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975 Fms-like Tyrosine Kinase 3 Ligand Kinetic Profile Is the Strongest Factor Predicting Refractoriness after Induction and Event-Free Survival in Adults with AML: A Filo Prospective Multicentric StudyClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 617. Acute Myeloid Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Response Predictors to Targeted Therapies and Transplant
Hematology Disease Topics & Pathways:
Research, clinical trials, Acute Myeloid Malignancies, AML, Clinical Research, Diseases, Myeloid Malignancies
Monday, December 11, 2023: 5:00 PM

Pierre Peterlin1*, Joëlle Gaschet, PhD2*, Sarah Bertoli3*, Marc Bernard, MD4*, Martin Carre, MD5*, Pierre-Yves Dumas, MD, PhD6*, Mathilde Hunault, MD, PhD7*, Amine Belhabri, MD8*, Anne Banos, MD9*, Caroline Bonmati, MD10*, Emmanuelle Tavernier, MD11*, Gaelle Guillerm12*, Sarah Bonnet, MD13*, Justine Decroocq, MD14*, Alain Saad, MD15*, Mario Ojeda-Uribe, MD16*, Romain Guieze, MD, PhD17*, Tony Marchand, MD, PhD18*, Christian Recher, MD, PhD3*, Alice Garnier, MD19*, Marie-Anne Vibet, PhD20* and Patrice Chevallier, MD1

1Nantes University Hospital, Nantes, France
2CRCI2NA UMR INSERM 1307 CNRS 6075 - Nantes Université - Université d'Angers, France, NANTES, France
3Service d'Hématologie, Centre Hospitalo-universitaire de Toulouse, Centre de Recherches en Cancérologie de Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole, Université de Toulouse, UPS, INSERM, CNRS, Toulouse, France, Toulouse, France
4Clinical Hematology Department, Rennes University Hospital, Rennes, France, Rennes, FRA
5Clinical Hematology Department, CHU Grenoble Alpes - Université Grenoble Alpes, Grenoble, France
6CHU Bordeaux, Service d'Hématologie Clinique et de Thérapie Cellulaire, F-33000 Bordeaux, France;BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, Univ. Bordeaux, F-33000 Bordeaux, France, Bordeaux, France
8Centre Leon Berard, Lyon, FRA
9Centre Hospitalier De Bayonne, Bayonne, FRA
10Service D'Hématologie, Centre Hospitalier Universitaire De Nancy, Nancy, FRA
11Institut De Cancérologie De La Loire, Saint Priest En Jarez, FRA
12Service d'hématologie, Hôpital Morvan, CHRU Brest, Brest, France
13Clinical Hematology Department, Montpellier University Hospital, Montpellier, France, montpellier, France
14Clinical Hematology Department, Hopital Cochin, APHP, Paris, France, Paris, France
15Clinical Hematology Department, Bezier Hospital, Beziers, France, Beziers, FRA
16Clinical Hematology Department, Mulhouse Hospital, Mulhouse, France, Mulhouse, FRA
17CHU Estaing, Clermont Ferrand, FRA
18Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY
19Hematology clinic, Nantes University Hospital, Nantes, France
20Clinical Research Centre, University Hospital of Nantes, Nantes, France

Background: Recently, a monocentric study has shown in adults with a non-previously treated acute myeloid leukemia (AML) that the stagnation of low levels of Fms-like tyrosine kinase 3 ligand concentration (FLc) in plasma, up to day 22 after an intensive induction, was associated with refractoriness and lower survivals (Peterlin et al, 2021). The present study wanted to confirm these results prospectively on a larger cohort of patients and in a multicentre way.

Methods: This was a prospective non-interventional multicentre investigator sponsored trial (FLAMVAL study, clinicaltrials.gov: NCT04641910. One of the main objective was to study the impact on various outcomes of FL levels, evaluated during an intensive induction, in adults (>=18 year (y) old) with a non-previously treated non-M3 AML. Patients could receive a standard intensive induction chemotherapy combining anthracycline + cytarabine as part of a trial or not. Outcomes to be studied were responses, 1y overall survival (OS) and event-free survival (EFS), and 1-y leukemia-free survival (LFS) and relapse in responders. Response was evaluated according to ELN2017 criteria at day+30 after induction. Using a new cytokine multiplex assay from Milliplex (MILLIPLEX®), FL levels (expressed in pg/mL) were evaluated at Day (D) 1, D8, D15 and D22 from Day 1 of induction.

