The synonymous IDH1 p.Gly105Gly (rs11554137) variant associates with AML post-transplant relapse via aberrant signal transduction pathways

Abstract Background Missense mutations in IDH1 are well-established therapeutic targets in acute myeloid leukemia (AML). In contrast, the synonymous IDH1 variant p.Gly105Gly (rs11554137), present in 5–10% of AML cases, has been considered a benign polymorphism due to its high population frequency (5.7% overall, 0.7–10.5%) and lack of protein-altering effect. However, prior studies have associated this variant with inferior outcomes (Wagner, J Clin Oncol, 2010), though findings have been inconsistent. Few studies have examined its prognostic significance in the context of treatment intensity or allogeneic stem cell transplantation (SCT). Methods With IRB approval, clinical and genomic data were extracted from the Mayo Clinic AML database for patients diagnosed between Jan 1, 2018, and Jan 31, 2025. Patients were stratified by IDH1 Gly105Gly (rs11554137) status via NGS on bone marrow. Outcomes included co-mutation profiles, treatment response, measurable residual disease (MRD) by multiparametric flow cytometry, and survival. Multivariable Cox and logistic regression models for relapse-free survival (RFS) and overall survival (OS) were adjusted for age at diagnosis, ELN 2022 risk category, and SCT conditioning regimen. Results Among 379 AML patients, 36 (9.5%) harbored the IDH1 Gly105Gly (rs11554137) variant (cases) (median VAF 49%, IQR 48–49.2). In the full cohort, median age was 68 years (IQR 59–74), M:F ratio was 1.5; 75% had de novo AML, and median follow-up was 52 months. Among cases, common cytogenetic abnormalities included complex karyotype (28%), del(7q) (14%), and trisomy 8 (6%), while frequently mutated genes included DNMT3A (19%), IDH2 (17%), and BCOR (14%). Of 345 treated patients, 43% received intensive, and 56% received low-intensity regimens, including hypomethylating agent (HMA) alone (n=13), HMA+venetoclax (n=159), and targeted therapy (n=7). Among cases, complete remission (CR) rates were higher with intensive vs. low-intensity therapy (70% vs. 17%, p=0.03). MRD positivity post induction was more common in cases (66% vs. 26%, p=0.01), suggesting suboptimal leukemic clearance. Among 103 patients who underwent allogeneic SCT in CR1 (47% received myeloablative conditioning), morphologic relapse occurred in 64.3% of cases compared to 23.6% of controls (p = 0.004). Cases experienced significantly inferior median RFS (8 months [95% CI 5–NA] vs. not reached for controls, p <0.001), indicating more durable post-SCT remission in the control group. In a multivariable Cox proportional hazards model adjusting for age, ELN risk, conditioning intensity, MRD status, and complex karyotype, the IDH1 Gly105Gly variant remained independently associated with shorter RFS (HR 3.97, 95% CI: 1.74–9.05, p = 0.001). Complex karyotype was also an independent predictor of relapse (HR 3.35, 95% CI: 1.28–8.73, p = 0.014). Consistent with this, logistic regression revealed a significantly increased odds of post-SCT relapse among cases (OR 7.95, 95% CI: 2.19–35.27, p=0.001), independent of clinical covariates. Relapsed cases were significantly more likely to harbor FLT3-ITD mutations than relapsed controls (p=0.041). Pathway-level analysis revealed increased frequency of mutations in signal transduction genes (FLT3-ITD, CSF3R, NF1) (p=0.002). All CNS relapses among cases occurred in patients harboring at least one of these mutations. Despite the higher relapse rate, there were no significant differences in OS (14.4 vs. 11.3 months, p=0.36) between cases and controls. The IDH1 Gly105Gly variant was not independently associated with OS (HR 1.26, p=0.30). In contrast, age (p<0.0001) and adverse ELN risk (p<0.0001) were significant predictors of inferior OS. These findings suggest that the prognostic impact of IDH1 Gly105Gly is most pronounced in the post-SCT setting. Conclusion The synonymous IDH1 Gly105Gly variant (rs11554137) is an independent predictor of post-SCT relapse in AML, potentially mediated by co-occurring mutations in signal transduction pathways. Despite no observed impact on OS, likely due to effective salvage therapies, the variant's link to lower CR rates with low-intensity therapy and higher MRD burden suggests treatment intensity influences its clinical relevance. These findings support reevaluating the prognostic role of synonymous variants in AML and call for larger studies and mechanistic investigations into splicing, transcript stability, and translation.