Impact Of Anthracycline Dose Intensification On Minimal Residual Disease and Outcome Of Core Binding Factors Acute Myeloid Leukemias
Authors: Prebet Thomas , Bertoli Sarah , Delabesse Eric , Mozziconacci Marie-Joelle , Etienne Anne , Recher Christian , Huguet Françoise , Vey Norbert 
Published: October 2019

Abstract

Introduction
Acute myeloid leukemias (AML) harboring core binding factor (CBF) alterations (namely t(8;21), inv(16), t(16;16) or variants) are associated with a favorable outcome and are highly sensitive to repeated cycles of high dose cytarabine (HD-Cy, Byrd Blood 2002). Evaluation of minimal residual disease (MRD) by RQ-PCR after first consolidation was recently shown as an important prognosis indicator in CBF AML patients (pts) treated with induction chemotherapy followed by repeated cycles of HD-Cy (Jourdan et al Blood 2013). In the recent years, several studies showed that dose intensification of anthracyclins (Daunomycin 90mg/m2 3 days vs. 45mg/m2) improved survival of younger AML patients (Fernandez NEJM 2009 Lowenberg NEJM 2009). However, there is only limited data for CBF AML. In the present report, we analyzed the MRD levels and the outcome of patients treated either with standard dose or intensified daunomycin (DNR) induction regimens.

Patients and Methods
This is a retrospective multicenter study. Patients were included consecutively. CBF AML was defined by presence of CBF alteration either by karyotyping, FISH, or RQ-PCR. All pts were treated by induction chemotherapy associating cytarabine 200mg/m2/d day 1-7 CIV with DNR 60mg/m2/d 3 days for patients before 2010 or DNR 90mg/m2/d 3 days between 2010 and 2012. 2 to 3 cycles of HD-Cy were planned for consolidation therapy. For pts after 2005, CBF transcript was assessed by RQ-PCR before induction, after induction (MRD1), cycle 1 (MRD2), and cycle 2 (MRD3) of consolidation. Optimal molecular response was defined as a 1000 fold reduction (3 log) of normalized CBF transcript compared to diagnosis level (Jourdan Blood 2013). Patients with less than 3 log reduction at MRD2 were eligible for allogeneic transplantation.

Results
111 patients were evaluated. It included 87 pts treated with DNR60 (37 with molecular follow-up) and 25 pts treated with DNR90 (24 with molecular follow-up). Median age was 42 years for both cohorts. Presence of t(8;21) or inv(16) was detected in 40 and 47 pts of DNR60 cohort, and 6 and 19 pts of DNR90 cohort. Median WBC and platelet counts at diagnosis were 17G/L, 47G/l in the DNR60 cohort and 10G/l, 88G/l in the DNR90 cohort. Median bone marrow blast counts were 70% and 59% respectively. CBF transcript levels at diagnosis were comparable between the 2 groups. All but one patient achieved CR in DNR60 cohort and all patients achieved CR in the DNR90 cohort. 2-years probability of overall survival were 78% and 100% respectively (p=NS). 2-years cumulative incidence of hematologic relapse were 41% and 13% respectively (p=0.04) with 2/3 of the relapses within the first year of follow-up. For patients with molecular follow-up, median CBF transcript level reduction after induction (MRD1) was 2.5 log for DNR60 and 3.7 log for DNR90 (p=0.002). After the first (MRD2) and second cycles (MRD3) of HD-Cy, difference was no longer significant 4.3 log vs. 5 (p=0.12) and 5 log vs.5 log respectively. Percentage of patients achieving optimal molecular response after induction, consolidation 1 and consolidation 2 were respectively: 36% vs. 63% (p=0.02); 75% vs. 91% (p=0.11); 83% vs. 100% (p=0.04). Achievement of molecular response after induction (MRD1) was associated with a lower probability of relapse (18% vs. 45%, p=0.04) whereas no difference was observed when MRD was evaluated after consolidation 1 (MRD2). Of note, OS and RFS of patients treated with DNR60 and with or without molecular follow-up were similar and in line with the recent publication of the French group.

Conclusion
This retrospective study suggests a benefit of dose-intensification of DNR90 over DNR60 in patients with CBF-AML in terms of early molecular responses and relapse free survival. This shows that molecular remission is a suitable surrogate for RFS in this population. Finally, it provides further evidence that the chemosensitivity of CBF AML is not restricted to HD-Cy.

Disclosures:
No relevant conflicts of interest to declare.