Until now, the development of personalized medicine in oncology has relied on the use of
somatic biomarkers to help therapists choose the right molecule(s) to administer, based
on the genetic and molecular profile of each hematological disease. In this project,
investigators propose to extend the strategy of therapeutic individualization to the
field of dosage targeting. Today, azacytidine is a standard treatment for patients with
acute myeloid leukemia (AML) and/or myelodysplastic syndromes (MDS), usually as
monotherapy. According to the treatment regimen, azacytidine is prescribed at a standard
dose (DS=75mg/m²/d), administered subcutaneously every day for 7 days. The treatment
cycle is repeated every 28 days.
No study has evaluated the relevance of "a priori" dose adjustment on an individual
basis, according to each patient's pharmacogenetic data. In current practice, doses are
adapted a posteriori, and reduced empirically, following the occurrence of observed
toxicity (6 to 71% of patients) (Schuck A et al. 2017). This ex-post adjustment in the
face of grade 3-4 toxicity is a loss of chance for the patient. Similarly, under-dosing
patients for fear of toxicity is another loss of chance. Investigator's hypothesis is
that the optimal dose of azacytidine depends not only on the characteristics of the
patient's pathology (risk groups including cytogenetic and molecular biology data), but
also on the patient's individual characteristics (genetic status of metabolic enzymes and
transporters). A mathematical model of the PK/PD type could, on the basis of early
observations of circulating levels, be capable of rapidly predicting the pharmacodynamic
repercussions in each patient, thus enabling rapid individualization of dosages. In the
future, such a tool could make it possible to propose dosage adjustments rapidly after
treatment initiation, before toxicity occurs, by predicting azacytidine exposure levels,
themselves correlated with the patient's clinical condition.
Study design: In this open-label, paucicentric, non-randomized study, patients with AML
and/or MDS, all of whom are receiving azacytidine-based chemotherapy as part of their
standard treatment regimen, will be included. Each patient will be monitored for
toxicities (EORTC), treatment response and progression-free survival. In addition to the
standard care described above, each patient will undergo a series of constitutional
genetic investigations conducted by NGS on markers linked to azacytidine pharmacokinetics
(CDA, dCK). Another series of blood samples will be taken to calculate individual
azacytidine pharmacokinetic parameters using a Bayesian approach.
Expected results: This study should make it possible to correlate pharmacogenetics with
patient plasma exposure, and ultimately improve the molecule's efficacy/toxicity balance
by personalizing dosage regimens, which until now have been carried out on an empirical
basis.
Prospects: If the data are validated, a pre-therapeutic ADC assay could predict
azacytidine pharmacodynamics and enable individual dose and/or dosage adjustment, as is
the case with 5-FU and DPD.