The MRD-Negativity Rate Measured By Flow Cytometry after the 1st and the 2nd Induction Course Among CR AML Patients from Different Cytogenetic Subgroups Does Not Differ Though the Morphological CR Achievement Does
Authors: Parovichnikova Elena , Troitskaya Vera V. , Galtseva Irina V. , Lobanova Tatiana I. , Davydova Yuliya O. , Kapranov Nikolay M. , Sokolov Andrey N. , Kokhno Alina V. , Tivikov Roman V. , Lukyanova Irina A. , Obukhova Tatiana N. , Savchenko Valery G. 
Published: October 2019

Abstract
Background. The recent ELN recommendations (2017) have introduced new criteria of response in AML - complete remission with MRD-negativity (CR/MRD-neg). It's a well-known fact that AML with different cytogenetics has different chemosensitivity, and so - CR rate in patients with favorable, intermediate or poor cytogenetic markers substantially differs. MRD negativity corresponds to more favorable long-term results in CR patients, but it's not clear whether the MRD-negativity rate is the same in favorable, intermediate or poor risk AML pts. As it is still poorly understood whether the high risk AML patients need classical «7+3» induction, we introduced a new approach for this cohort of patients - prolonged low-dose cytostatic exposure after hypomethylating priming.
Aim. To evaluate the MRD-negativity in CR AML patients from different cytogenetic subgroups after the first classical non-intensive induction: «7+3», «Aza+7+3», «Aza-Ida-Ara-C», and the second induction differed by intensity.
Materials and patients. 83 AML patients with a median age of 37 y.o. (17-59), m/f 31/52, after achieving CR (69 pts) were included in the MRD study in the National Research Center for Hematology. From March 2016 till Dec 2017, 49 pts disregarding cytogenetic risk were treated with «7+3» as the first induction course (Dauno 60 mg/m2 1-3 days, Ara-C 100 mg/m2 bid 1-7 days). The second induction course for these pts was «7+3» with continuous Ara-C infusion (200 mg/m2 1-7 days). Since Dec 2017 till July 2018 in all patients epigenetic priming with 3 days of Azacitidine (75 mg/m2) was applied additionally in order to obtain the cytogenetic results prior to cytostatic exposure. All patients were tested by molecular markers (FLT3, CEBPa, mNPM1) but this data did not influence the treatment choice. 8 pts from favorable/intermediate cytogenetic risk group after Aza-prephase have got «7+3» (Dauno 60 mg/m2 4-6 days, Ara-C 200 mg/m2 by continuous infusion, 4-10 days), and 13 pts from poor cytogenetic risk group (complex, -7,-5, inv3, monosomy) after Aza-priming received prolonged low-dose schedule (Ida 3 mg/m2 4-10 days, Ara-C 10 mg/m2 bid sc 4-17 days). The second induction course for favorable/intermediate risk group was FLAG-Ida, for poor risk group - the same as the 1st induction. MRD testing was performed by 6-color flow cуtometry with FACS Canto II (BD) machine after 1st and 2nd chemotherapy courses. The rate of MRD-negativity was calculated among CR patients.
Results. Totally among 83 patients CR was achieved in 83%, early death was registered in 6% and refractory AML was diagnosed in 11%. The induction and MRD testing results after the 1st and the 2nd induction course according to prognostic group and treatment arm are demonstrated in the Table.1. Morphological CR rate differs substantially in patients from favorable/intermediate and poor risk by any treatment approach (p=0,04). The prolonged low-dose induction with Aza-prephase induced the same numbers of CRs as the classical «7+3»: 69% vs 46% (p=0,42). Epigenetic priming provided identical MRD-negative CRs in all treatment and cytogenetic groups: 75% vs 62% in favorable/intermediate risk group (p=0,29), 67% vs 50% in poor risk (p=0,62). The second intensive induction with Flag-Ida in favorable/intermediate risk group did not increase the portion of MRD-neg CR pts in comparison with «7+3»: 88% vs 71% (р=0,14). Early relapse rate through all groups showed comparable results.
Conclusion. Though the morphological CR achievement is highly influenced by cytogenetic subgroup in AML, the MRD-negativity rate among CR pts by flow cytometry after the 1st and the 2nd induction course is similar. The de-intensification of induction for poor risk group did not lead to the deterioration of therapy efficacy and provided the same rate of MRD-negativity. The 2nd intensified induction after «7+3» did not increase the MRD-negativity in CR pts.

Disclosures
No relevant conflicts of interest to declare.