NPM1 and IDH1/2 mutations show limited prognostic impact in relapsed AML: Evidence from the avalon cohort
Year: 2025
Type: conference-abstract
Abstract: Background: NPM1 and IDH1/2 mutations are established prognostic biomarkers in newly diagnosed (ND) acute myeloid leukemia (AML) treated with venetoclax (VEN) and hypomethylating agents (HMAs). However, their role in relapsed/refractory (R/R) AML treated with VEN+HMA remains unclear. The AVALON study is a multicenter real-world cohort including both ND and R/R AML patients. We aimed to investigate the prognostic impact of NPM1, IDH1, and IDH2 mutations in both disease settings. Methods: The study population included AML patients from AVALON, both R/R and ND cases, with available molecular testing for IDH1, IDH2, or NPM1 mutations. Overall response rate (ORR, calculated in patients with available response assessment), event-free survival (EFS), duration of response (DOR), and overall survival (OS) were compared between mutated versus wild-type patients. An additional analysis was performed in patients from both settings who were tested for all three genes. Results: Among 190 AML patients, 147 had R/R disease and 43 were ND. In the R/R cohort, 114 (78%) underwent molecular profiling for at least one mutation: IDH1 (n=50), IDH2 (n=56), NPM1 (n=91). IDH1 mutations were found in 3/50 patients (6%). ORR was 2/3 (67%) in mutated versus 20/41 (49%) in wild-type (p=1.00); median EFS was 2.4 vs 6.9 months (p=0.37), DOR 1.0 vs 4.7 months (p=0.24), and OS 2.4 vs 8.9 months (p=0.18).IDH2 mutations were identified in 10/56 patients (18%); ORR was 5/8 (63%) vs 18/41 (44%) in wild-type (p=0.45); median EFS was 11.3 vs 5.4 months (p=0.51), DOR 6.5 vs 4.7 months (p=0.87), and OS 11.3 vs 6.2 months (p=0.56). NPM1 mutations were present in 12/91 patients (13%); ORR was 6/11 (55%) vs 37/73 (51%) in wild-type (p=1.00); median EFS was 5.4 vs 6.3 months (p=0.77), DOR 6.8 vs 8.3 months (p=0.13), and OS 6.0 vs 9.1 months (p=0.72). In the subset of 55 R/R patients with complete profiling for NPM1, IDH1, and IDH2, patients with at least one mutation (n=25) had an ORR of 13/22 (59%), median DOR of 6.5 months, EFS of 8.9 months, and OS of 8.9 months. Triple-wild-type patients (n=30) had an ORR of 12/27 (44%), DOR of 6.5 months, EFS of 8.0 months (p=0.84), and OS of 9.7 months (p=0.99), with no statistically significant differences between groups. In the 43 ND AML patients, NPM1 or IDH1/2 mutated patients (n=9) showed higher response rates and longer survival compared to triple-wild-type cases (n=7). ORR was 7/8 (88%) vs. 3/6 (50%) (p=0.12). Median DOR was 13.1 vs 3.2 months (p=0.01), EFS 20.1 vs 5.1 months (p=0.006), and OS 25.6 vs 6.3 months (p<0.001). Conclusions: In this real-world cohort of AML patients treated with VEN+HMA, NPM1, IDH1, and IDH2 mutations retained their favorable prognostic value in the newly diagnosed setting but were not predictive of improved outcomes in the relapsed/refractory setting. In R/R AML, response rates and survival did not significantly differ between mutated and wild-type patients. These findings suggest that the prognostic value of commonly favorable mutations is context-dependent and may diminish after disease relapse, highlighting the need for dynamic and phase-specific prognostic models in AML.
Source: Blood
Authors: Calogero Vetro, Irene Azzali, Elisabetta Petracci, Cristina Papayannidis, Eleonora Eleuteri, Fanny Erika Palumbo, Vincenzo Federico, Nicola Stefano Fracchiolla, Patrizia Zappasodi, Maria Paola Martelli, Maria Benedetta Giannini, Lorenzo Brunetti, Raffaele Palmieri, jacopo nanni, Giorgia Simonetti, Fabio Guolo, Paola Minetto, Luca Maurillo, Federica Gigli, Atto Billio, Elisabetta Todisco, Giovanni Martinelli, Giovanni Marconi
Institutions: Ospedale di Bolzano, Azienda Sanitaria dell'Alto Adige, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola, University of Bologna, Azienda Ospedaliero Universitaria Policlinico "G.Rodolico - San Marco", Ospedale Vito Fazzi, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Policlinico San Matteo Fondazione, University of Perugia, Marche Polytechnic University, University of Rome Tor Vergata, University of Genoa, Policlinico Tor Vergata, European Institute of Oncology, Azienda Socio Sanitaria Territoriale della Valle Olona, Ospedale "Santa Maria delle Croci" di Ravenna
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4417020639
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