The Impact of FLT3-ITD and NPM1 Mutational Status on the Outcome of ATRA Therapy in Patients with Non-APL AML: Results of the UK MRC AML12 Trial
Authors: Gale Rosemary , Hills Robert , Green Claire , Patel Yashma , Gilkes Amanda , Lazenby Michelle , Wheatley Keith , Linch David C. , Burnett Alan 
Published: April 2020

Abstract
Background: The prognostic value of mutations in NPM1 and FLT3-ITD is well known. Previously, Schlenk et al. (ASH 2007, Abstract 297) have reported that survival was significantly improved in a group of older patients who were NPM1 mutant/FLT3-ITD Wild Type when treated with ATRA; there was no significant improvement in overall survival in patients who were either NPM1 WT or FLT3-ITD mutant. We report here on a subset of the UK MRC AML12 trial who have been characterised for FLT3-ITD and NPM1 and who were randomised between ATRA in induction and no ATRA.
Patients and Methods: A total of 393 patients were identified and characterised. The median age was 46 years (range 16–68); NPM1 and FLT3-ITD status were determined using methods previously reported (Gale et al. Blood 2008). Median follow-up for survival is 7.1 years. The overall results of the ATRA randomisation have previously been reported (Burnett et al. ASH 2002 Abstract 529) and show no benefit for ATRA treatment. All patients were treated with Daunorubicin, Ara-C and Thioguanine (DAT) with a randomisation between two doses of Ara-C, and were randomised to receive, or not, ATRA 45mg/m2/d during courses 1 and 2 of chemotherapy. ATRA was given for a median of 56 days.
Results: A total of 143 (36%) patients had an NPM1 mutation and 93 (24%) had a FLT3-ITD mutation. No significant interactions were seen between either NPM1 status, or FLT3-ITD status and ATRA treatment with respect to complete remission, overall survival or relapse free survival (see Table). Estimates of the hazard ratios (HR) for the interaction between FLT3-ITD and ATRA, and NPM1 and ATRA for overall survival were 0.75 (95% CI 0.42–1.32 p=0.3) and 0.66 (95% CI 0.38–1.12 p=0.13), where an HR&lt;1 indicates greater benefit for ATRA in the mutant group. Looking at patients stratified by both FLT3-ITD and NPM1 status (84 NPM1+ITD−, 34 NPM1−ITD+, 59 NPM1+ITD+, 216 NPM1−ITD−) showed no significant interaction (p=0.4 for heterogeneity of ATRA effect between the four groups, p=0.5 for difference in treatment effect between FLT3 WT/NPM1 mutant and others). The results were not significantly different if restricted to patients with a normal karyotype only.
Conclusions: In this randomised comparison of ATRA therapy in younger patients with AML there were no significant interactions. Any impact of NPM1 or FLT3-ITD status on treatment with ATRA is likely to be relatively small or non-existent.
CR OS at 5years RFS at 5 years ATRA No ATRA OR, 95% CI ATRA No ATRA HR, 95% CI ATRA No ATRA HR, 95% CI NPM1 WT 80% 86% 1.59 (0.82–3.09) 36% 35% 1.07 (0.79–1.45) 33% 29% 1.05 (0.76–1.46) NPM1 Mutant 91% 89% 0.81 (0.27–2.43) 57% 44% 0.70 (0.45–1.11) 49% 39% 0.83 (0.63–1.31) Interaction with ATRA p=0.3 0.1 0.4 FLT3 WT 83% 87% 1.46 (0.77–2.74) 45% 42% 0.97 (0.73–1.30) 42% 35% 0.87 (0.64–1.18) FLT3 ITD 89% 88% 0.89 (0.25–3.17) 40% 25% 0.73 (0.44–1.21) 32% 26% 0.89 (0.53–1.50) Interaction with ATRA p=0.5 0.4 0.9