Karyotypic Instability Is Common in t(8;21) AML at Relapse.

The t(8;21) is one of the most frequent chromosomal translocation in acute myeloid leukemia (AML). The t(8;21) AML is commonly associated with a favorable prognosis in regard to overall survival (OS) as well as high complete remission (CR) rate. However, approximately 35–45% of patients in first CR will relapse within 5 years. In t(8;21) AML, a worse outcome has been reported in patients with a high presenting white blood cell count, expression of CD56, and activating mutation of c-Kit (D816V). The clinical outcome of t(8;21) AML in first relapse have not been clarified. Further, factors predicting the outcome of patients in first relapse have not been defined. In this study, we evaluated the clinical features, the prognostic significance of c-Kit (D816V) mutation and karyotype instability in 14 relapsed patients among 32 de novo t(8;21) AML patients treated in our institution during the period 1987 to 2006. These 32 patients’ ages ranged from 15 to 73 years (median, 46 years) and they were classified as RAEB-T (n=2), M1 (n=2) and M2 (n=28) according to the FAB classification. Another additional cytogenetic aberrations at diagnosis were loss of Y (n=5), del(9q) (n=3), del(7q) (n=1), and trisomy 4 and 6 (n=1). Of the 32 patients, 14 (44%) were treated with BHAC-DMP (behenoylcytosine arabinoside, daunorubicin, 6-mercaptopurine, and prednisolone) induction therapy and 18 (56%) were treated with induction therapy consisted of an idarubicin or daunorubicin in combination with cytarabine (200mg/m2 for 7 days). For post remission therapy, 26 (82%) were received sequential multiagent chemotherapy and 6 (18%) were received high dose cytarabine alone. All patients achieved first CR (100%), median OS and disease-free survival (DFS) was 5.1 years and 2.4 years, respectively. 14 (44%) had a relapsed and the median duration from initial diagnosis to relapse amounted to 10.5 months (range, 3.8 months to 2.4 years). Among the 14 relapsed patients treated with salvage therapy, 9 (64%) of patients achieved second CR and median OS and DFS after first relapse was 2.0 years and 1.0 year. 4 patients (12%) with c-Kit (D816V) mutation at first diagnosis relapsed within 12 months with the same mutation and died within 2.2 years. Karyotype examination at first relapse were performed in 12 patients and additional karyotypic abnormalities were found in 6 patients. Three or more complex aberrations involving del(5q), del(6q), del(7q) or del(9q) were found in all of 6 patients. Among 6 patients showing karyotypic evolution (KE), 5 achieved second CR and relapsed again shortly. Two patients with KE had c-Kit D816 mutation at diagnosis, however, c-Kit mutations of exon 17 and 8 were not detected in 4 patients with KE at diagnosis and during the course of disease. In conclusion, karyotypic instability is common in t(8;21) AML at relapse and is not associated with c-Kit mutation. Karyotypic instability may contribute to the development of refractoriness of AML to chemotherapy.