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1552 Enhanced Validation of the FLT3-like Gene Expression Signature As a Predictive Biomarker for Quizartinib Response in FLT3-ITD Negative Acute Myeloid Leukemia: Expanded Cohort and Extended Follow-up from the Pethema Quiwi Trial

Program: Oral and Poster Abstracts
Session: 618. Acute Myeloid Leukemias: Biomarkers and Molecular Markers in Diagnosis and Prognosis: Poster I
Hematology Disease Topics & Pathways:
Research, Clinical trials, Acute Myeloid Malignancies, AML, Adult, Clinical Research, Genomics, Diseases, Myeloid Malignancies, Biological Processes, Molecular biology, Study Population, Human
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Adrian Mosquera Orgueira, MD, PhD1*, Manuel Perez Encinas, MD2*, Carlos Pérez Míguez3*, Rebeca Rodriguez Veiga, MD, PhD4*, Juan Miguel Bergua Burgues, MD5*, Jesus Lorenzo Algarra6*, Carmen Botella7*, Jose Antonio Perez Simon8*, Teresa Bernal9,10,11*, Mar Tormo, MD12*, Maria Calbacho, MD13*, Olga Salamero, MD14,15*, Josefina Serrano, MD16*, Victor Noriega17*, Juan Antonio Lopez Lopez18*, Susana Vives, MD19*, Mercedes Colorado, MD20*, Jose Luis Lopez Lorenzo, MD21*, Maria Vidriales Vicente22*, Raimundo Garcia Boyero, MD23*, Maria Teresa Olave Rubio24*, Pilar Herrera Puente25*, Olga Arce, MD26*, Manuel Barrios Garcia27*, Maria Jose Sayas Lloris, MD28*, Marta Polo, MD29*, Maria Isabel Gomez Roncero30*, Eva Barragán, PhD31*, Rosa Ayala, MD, PhD32*, Carmen Chillon, MD33*, Maria Jose Calasanz, PhD34*, Blanca Boluda35*, Andres Peleteiro Raindo36*, Raquel Amigo37*, David Martinez-Cuadron, PhD38, Jorge Labrador, MD39* and Pau Montesinos, PhD, MD40*

1University Hospital of Santiago de Compostela, Department of Hematology, IDIS, SANTIAGO DE COMPOSTELA, Spain
2Department of Hematology, Hospital Unviersitario de Santiago de Compostela, IDIS, Santiago de Compostela, ESP
3University Hospital of Santiago de Compostela, Department of Hematology, Santiago de Compostela, Spain, Santiago de Compostela, Spain
4Hospital Universitary i Politecnic La Fe, Valencia, ESP
5Hospital San Pedro de Alcántara, Caceres, Spain
66. Hospital General de Albacete, Albacete, Spain
7Hospital General Universitario de Alicante, Alicante, Spain
8University Hospital Virgen del Rocío, Sevilla, Spain
9Hospital Universitario Central de Asturias, Oviedo, Spain
10Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Asturias, Spain
11Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Asturias, Spain
12Department of Hematology, Hospital Clínico de Valencia, Valencia, Spain
13Hematology Department, Hospital Universitario 12 de Octubre, Madrid, Madrid, Spain
14Hematology Department, University Hospital Vall d’Hebron, Barcelona, Spain
15Experimental Hematology, Vall d’Hebron Institute of Oncology, Barcelona, Spain
16Department of Hematology, Hospital Universitario Reina Sofía, IMIBIC.UCO, Cordoba, ESP
17Hospital Clínico de A Coruña, A Coruña, Spain
18Hospital Universitario de Jaen, Jaen, Spain
19Hematology Department, Institut Catala d'Oncologia - Hospital Germans Trias i Pujol, Badalona, Spain
20Hematology Department, University Hospital Marques de Valdecilla, Santander, Spain
21Fundacion Jimenez Diaz, Madrid, ESP
22Hospital Universitario de Salamanca, Salamanca, Spain
23Hospital General Universitario de Castellon, Castellon, Spain
24Hospital Clinico Universitario Lorenzo Blesa, Zaragoza, ESP
25Hospital Universitario Ramón y Cajal (IRYCIS), Madrid, Spain
26Hospital Universitario de Basurto, Bilbao, Spain
27Hospital Universitario Regional de Malaga, Malaga, Spain
28Hospital Dr. Peset, Valencia, Spain
29Department of Hematology, Hospital Universitario Clinico San Carlos, Madrid, Spain
30Hospital Virgen de la Salud, Toledo, Spain
31Department of Hematology, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
32Hospital Universitario 12 De Octubre, Madrid, Spain
33Haematology Department, University Hospital of Salamanca, Research Biomedical Institute of Salamanca (IBSAL), CIBERONC and Center for Cancer Research-IBMCC (USAL-CSIC), Salamanca, Spain
34Cancer Center Clinica Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), IDISNA, CIBER-ONC number CB16/12/00369 and CB16/12/00489, Pamplona, Spain
35Hospital Universitari I Politècnic La Fe, Valencia, ESP
36University Hospital of Santiago De Compostela, Department of Hematology, IDIS, SANTIAGO DE COMPOSTELA, ESP
37Instituto de Investigaciones Santiarias La Fe, Valencia, Spain
38Hematology, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
39Department of Hematology, Hospital Universitario de Burgos, Universidad Isabel I, Burgos, Spain
40Hematology, Hospital Universitari I Politécnic La Fe and Programa Español de Tratamientos en Hematología (PETHEMA) Group, Valencia, Spain

