Abstract
BACKGROUND: Concomitant NPM1 and FLT3 mutation occurs in 20% of AML patients. Molecular response and achievement of negative minimal residual disease (MRD) are strong predictors of long-term outcome. However, little is known about the dynamics of molecular response in NPM-1 and FLT-3 double positive mutations.
OBJECTIVE: To assess the dynamics of molecular response to treatment in AML adult patients with concomitant FLT3 and NPM1 mutations.
DESIGN: Retrospective single center study.
SETTING: This study was approved by the institutional review board of American University of Beirut Medical Center.
PATIENTS OR OTHER PARTICIPANTS:
Twelve consecutive newly diagnosed (n=11) or relapsed (n=1) AML patientsreceived Idarubicin/cytarabineinduction and one or two consolidation(s) (Table 1). Ten patients received allogeneic stem cell transplant (allo-SCT) followed by post-transplantsorafenibmaintenance. Median follow-up was 11.5 (6-27) months. All transplanted patients remain alive and disease free.
INTERVENTIONS: FLT3 mutation was tested on DNA using a qualitative method with a sensitivity of0.01%. NPM-1 mutation was tested on cDNA using a qualitative or a quantitative RT-PCR with a sensitivity of 0.01% and0.008 NCN respectively. Patients were tested at diagnosis, after induction, after each consolidation, before and at days 30, 60 and 100 afterallo-SCT.
MAIN OUTCOMES MEASURES: Kinetics of NPM1 and FLT3 molecular response.
RESULTS:
After induction, FLT3 became negative in all tested patients (n=10). After first consolidation, FLT-3 remained or became positive in 10/11 tested patients whereas a molecular relapse was noted in one patient who developed a hematological relapse and rapidly died. No molecular positivity for FLT-3 was noted later on, whether after second consolidation or post-transplant. Conversely, NPM-1 mutation became negative in 2 out of 12 tested patients after induction, in 1 additional patient after first consolidation and in 6 additional patients afterallo-SCT, mostly after startingsorafenib. NPM-1 MRD value remained elevated in 3 out of 4 patients with quantitative assessment at diagnosis and post induction.
CONCLUSION: FLT3 become negative early after induction while NPM1 negativity lags behind. Persistent NPM-1 MRD does not seem to predict post-transplant outcome and may indeed become negative after sorafenib. These results need confirmation in larger studies.
Dynamics of NPM1 and FLT3 Molecular Response
No relevant conflicts of interest to declare.
