Johns Hopkins Hospital, Baltimore, MD
Sushant Puri , Jessica Shi , Lindsay Blair , Jaishri O'Neill Blakeley , John Laterra , David Kamson
Background: Isocitrate Dehydrogenase (IDH) mutant gliomas represent a distinct class of primary brain tumors. Mutant IDH is a driver mutation implicated in gliomagenesis and a potential therapeutic target. Ivosidenib, an inhibitor of mutant IDH1, is currently being evaluated to treat gliomas. In the present study we assess our single-institutional experience with the off-label use of ivosidenib to reduce tumor growth rate in patients with IDH mutant gliomas. Methods: We have longitudinally analyzed the imaging of patients with histology-proven radio- and chemotherapy-naïve IDH-mutant WHO Grade 2 and 3 astrocytomas (AS) and oligodendrogliomas (OG) treated with off-label ivosidenib between 2019 and 2022. First, each patients’ FLAIR images were anonymized, bias-corrected, co-registered and semi-automatically segmented for volumetric analysis using 3D Slicer 4.11. MR acquisition dates were hidden, and the order of scans was randomized to prevent expectation bias. Volumetric trends and PFS were analyzed. Progressive disease was defined as a ≥40% increase in volume from baseline as per modified RANO criteria. Results: Eleven patients were included in the analysis (median age 46 years [range 26-62], 2F, 8AS/3OG, 7 Grade 2). Mean±SD follow-up time on ivosidenib was 16.1±15.5 months. Tumor volume reduction was noted in 82% of patients at least at one time point. Average volume change at best response was -11.4±12.8%. Mean time to best response was 12.1±9.3 months. PFS-6 and PFS-12 were 91% (n = 11), and 88% (n = 8), respectively. Mean PFS was 24.4 months (CI95% 18.8-29.9). Median PFS was not reached. Patients older than 45 years had significantly higher volume reduction compared to younger patients (18.9±6.3% vs. -2.4±13.2%;-p = 0.047, 2-tailed T-test). Ivosidenib was discontinued in in 2 patients for 2D radiographic changes, and in one for increased seizure frequency. Conclusions: The use of ivosidenib in treatment-naïve gliomas was associated with a high response rate; however, on average it required longer than a year to achieve best response. In this cohort, older patients had higher volume reduction. The drug was well tolerable. Further analysis of an expanded cohort is underway.
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