Background

The identification of predictive biomarkers is crucial for guiding treatment decisions in acute myeloid leukemia (AML). Previously, we identified a FLT3-like gene expression signature in FLT3 wild-type AML patients, which clustered a proportion of patients with FLT3-ITD and TKD mutated cases. The QUIWI trial, a randomized, placebo-controlled, phase II study (n=273), showed a significant increase in overall survival (OS) in FLT3-ITD negative AML patients treated with the FLT3 inhibitor quizartinib (Quiza) plus intensive chemotherapy (3+7). Our initial study including 161 randomized patients in the QUIWI trial demonstrated that the FLT3-like signature could predict responses to Quiza, highlighting its potential as a biomarker for personalized treatment in AML.

Methods

In this final report, we analyzed a total of 248 patients randomized in the QUIWI clinical trial, including an extended follow-up of the initial patient set (N=161) and an additional set of 87 patients included in the trial. RNA was extracted using standard methods, followed by assessment of nucleic acid integrity (TapeStation) and quantification (Qubit). Total mRNA sequencing was performed using polyA RNAseq with TruSeq technology. The sequences were aligned to the GRCh37 reference genome using the Hisat algorithm. Gene expression quantification was performed using the Bioconductor workflow, and gene expression estimates (FPKM) were obtained and log2 normalized. The original FLT3-like signature (595 genes) was selected for downstream analysis. The method to assign new patients to predefined clusters involved calculating the distances between the new samples and the centroids of the existing groups, then assigning the new samples to the group with the nearest centroid. OS was defined as time from start of screening to death.

Results

The first step was to evaluate the outcomes of patients in the original training set (N=161) with longer patient follow-up (median follow-up 3.20 years and median OS was not yet reached). Within the FLT3-like cluster (N=80), a significant benefit for Quiza over placebo was observed with a p-value of 0.002 and a hazard ratio (HR) of 0.34 (95% CI: 0.17-0.68). No benefit for Quiza over placebo was observed in the non-FLT3-like cluster (p-value 0.43, HR 1.35, 95% CI: 0.64-2.84).

Next, we used the FLT3-clusterization to identify FLT3-like patients among the 87 newly sequenced cases. 24 cases (27.6%) were identified as FLT3-like, and these patients showed a significant benefit for Quiza over placebo (p-value 0.02, HR 0.08, 95% CI: 0.01-0.71). Among these, 50% of cases harbored NPM1 mutations, and 29% had concurrent DNMT3A mutations, but a tendency for better response to Quiza was observed independently of these mutations.

Finally, when merging the two cohorts (N=248), a significant benefit for Quiza over placebo was observed in the FLT3-like group (N=104) with a p-value <0.001, an HR of 0.27, and a 95% CI of 0.14-0.52. This effect was independent of NPM1 and DNMT3A mutations (p-value <0.001).

Conclusion

Our study confirms the predictive value of the FLT3-like signature for identifying FLT3-ITD negative AML patients who benefit from Quiza. The extended follow-up reinforces the significant survival benefit observed in FLT3-like patients treated with Quiza. Furthermore, the identification of new FLT3-like patients who exhibited superior response to Quiza over placebo validates the robustness of the FLT3-like clusterization method. This predictive strategy was effective regardless of NPM1 or DNMT3A mutation status, supporting its potential use in personalized treatment approaches for FLT3-ITD negative AML.

Disclosures: Mosquera Orgueira: Takeda: Speakers Bureau; Roche: Consultancy; Pfizer: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Other; Biodigital THX: Current equity holder in private company; Novartis: Other; GSK: Consultancy. Salamero: Jazz, Abbvie: Honoraria; Astellas, Jazz, BMS: Consultancy. Vidriales Vicente: F. Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Bena Lim, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Ayala: Astellas: Speakers Bureau; BMS: Speakers Bureau; Altum Sequencing: Current equity holder in private company; Incyte: Consultancy; Novartis: Consultancy, Speakers Bureau. Montesinos: Janssen: Membership on an entity's Board of Directors or advisory committees, Other: research support, Speakers Bureau; Daiichi Sankyo, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Research Funding, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Research Funding, Speakers Bureau; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Research Funding, Speakers Bureau; Jazzpharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Kura Oncology: Consultancy; Syndax: Consultancy; Glycomimetics: Consultancy.

*signifies non-member of ASH