Results: Between June 2021 and August 2022, 226 patients from 16 FILO centres were included but 204 with full evaluation of FL levels (816 samples) were considered for analyses. Their characteristics are reported in Table 1. At the time of analysis (July 2023), 1-y OS, EFS and LFS were 87+-5%, 78.3+-6% and 59.8+-8%, respectively.

Median [Q1-Q3] FLc were 1.22 [0-4.19] at D1, 13.83 [2.26-72.46] at D8, 128.55 [13.06-293.43] at D15 and 24.14 [4.60-155.14] at D22. The number of refractory patients was significantly higher for those patients with a FLc < median at Day 8 (30.4% vs 13.7%, p=0.01), D15 (35.6% vs 8%, p<0.001) and D22 (31.1% vs 12.9%, p=0.007). 1-y OS and LFS were similar between patients with a FLc < or >= median at the four times considered. This was true also for 1y-EFS at D1 and D22. However, 1-y EFS was significantly worse for those with a FLc < median at D8 (48.5 % (41-55) vs 31 % (25-37), p=0.004) and at D15 (47.6 (40-55) vs 31% (25-37), p=0.002).

As reported before (Peterlin et al, 2021), all patients but 4 (with a decrease of levels all along) can be categorized according to three FLc kinetic profiles: i) sustained increase from days 1 to 22 (FLI group n=39, 19% of the cohort), ii) increase from days 1 to 15, then decrease at day 22 (FLD group, n=86, 42% of the cohort) and iii) stagnation of low levels all along (<100 pg/mL from days 1 to 22, FLL group, n=75, 37% of the cohort). OS and LFS were similar between these three groups while 1-y EFS was significantly lower for the FLL group (45% [33; 57]) compared to FLI and FLD groups (64% [49; 79] and 71% [ 61; 80], p<0.001) (Figure 1). This difference was due to a higher proportion of refractory patients in the FLL group (n=45/75 42.7% vs FLI =5/39, 12.8% vs FLD n=8/86, 9.3%, p<0.001, 2 patients not evaluated for response). Similar incidence of relapse was observed for responders comparing the three groups. Interestingly, only 8.8% (n=11/125) of the FLI/FLD patients had a FLc level <100 pg/ml at both times D8 and D15, suggesting that a FLL status can be predicted as soon as D15.

For multivariate analyses, we compared FLc kinetic profiles (FLL vs FLI/FLD) on one hand and FLc medians (D1 D8 D15 and D22) on the other hand with other factors associated with a p value <0.20 by univariate analyses. In both models, only FLc kinetic profile and medians together with ELN2017 classification were found to be independent factors predicting response and EFS. However, FLL status was the strongest factor associated with refractoriness (OR: 6.2, 95%CI: 2.94-13.73, p<0.001, ELN favorable vs Intermediate p=0.003, favorable vs adverse p=0.002) and lower EFS (OR: 2.58, 95%CI: 1.40-4.79, p=0.002, ELN p=0.01 and 0.004).

Conclusion: This large prospective multicentre trial confirms that a stagnation of low levels of FLc during a first-line induction in adults with non-M3 AML is the strongest factor (above ELN classification) associated with refractoriness and lower EFS in these patients. The study suggests also that this simple test could be useful to envisage salvage therapy including allotransplant just after D15 of induction.


This study was funded by Astellas Pharma Inc.

Disclosures: Bertoli: Abbvie: Honoraria, Other: Travel; Astellas: Honoraria; Servier: Honoraria; Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria, Other: Travel; BMS-Celgene: Honoraria. Dumas: Novartis: Honoraria, Other: Research support for institution; Servier: Honoraria, Other: Research support for institution; BMS: Honoraria, Other: Research support for institution; Abbvie: Honoraria; Astellas: Honoraria, Other: Research support for institution; Daiichi-Sankyo: Honoraria, Other: Research support for institution; Jazz pharmaceutical: Honoraria; Janssen: Honoraria; Roche: Other: Research support for institution. Marchand: SERVIER: Consultancy, Honoraria; JAZZ PHARMACEUTICALS: Consultancy, Honoraria; SOBI: Consultancy; ASTELLAS: Consultancy. Recher: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharamceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Iqvia: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chevallier: Incyte: Honoraria, Research Funding; Sanofi: Honoraria; Mallinckrodt Pharmaceuticals: Honoraria; Takeda: Honoraria; Immedica Pharma: Honoraria; Servier: Honoraria.

*signifies non-member of ASH