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2707 Prognostic Impact of NPM1 and FLT3-ITD Mutations in Patients Treated with Non-Intensive Regimens: A Pethema Registry Study

Program: Oral and Poster Abstracts
Session: 613. Acute Myeloid Leukemias: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Acute Myeloid Malignancies, AML, Biological therapies, Non-Biological therapies, elderly, Chemotherapy, Diseases, Therapies, Myeloid Malignancies, Study Population, Human
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Edwin Uriel Suárez1*, Juan Manuel Alonso1*, Blanca Boluda2*, Esperanza Lavilla3*, Mar Tormo4,5, Carmen Botella6*, Susana Vives, PhD7*, Carlos Rodriguez8*, Josefina Serrano9,10*, María José Sayas11*, Pilar Martínez Sánchez12*, Fernando Ramos13*, Teresa Bernal del Castillo14*, Lorenzo Algarra15*, Juan Miguel Bergua Burgués16*, José Pérez-Simón17,18, Pilar Herrera19*, Manuel Barrios-García20*, Víctor Noriega-Concepción21*, Jóse Ángel Raposo-Puglia22*, Rosa Ayala23,24*, Eva Barragán2*, David Martinez-Cuadron2* and Pau Montesinos, MD, PhD2*

1Hospital Universitario Fundación Jiménez Díaz, IIS-FJD, Madrid, Spain
2Hospital Universitari i Politécnic-IIS La Fe, Valencia, Spain
3Hospital Universitario Lucus Augusti, Lugo, Spain
4Hospital Clínico Universitario de Valencia, Valencia, Spain
5INCLIVA, Valencia, Spain
6Hospital General Universitario de Alicante, Alicante, Spain
7ICO-Hospital Germans Trias i Pujol, Badalona, Spain
8Hospital Universitario Dr Negrín, Las Palmas, Spain
9Hospital Universitario Reina Sofía, Córdoba, Spain
10IMIBIC, Cordoba, Spain
11Hospital Universitario Dr. Peset, Valencia, Spain
12Hospital Universitario 12 de Octubre, Madrid, Spain
13Hospital Universitario de León, León, Spain
14Hospital Universitario Central de Asturias, Oviedo, Spain
15Hospital Universitario General de Albacete, Albacete, Spain
16Hospital San Pedro de Alcántara, Cáceres, Spain
17Hospital Universitario Virgen del Rocío, Sevilla, Spain
18Instituto de Biomedicina de Sevilla (IBIS)/CSIC/Universidad de Sevilla, Sevilla, Spain
19Hospital Universitario Puerta de Hierro, Majadahonda, Spain
20Hospital Regional Universitario de Málaga, Málaga, Spain
21Hospital Universitario de A Coruña, A Coruña, ESP
22Hospital Universitario Puerta del Mar de Cádiz, Cádiz, Spain
23Haematological Malignancies Clinical Research Unit, Hospital 12 de Octubre Universidad Complutense, CNIO, CIBERONC, Madrid, Spain
24Spanish National Cancer Research Center (CNIO), Madrid, Spain

Introduction: Acute myeloid leukemia (AML) is the most common acute leukemia of adults, with median age at diagnosis of 68 years. Mutations in FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) are associated with a higher risk of relapse and inferior overall survival (OS) in younger patients treated with intensive chemotherapy, but the prognostic relevance among older patients treated with non-intensive approaches is not well established. As well, the role of nucleophosmin (NPM1), and its interaction with FLT3-ITD status and allelic ratio (AR) remains unclear among elderly. We aimed to assess the prognostic impact of FLT3-ITD and NPM1 mutations in older/unfit newly diagnosed AML patients treated with non-intensive front-line therapies.

Methods: We conducted a retrospective analysis that included 707 patients treated with different non-intensive regimens in the PETHEMA AML registry, between 2007 and 2020. FLT3-ITD and NPM1 mutations were studied by fragment length analysis. The karyotype information was available in 615 patients. Associations of demographic and clinical parameters in patients harboring FLT3-ITD and NPM1 mutations was performed using Mann-Whitney-U-test for continuous and Chi-square test for discrete variables. Overall survival (OS) and relapse curves were constructed using Kaplan-Meier and a log-rank test. All analyses were performed by SPSS.

