In Acute Myeloid Leukemia, the Use in Induction of Standard Dose Arac Is Associated with a Better Quality of Response as Compared to An Induction Regimen Containing High Dose Arac.
Authors: Maurillo Luca , Buccisano Francesco , Spagnoli Alessandra , Del Principe Maria Ilaria , Neri Benedetta , Sarlo Chiara , Del Poeta Giovanni , Coco Francesco Lo , Amadori Sergio , Venditti Adriano 
Published: October 2019

Abstract
Abstract 1584
Poster Board I-610
The clinical advantage of using high-dose cytarabine (HDARAc) in induction chemotherapy for acute myeloid leukemia (AML) is still controversial. The purpose of our study was to explore the impact on the “quality of response” of an induction regimen containing standard dose (SD) ARAc versus HDARAc, by measuring minimal residual disease (MRD) once CR was achieved. MRD was determined by multiparametric flow cytometry on bone marrow samples collected at the end of induction and consolidation therapy. The threshold for MRD negativity was set below the number of 3.5×10-4 residual leukemic cells. We evaluated 111 patients with de novo AML, enrolled sequentially in DCE arm of AML10 (n=40) and in AML12 (n=71) EORTC/GIMEMA randomized trials between 1995 and 2007. In DCE arm of AML10, induction treatment combined ARAc (100 mg/m2 day 1-10), etoposide (50 mg/m2 day 1-5), and on days 1,3,5, daunorubicin (50 mg/m2). In AML12 trial, patients received the same treatment of DCE arm except for ARAc dose that was 100 mg/m2 day 1-10 or 3000 mg/m2/q12 hrs on days 1,3,5, and 7 according to randomization. As consolidation, all patients received ARAc (500 mg/m2/q12 hrs day 1-6) and daunorubicin (50 mg/m2, day 4-6). Median age was 45 yrs (range 18-60), 65 males and 46 females. Seventy-five patients were treated on SDARAc regimen and 36 on HDARAc regimen. The two groups were well balanced in terms of FAB classes, WBC count, cytogenetics, Pgp-170 expression, FLT3 and NPM1 mutation and post-remission transplant procedure (autologous or allogeneic) delivered. After induction, we observed a significantly higher frequency of MRD negativity in SDARAc arm vs HDARAc arm (82.% vs 18%, p=0.02). After consolidation, this figure was confirmed (84% vs 16%, p=0.01). At this stage, 3 further patients treated on the SDARAc arm, became MRD negative, whereas none in the HDARAc arm did so. Overall, median level of MRD was significantly lower in SDARAc group both after induction (1.1×10-2 vs 5.4×10-2, p=0.015) and consolidation (9×10-3 vs 3×10-2, p=0.02). Based on the combination of MRD status after consolidation and ARA-C schedule delivered, we identified 4 different groups of patients. Five years OS for SDARAc-MRDneg, HDARAc-MRDneg, SDARAc-MRDpos and HDARAc-MRDpos was 67%, 33%, 21% and 24%, respectively (p<0.0001). Similarly, 5 years DFS for SDARAc-MRDneg, HDARAc-MRDneg, SDARAc-MRDpos and HDARAc-MRDpos was 67%, 33%, 13% and 26%, respectively (p<0.0001). Since calculation of survival estimates is influenced by the occurrence of toxic events, 3 patients in the HDARAc-MRDneg group died because of complications, cumulative incidence of relapse (CIR) was also evaluated. Five years CIR for SDARAc-MRDneg, HDARAc-MRDneg, SDARAc-MRDpos and HDARAc-MRDpos was 20% (95% CI, 19-21), 17% (95% CI, 12-24), 75%(95% CI, 74-76) and 57% (95% CI, 55-60), respectively (p<0.0001); analysis of CIR confirmed the prognostic importance to achieve a MRD negative status at the end of consolidation, whatever the regimen used. In conclusion, delivery of an induction regimen containing daunorubicin, etoposide and SDARAc given for 10 days, results in a more efficient clearance of leukemic burden compared to a similar regimen HDARAc based. Such superior efficiency translates into a better “quality” of response, as demonstrated by the more frequent achievement of a MRD negative status, and then into a more favorable outcome. In addition, it should also be considered that the lower probability to gain a condition of MRD negativity by giving HDARAc, might further be jeopardized by fatal toxicities.

Disclosures
No relevant conflicts of interest to declare.