Incidence of acute promyelocytic leukemia during gefitinib treatment for advanced non-small cell lung cancer

Abstract

7189 Background: Gefitinib is an orally active epidermal growth factor receptor tyrosine kinase inhibitor. The introduction of gefitinib had a great clinical impact in the treatment of advanced and chemotherapy-refractory non-small cell lung cancer (NSCLC). Although short-term adverse events of gefitinib such as skin rash, hepatotoxicity, and interstitial lung disease have been identified, long-term adverse events have not been clearly elucidated. Method: We retrospectively reviewed 108 cases of NSCLC treated with gefitinib between November 2001 and December 2004 in our single institution, and they were included in our gefitinib cohort. Results: We found three cases of acute promyelocytic leukemia (APL) among 108 NSCLC patients treated by gefitinib. Durations from the beginning of initial gefitinib treatment to onset of APL were 15.5, 22 and 25 months. All three cases showed t(15;17) rearrangement and responded well to all-trans retinoic acid. Our gefitinib cohort included 67 men and 41 women with a median age of 60.5 years (range, 28 to 81 years), 92 (85%) adenocarcinoma including three bronchioloalveolar cell type, 10 (9%) squamous cell carcinoma, two adenosquamous cell carcinoma, two large cell neuroendocrine carcinoma, and two large cell carcinoma. Total person-years observed from gefitinib initiation until November 30, 2004 or the last day of follow-up was 75. Crude incidence rate of APL in our cohort based upon Poisson distribution was 2309 (95% confidence interval (CI): 824–11690) per 100,000. In contrast, crude incidence of whole leukemia (coded as ICD10 C91–95) in Okayama prefecture during 1996 to 2000 was 6.3 (95% CI: 5.8–6.8) per 100,000. Therefore, crude incidence rate ratio was 639.9 (95% CI: 131.6–1878.9, exact p-value < 0.0001), indicating extremely high incidence of APL among NSCLC patients who received gefitinib treatment. Conclusions: Although we cannot exclude an effect of other cytotoxic agents as well as radiotherapy, high incidence of APL in our cohort suggest that gefitinib may induce APL. Further clarification of clinical and biological association between gefitinib and APL is required. No significant financial relationships to disclose.