DIFFERENCES IN EX-VIVO CHEMOSENSITIVITY TO ANTHRACYCLINES IN FIRST LINE ACUTE MYELOID LEUKEMIA

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Juan Eduardo Megias-Vericat *
David Martínez-Cuadrón
Joaquin Martínez López
Juan Miguel Bergua
Mar Tormo
Josefina Serrano
Ataulfo González
Jaime Pérez de Oteyza
Susana Vives
Belen Vidriales
Pilar Herrera
Juan Antonio Vera
Aurelio López Martínez
Adolfo De la Fuente
María Lourdes Amador
José Ángel Hernández-Rivas
María Ángeles Fernández
Carlos Javier Cerveró
Daniel Morillo
Pilar Hernández Campo
Julián Gorrochategui
Daniel Primo
José Luis Rojas
Margarita Guenova
Joan Ballesteros
Miguel Ángel Sanz
Pau Montesinos
(*) Corresponding Author:
Juan Eduardo Megias-Vericat | megias_jua@gva.es

Abstract

BACKGROUND: Induction schedules in acute myeloid leukemia (AML) are based on combinations of cytarabine and anthracyclines. The choice of the anthracycline employed has been widely studied in multiple clinical trials showing similar complete remission rates.

MATERIALS AND METHODS: Using an ex vivo test we have analyzed if a subset of AML patients may respond differently to cytarabine combined with idarubicin, daunorubicin or mitoxantrone.  Bone marrow (BM) samples of 198 AML patients were incubated for 48 hours in 96 well plates, each well containing different drugs or drug combinations at different concentrations. Ex vivo drug sensitivity analysis was made using the PharmaFlow platform maintaining the BM microenvironment. Drug response was evaluated as depletion of AML blast cells in each well after incubation. Annexin V-FITC was used to quantify the ability of the drugs to induce apoptosis, and pharmacological responses were calculated using pharmacokinetic population models.


RESULTS: Similar dose-respond graphs were generated for the three anthracyclines, with a slight decrease in EC50 with idarubicin (p=1.462E-06), whereas the interpatient variability of either drug was large. To identify those cases of selective sensitivity to anthracyclines, potency was compared, in terms of area under the curve. Differences in anthracycline monotherapy potency greater than 30% from 3 pairwise comparisons were identified in 28.3% of samples. Furthermore, different sensitivity was detected in 8.2% of patients comparing combinations of cytarabine and anthracyclines.


DISCUSSION: A third of the patients could benefit of the use of this test in the first line induction therapy selection, although it should be confirmed in a clinical trial specifically designed.


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