A single-institution retrospective analysis of the distinct differences between spontaneous malignant transformation and treatment-associated transformation in <i>IDH</i> -mutant gliomas.

e14094 Background: Malignant transformation (MT) of IDH mutant gliomas is a poorly characterized process by which a lower grade glioma evolves into a higher grade glioma. We stratified patients based on histology and treatment to examine the prevalence of MT in IDH -mutated patients, the prognostic implications of early and late MT, and the differences between spontaneous, treatment associated, and IDH mutant inhibitor associated MT. Methods: We identified 935 IDH mutant patients seen at UCLA from 1998 to 2025 who provided IRB consent. pMT was defined by a second resection with pathology indicating a worsened grade (2 to 3, 2 to 4, 3 to 4). To increase sample size, new contrast enhancement (CEnew) on MRI scans indicative of true progression (TP) was considered iMT. CEnew identified as pseudoprogression (PsP) was not included as MT. Patients were then stratified by pre-MT treatment (none/spontaneous, radiation and/or chemotherapy, or IDH mutant inhibitor only). We defined early MT as shorter than one standard deviation &lt; median ttMT, and late MT as longer than one standard deviation &lt; median ttMT. Time to MT (ttMT), overall survival (OS), and residual survival (censored patients excluded) were analyzed by Kaplan-Meier and Cox multivariate analyses. Results: In our cohort, 328/935 had MT (pMT + iMT): 88 spontaneous, 234 post chemotherapy and/or radiation, and 6 post IDH mutant inhibitor. 111 were early transformers and 26 were late transformers. Early transformers had shorter median ttMT (early=2.841, late=28.66 years, p&lt;0.0001) as expected, and shorter median OS (early=9.784, late=undefined years, p&lt;0.0001). There was no difference in residual survival after MT. Grade 2 astrocytomas had a median time to transformation of 8.55 years while grade 2 oligodendrogliomas had a median time to MT of 16.42 years. There was no difference between time to iMT versus pMT. Older age predicted shorter ttMT (HR 1.022, p=0.0003) and worse OS (HR 1.026, p&lt;0.0001) while higher KPS predicted increased OS (HR 0.983, p=0.0033). Using grade 3 astrocytoma as reference, lower grade tumors had significantly lower hazard ratios of ttMT (G2O HR 0.05438, p=0.0003; G2A HR 1.118, p=0.4740). Relative to RT/Chemo associated MT, spontaneous (HR 1.407, p=0.0131) and IDH mutant inhibitor MT (HR 2.705, p=0.0202) were associated with shorter ttMT. However, among MT patients only (censored patients excluded), only spontaneous MT was associated with a better OS (HR 0.521, p=0.0013). Residual survival was higher in G2Os (HR 0.4817, p=0.0018), but no differences were observed based on treatment received before MT. Conclusions: Treatment type, along with tumor grade and age at diagnosis, emerged as clinically relevant predictors of transformation risk and survival. Using this clinical cohort, future studies will focus on defining molecular features associated with MT.