Secondary Genetic Alterations and Measurable Residual Disease in Core Binding Factor Acute Myeloid Leukemia - a Study from the Acute Leukemia French Intergroup
Authors: Vasseur Loic , Duchmann Matthieu , Duployez Nicolas , Raffoux Emmanuel , Berthon Celine , Heiblig Mael , Genthon Alexis , Braun Thorsten , Leclerc Mathieu , Lebon Delphine , Chantepie Sylvain , Micol Jean-Baptiste , Lambert Juliette , Recher Christian , Chrétien Marie-Lorraine , Cluzeau Thomas , Vaidie Julien , Malfuson Jean-Valère , Uzunov Madalina , Pigneux Arnaud , Peterlin Pierre , Tarfi Sihem , Hirsch Pierre , Penther Dominique , Jourdan Eric , Celli-Lebras Karine , Preudhomme Claude , Dombret Hervé , Lambert Jérôme , Boissel Nicolas , Itzykson Raphael 
Published: December 2024

Context. Measurable residual disease (MRD) is a major prognostic factor in Core Binding Factor (CBF) AML (Jourdan et al. 2014, Döhner et al., 2022). Recurrent genetic alterations like KIT or FLT3 gene mutations have also shown prognostic relevance but little is known about their prognostic value when accounting for MRD.
Objective. We analyzed the prognostic value of recurrent genetic alterations when adjusted on early MRD response during the first line treatment of adult CBF-AML patients.
Methods. We merged data from a retrospective multicenter study (NCT05070208) and the prospective CBF-2006 trial (NCT00428558) with similar fusion transcript MRD monitoring. Patients with CBFA (t(8;21)/RUNX1::RUNX1T1) or CBFB (inv(16)/CBFB::MYH11) AML in first CR/CRi after intensive chemotherapy were eligible if: 1) next-generation sequencing (NGS) was available at diagnosis; or 2) MRD was assessed at ≥ 1 timepoint during first line therapy. In patients with adequate samples, centralized NGS was performed using a CBF-AML specific panel of 62 genes. Primary endpoint was the risk for relapse including molecular relapse as defined by ELN (Döhner et al., 2022), with non-relapse mortality as a competing event. Variable selection was performed by a LASSO penalized cause-specific Cox model. Impact of genetic alterations on MRD kinetics was evaluated by clustering MRD by k-means. Discrimination was evaluated using time-dependent ROC-AUC for risk of relapse at 3 years.
Results. 634 CBF-AML patients were included between 2007 and 2021 (311 females, 323 males; median age 45 years [range 18-80]), 295 (47%) with CBFA and 339 (53%) with CBFB AML. Induction regimens were based on 7+3 (72%), 9% and 2% patients receiving additional gemtuzumab ozogamicin or tyrosine kinase inhibitor, respectively. Consolidation courses were mainly intermediate/high dose cytarabine courses (93%) and only 5% patients were transplanted in first CR/CRi.
In eligible CBFA AML patients (n=172), only KIT exon 17 mutation was selected using LASSO penalization. Exon 17 mutations (n=44 [26%]) significantly increased (csHR=2.27 [95%CI:1.38-3.74], p=0.001) but not other types of KIT mutations (n=19 [11%], csHR=1.23 [95%CI:0.57-2.63], p=0.60). Of note, KIT exon 17 mutations were not associated with a specific RUNX1::RUNX1T1 MRD trajectory.
In eligible CBFB AML patients (n=190), FLT3 mutations were associated with a higher risk of relapse (csHR=1.03) whereas MYC mutations (csHR=0.96) or presence of any trisomy (csHR=0.99) had a favorable impact. Specifically, FLT3-ITD significantly increased risk of relapse (n=10 [5%], csHR=2.86 [95%CI:1.31-6.26], p=0.009) whereas the trend was non-significant for FLT3-TKD (n=32 [17%], csHR=1.62 [95%CI:0.94-2.77], p=0.08). MRD were clustered in 3 trajectories with rapid (36%), intermediate (30%), and slow responders (34%). Presence of any trisomy was associated with rapid responders (55% vs 28% without trisomy, p&lt;0.0001) whereas FLT3 and MYC mutations were not associated with a specific MRD trajectory.
Among early BM and PB MRD timepoints, post-induction BM MRD had the highest discrimination for CBFA AML (ROC-AUC: 0.633) and post-consolidation 1 PB MRD for CBFB AML (ROC-AUC: 0.628). In CBFA AML, post-induction BM MRD &gt; 10-3 was a significant predictor of relapse (n=158/265, csHR=2.88 [95%CI:1.79-4.62], p&lt;0.0001). In CBFB AML, post-consolidation 1 PB MRD &gt; 10-5 was a strong predictor of relapse (n=80/195, csHR=2.64 [95%CI:1.66-4.21], p&lt;0.0001). In CBFA AML multivariable analysis, KIT exon 17 mutations were associated with a higher risk of relapse (csHR=2.48 [95%CI:1.6-3.86], p=0.0001), independently of higher age (csHR=1.03 [95%CI:0.9-1.19], p=0.67), WBC (log10-scale, csHR=1.82 [95%CI:1.13-2.91], p=0.01), and post-induction BM MRD (csHR=2.49 [95%CI:1.53-4.07], p=0.0005). In CBFB AML, only post-consolidation 1 PB MRD was independently associated with risk of relapse (csHR=2.34 [95%CI:1.47-3.74], p=0.0009), when accounting for age (csHR=1.05 [95%CI:0.92-1.19], p=0.50), WBC (csHR=1.01 [95%CI:0.73-1.4], p=0.94),FLT3 mutation (csHR=1.51 [95%CI:0.98-2.3], p=0.06), MYC mutation (csHR=0.35 [95%CI:0.09-1.47], p=0.16) and trisomies (csHR=0.74 [95%CI:0.48-1.15], p=0.19).
Conclusion. MRD remains the most important prognostic factor in patients with CBF-AML. Among recurrent genetic lesions, only KIT exon 17 mutations worsen prognosis independently of MRD in CBFA AML patients.