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227 Secondary Genetic Alterations and Measurable Residual Disease in Core Binding Factor Acute Myeloid Leukemia - a Study from the Acute Leukemia French Intergroup

Program: Oral and Poster Abstracts
Type: Oral
Session: 619. Acute Myeloid Leukemias: Disease Burden and Minimal Residual Disease in Prognosis and Treatment: Measurable Residual Disease in AML in 2024 and Beyond
Hematology Disease Topics & Pathways:
Biological Processes, Molecular biology, Measurable Residual Disease
Saturday, December 7, 2024: 3:00 PM

Loic Vasseur1,2*, Matthieu Duchmann, MD, PhD3,4*, Nicolas Duployez, PharmD, PhD5,6*, Emmanuel Raffoux, MD7*, Celine Berthon, MD, PhD6,8*, Mael Heiblig, MD, PhD9*, Alexis Genthon, MD10*, Thorsten Braun, MD, PhD11, Mathieu Leclerc, MD, PhD12*, Delphine Lebon, MD13*, Sylvain Chantepie, MD14*, Jean-Baptiste Micol, MD15, Juliette Lambert, MD, PhD16*, Christian Recher, MD, PhD17*, Marie-Lorraine Chrétien, MD18*, Thomas Cluzeau, MD, PhD19, Julien Vaidie, MD20*, Jean-Valère Malfuson, MD21*, Madalina Uzunov, MD22*, Arnaud Pigneux, MD, PhD23*, Pierre Peterlin24*, Sihem Tarfi, PharmD25*, Pierre Hirsch, MD, PhD26*, Dominique Penther, MD27*, Eric Jourdan, MD, PhD28*, Karine Celli-Lebras, RN29*, Claude Preudhomme, PharmD, PhD5,6*, Hervé Dombret, MD, PhD7,30, Jérôme Lambert, MD, PhD2,31*, Nicolas Boissel, MD, PhD1,30 and Raphael Itzykson3,7

1Adolescent and Young Adult Hematology Unit, Saint Louis University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
2ECSTRRA team, Centre for Research in Epidemiology and Statistics, INSERM U1153, Université Paris Cité, Paris, France
3Unité 944/7212-GenCellDi, Saint-Louis Research Institute, INSERM, CNRS, Université Paris Cité, Paris, France
4Hematology Laboratory, Saint Louis University Hospital, AP-HP, Paris, France
5Laboratory of Hematology-Molecular Biology, Centre Hospitalier Universitaire (CHU) de Lille, Lille, France
6ONCOLILLE - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, Univ. Lille, IRCL, CNRS-UMR9020, Inserm-U1277, Lille, France
7Hematology Department, Saint Louis University Hospital, AP-HP, Paris, France
8Hematology Department, CHU Lille, Lille, France
9Hematology Department, CHU de Lyon, Pierre-Bénite, France
10Hematology Department, Saint Antoine University Hospital, AP-HP, Paris, France
11Hematology Department, Avicenne University Hospital, AP-HP, Bobigny, France
12Hematology Department, Henri Mondor University Hospital, AP-HP, Créteil, France
13Hematology Department, CHU Amiens, Amiens, France
14Basse-Normandie Institute of Hematology, CHU de Caen, Caen, France
15Hematology Department, Gustave Roussy Institute, Villejuif, France
16Clinical Hematology Department, Versailles Hospital, Le Chesnay-Rocquencourt, France
17Hematology Department, Cancer University Institute of Toulouse Oncopole, Toulouse, France
18Hematology Department, CHU Dijon, Dijon, France
19Department for Clinical Hematology, Nice University Hospital, Nice, France
20Hematology Department, Dupuytren University Hospital, Limoges, France
21Clinical Hematology Department, Percy Army Training Hospital, Clamart, France
22Clinical Hematology Department, Pitié-Salpétrière University Hospital, AP-HP, Paris, France
23Department of Clinical Hematology, Haut-Lévèque Hospital, CHU Bordeaux, Pessac, France
24Hematology Department, Hôtel-Dieu University Hospital, NANTES CEDEX 1, France
25Hematology and Immunology Department, Henri Mondor University Hospital, AP-HP, Créteil, France
26Hematology Laboratory, Saint Antoine University Hospital, AP-HP, Paris, France
27Department of Genetic Oncology, Henri Becquerel Center, CHU Rouen, Rouen, France
28Clinical Hematology Departement, CHU de Nimes, Nimes, France
29ALFA Group Coordination, Saint Louis Research Institute, Paris, France
30EA-3518, Saint Louis Research Institute, Université Paris Cité, Paris, France
31Biostatistics and Medical Information Department, Saint Louis University Hospital, AP-HP, Paris, France

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<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 > 10-3 was a significant predictor of relapse (n=158/265, csHR=2.88 [95%CI:1.79-4.62], p<0.0001). In CBFB AML, post-consolidation 1 PB MRD > 10-5 was a strong predictor of relapse (n=80/195, csHR=2.64 [95%CI:1.66-4.21], p<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.

Disclosures: Braun: BMS: Consultancy, Honoraria. Micol: Jazz Pharmaceuticals: Honoraria; Astellas Pharma: Honoraria; SERVIER: Honoraria; AbbVie: Honoraria; Gilead Sciences: Honoraria. Cluzeau: BMS: Consultancy, Speakers Bureau; Jazz Pharma: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Syros: Speakers Bureau; Pfizer: Other: International Congress. Jourdan: Novartis: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Preudhomme: jazz: Honoraria; servier: Honoraria; astellas: Honoraria; abbvie: Other: travel cost and ash registration. Dombret: Incyte: Other: Personal Fees, Research Funding; Jazz Pharmaceuticals: Other: Personal Fees, Research Funding; Pfizer: Research Funding; Servier: Research Funding; BMS-Celgene: Research Funding; Amgen: Research Funding; Astellas: Research Funding; Daiichi Sankyo: Other: Personal Fees; Servier: Other: Personal Fees. Boissel: Amgen: Other; Pfizer: Other; Sanofi: Other; Adveysa: Other. Itzykson: Abbvie: Research Funding; Advesya: Research Funding.

*signifies non-member of ASH