Results: The median age was 74 years (range: 43-91), and 410 patients (58%) were male. ECOG status was 0/1 in 474 patients (72%) and 2 in 124 patients (18.9%). FLT3-ITD mutation was identified in 99 patients (14%). When available, 33 patients (40.7%) showed FLT3-ITDlow (AR <0.5). NPM1 mutation was detected in 144 patients (20%). Karyotype was abnormal in 301 patients (42.7%). Regarding the frontline therapy 328 (46.3%) patients received hypomethylating agents (HMA); 353 (49.9%) fludarabine + low dose cytarabine (LDAC) (FLUGA); 11 (1.6%) fludarabine + LDAC + oral idarubicin (FLAG-IDA Lite); and 15 (2.1%) LDAC. Mortality at 2 years was 77.6% and median OS 6 months.

FLT3-ITD patients (N=99) showed a non-significant difference in OS compared to FLT3 wild-type (FLT3WT) patients (N=608): median OS 5 vs 7.3 months (p=0.17). There were no differences when comparing low and high AR: FLT3-ITDlow (N=34) vs FLT-ITDhigh (N=47): median OS 5.5 vs 4.9 months (p=0.64). Survival in NPM1-mutated patients (N=144) was similar than in NPM1WT patients (N=519): median OS 7.2 vs 6.8 months (p=0.24). OS according to ELN 2017 risk stratification, considering only NPM1 and FLT3-ITD mutations, was similar in subgroups low risk (N=117), intermediate risk (N=31), high risk (N=23): median OS 7.6 vs 5.4 vs 7.2 (p=0.26) (Fig. 1).

In the subgroup of normal karyotype (N=314), FLT3-ITD patients (N=64) showed a trend towards lower survival as compared to FLT3WT patients (N=249): median OS 5.4 vs 10.9 months (p=0.058), with no impact of AR: FLT3-ITDlow (N=19) vs. FLT3-ITDhigh (N=32) median OS 5.8 vs 4.8 months (p=0.73). NPM1 mutated patients (N=102) showed a non-significant difference with NPM1WT patients (N=196): median OS 7.2 vs 10.3 months (p=0.66). OS according to ELN 2017 considering only NPM1 and FLT3-ITD status was similar in subgroups: low risk (N=80), intermediate risk (N=24), high risk (N=12): median OS 2.3 vs 11 vs 2.5 months, respectively (p=0.64). AML patients treated with azacitidine (N=281) had longer median OS of 10 months (p=0.005; 95% CI 1.03 to 1.37) vs decitabine (N=47) median OS 6.1 months and FLUGA median OS 5 months (N=352) (Fig. 2).

Conclusions: Data from this large cohort of AML patients treated with non-intensive regimens underlines the limitations of the ELN 2017 risk stratification in this setting. Nonetheless, there was a trend towards worse OS in patients with normal karyotype and FLT3-ITD mutation (irrespectively of the allelic burden) as compared to FLT3WT patients.

Figure 1. Overall survival according to ELN 2017 risk stratification

Figure 2. Overall survival regarding non-intensive regimens.

Disclosures: Alonso: Incyte: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; Celgene: Research Funding. Ramos: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Novartis: Honoraria; Abbvie: Honoraria; Pfizer: Honoraria; Astellas: Consultancy, Honoraria; Sandoz: Honoraria; Jazz: Honoraria. Bergua Burgués: Incyte: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; Celgene: Research Funding. Montesinos: Kura Oncology: Consultancy; Beigene: Consultancy; Nerviano: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding; Incyte: Consultancy; Astellas: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Menarini/Stemline: Consultancy, Research Funding; Otsuka: Consultancy; Ryvu: Consultancy.

*signifies non-member of ASH