IDH2 R172 mutation is associated with improved survival in IDH-mutated AML/MDS patients undergoing allogeneic stem cell transplantation: A geth-TC multicenter study
Year: 2025
Type: conference-abstract
Abstract: Introduction: Mutations in isocitrate dehydrogenase (IDH1 and IDH2) occur in approximately 15–20% and 5-15% of AML and MDS patients, respectively. However, their prognostic significance in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) remains unclear. While prior studies have reported inconsistent results for IDH1 and IDH2R140 mutations, the IDH2R172 variant has been associated with improved survival and is thought to represent a biologically distinct entity. Given the lack of consensus and limited data in the transplant setting, we performed a multicenter analysis to evaluate post-transplant outcomes according to IDH mutational subtype in AML/MDS patients. Methods:We conducted a retrospective, multicenter study across nine EBMT/GETH-CT institutions, Inclusion criteria were: 1)diagnosis of AML or MDS according to WHO 2016 criteria; 2)IDH1 or IDH2 identified via Sanger sequencing or next-generation sequencing (NGS) and 3)recipients of first allo-HCT. All patients signed informed consent. The primary endpoint was 1-year overall survival (OS); secondary endpoints included progression-free survival (PFS), relapse incidence (RI), non-relapse mortality (NRM), and graft-versus-host disease (GvHD) outcomes. Multivariable Cox and Fine-Gray models were used to assess prognostic factors. Results: From 2012 to 2021, a total of 101 AML (n=88, 87%) and MDS(n=13, 13%) patients were included: 46 (46%) carried IDH1R132 and 54 (54%), IDH2 mutations (29 R140, 15 R172, 10 unspecified). Median age was 54.5 years (IQR, 44-63).Most patients (70%) had a normal karyotype, and 76% carried additional mutations (median of 2 per patient). NPM1 was the most frequent co-mutation (30%), enriched in IDH2R140 (45%) and absent in IDH2R172 (p=0.01). IDH2R172 was more often associated with epigenetic alterations such as BCOR.With a median follow-up of 21.2 months (IQR, 18-31), 1-year OS was 79% (95% CI, 71–89). In univariate analysis, patients with IDH2R172 showed superior 1-year OS (93%) compared to those with IDH1 or IDH2R140 (74%) (p=0.05). MRD positivity before allo-HCT correlated with worse OS (HR 3.0; p=0.02). Multivariable analysis (MVA) confirmed the favorable prognostic impact of the IDH2R172 mutation on OS (HR 0.09; 95% CI, 0.01- 0.8) (p=0.03). The 1-year PFS was 75% (95% CI, 67–85), IDH2R172 was associated with a higher 1-year PFS: 93% vs. 74% (p=0.06). MRD positivity before allo-HCT was associated with impaired PFS compared to MRD negative fraction (64% vs. 85%, p=0.01; HR 3.4, 95%CI 1.3-8.9, p=0.01). MVA PFS analysis demonstrated that IDH2R172 conferred a significantly lower risk of progression (HR 0.10; 95% CI, 0.01–0.90; p=0.04). The 1-year RI was 16% (95% CI, 8–24). Notably, patients with IDH2R172 had a 0% repalse incidence vs. 14% in other subtypes (p<0.001). In MVA, IDH2R172 independently predicted absence of relapse (HR 0.0; p<0.001). 1-year NRM was 9.5% (95% CI, 3–15),), and no significant predictors were identified in univariate analysis. The 100-day cumulative incidence (CI) of acute GvHD was 40% (95% CI, 30–49), significantly higher among patients receiving Tacrolimus–SirolimusGVHD prophylaxis compared with PTCy (HR 9.3; p<0.001). The 1-year CI of Chronic GvHD was 27% (95% CI, 18–37). TCD was associated with a lower cGvHD (HR 0.3; 95% CI 0.1-1, p=0.048).Lastly, 1-year GRFS was 51% (95% CI, 37–62), and was significantly improved in IDH2R172 patients (82%) compared to IDH2R140 (46%) and IDH1 (40%) (HR 0.19; p=0.02) (HR 0.19; p=0.02) and among those receiving grafts from sibling donors (HR 0.4; p=0.01). Conclusions: In this large multicenter series of IDH-mutated AML/MDS undergoing allo-HCT, the IDH2R172 mutation was associated with a improved survival, a lower RI, and a higher GRFS. Whether this reflects favorable disease biology or increased sensitivity to graft-versus-leukemia effects following allo-HCT remains unclear. Our findings may have direct clinical implications for risk stratification and transplant decision-making and warrant prospective validation.
Source: Blood
Authors: Ana Perez Gonzalez, Víctor Navarro Garces, Manuel Guerreiro, Marta Villalba Montaner, Alejandro Avendaño, Estefanía Pérez López, Ana Pilar Gonzalez, Alberto Mussetti, Rocio Parody, Mi Kwon, Irene García-Cadenas, Eva Bandres, Teresa Zudaire, Izarbe Delgado, Oriana López Godino, Olga Salamero, Guillermo Orti
Institutions: Vall d'Hebron Hospital Universitari, Hospital Universitario Central de Asturias, Vall d'Hebron Institute of Oncology, Hospital Universitari i Politècnic La Fe, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca, Centro de Investigación Biomédica en Red de Cáncer, Instituto de Biología Molecular y Celular del Cáncer de Salamanca, Institut d'Investigació Biomédica de Bellvitge, Institut Català d'Oncologia, Universitat de Barcelona, Universidad Complutense de Madrid, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Universitat Autònoma de Barcelona, Hospital de Sant Pau, Josep Carreras Leukaemia Research Institute, Institut de Recerca Sant Pau, Complejo Hospitalario de Navarra, Hospital Universitari Arnau de Vilanova, Centro Regional de Hemodonación
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4417007936
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