Is Standard Treatment (DA 3+7) Is Still Recommended As Front Line Therapy for Adult Patients with De Novo AML? the Role of Etoposide
Authors: Sabty Firas Al , Demeckova Eva , Sopko Ladislav , Weismanova Eva , Mistrik Martin 
Published: October 2019

Abstract
Abstract 4272

Background:
Early intensification of chemotherapy in the remission induction phase of patients with acute myeloid leukemia (AML) has been shown to improve the remission rate and long-term leukemia-free survival.

Aim:
This trail is designed to assess the role of etoposide in the induction remission schedules in younger patients with de novo AML.

Methods:
Newly diagnosed previously untreated younger patients (15–60 years) with AML were randomly assigned to 3 groups; group A received conventional treatment DA 3+7 [daunorubicin 60 mg/m2/day (days 1–3) and cytosine arabinoside (Ara-C) 200 mg/m2/day by continuous iv infusion (days 1–7)], group B received conventional treatment [ Ara-C 100 mg/m2/day by continuous iv infusion (days 1–10) + daunorubicin 50mg/m2/day (days 1,3,5)] + etoposide (50 mg/m2/day; days 1–5), and group C received high dose AraC (HD-AraC) 3g/m2/12 hrs. (days 1, 3, 5 and 7) + daunorubicin and etoposide in the same dose as above (as in group B). All patients were treated in the Department of Hematology, University Hospital, Bratislava. Informed consents were obtained. RT-PCR was done to determine the expression of topoizomerase I, II-alpha and II-beta genes in bone marrow samples at diagnosis. The data were analyzed using SPSS statistical software versions 16.0, 2008.

Results:
Between September 2000 and August 2011, 128 patients were recruited (group A = 27, group B = 57, and group C = 44). There was no statistically significant difference in age, sex, performance state, AML subtype (M4-5), WBC count and cytogenetic risk distribution in the 3 groups. Patients have been followed for a median of 92 months. After 1 course of induction the complete remission (CR) rate was 55.6%, 75.4% and 81.8% in group A, B and C respectively (P = 0.048). Group A vs. B (P = 0.025), group A vs. C (P = 0.027), group B vs. C (P = 0.81). Induction toxicity profile and grade was similar in all groups except for conjunctivitis grade 2 and 3 which was higher in group C. The 5 year’s overall survival (OS) was 17%, 41% and 33% (P = 0.36) and disease free survival (DFS) was 25%, 44% and 35% (P = 0.21) in group A, B and C respectively. There was statistically significant improvement in OS but not DFS in patient receiving etoposide (P < 0.00001). Overexpression of topoisomerase I and II genes were detected in 12/19 (63%) and 14/19 (74%) patients at diagnosis; respectively. Topoisomerase II-alpha and II-beta genes were increased by a median of 4.1 (range 1.7–27.3) and 2.9 (range 2.4–5.1) than normal; respectively.

Conclusion:
the addition of etoposide to standard treatment of AML can improve the rate of complete remission and outcome in adult de novo AML patients. The incorporation of etoposide to HD-AraC regimens during induction may further improve the rate of CR without effect on outcome (DFS and OS). Measurement of topoisomerase II gene expression at diagnosis can help in selecting patients who will benefit from the addition of etoposide.

Disclosures:
No relevant conflicts of interest to declare.