to develop from days to months after initiation of treatment with the offending drug.4Vandendries E.R. Drews R.E. Drug-associated disease: hematologic dysfunction.Crit Care Clin. 2006; 22: 347-355Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar The present patient had taken L. bifidus, ethyl icosapentate, eldecalcitol, lansoprazole, amlodipine, and sitagliptin phosphate hydrate for more than 2 years, with none of these agents having previously been associated with aplastic anemia. Osimertinib was therefore most likely the cause of aplastic anemia in the proband, although other causes cannot be completely ruled out. As far as we are aware, this would be the first report of a case of osimertinib-induced severe aplastic anemia. Aplastic anemia is a rare hematopoietic stem cell disorder that results in pancytopenia and hypocellularity of bone marrow and can be acquired, hereditary, or idiopathic. Acquired aplastic anemia has been causally associated with many agents including drugs. The three major causes of acquired aplastic anemia are direct toxicity, metabolite-driven toxicity, and immune-mediated mechanisms,5Young N.S. Maciejewski J. The pathophysiology of acquired aplastic anemia.N Engl J Med. 1997; 336: 1365-1372Crossref PubMed Scopus (4) Google Scholar with the pathogenesis of osimertinib-associated aplastic anemia being unknown. Other EGFR TKIs have not been found to induce irreversible bone marrow failure, suggesting that EGFR inhibition itself is not a cause of aplastic anemia. In conclusion, physicians should be aware of the risk for aplastic anemia in patients treated with osimertinib. Such patients should therefore be monitored carefully, and the frequency of this severe adverse effect should be determined.