Treatment Response Assessment in IDH-Mutant Glioma Patients by Noninvasive 3D Functional Spectroscopic Mapping of 2-Hydroxyglutarate

Abstract

Purpose: Measurements of objective response rates are critical to evaluate new glioma therapies. The hallmark metabolic alteration in gliomas with mutant isocitrate dehydrogenase (IDH) is the overproduction of oncometabolite 2-hydroxyglutarate (2HG), which plays a key role in malignant transformation. 2HG represents an ideal biomarker to probe treatment response in IDH-mutant glioma patients, and we hypothesized a decrease in 2HG levels would be measureable by in vivo magnetic resonance spectroscopy (MRS) as a result of antitumor therapy.

Experimental design: We report a prospective longitudinal imaging study performed in 25 IDH-mutant glioma patients receiving adjuvant radiation and chemotherapy. A newly developed 3D MRS imaging was used to noninvasively image 2HG. Paired Student t test was used to compare pre- and posttreatment tumor 2HG values. Test-retest measurements were performed to determine the threshold for 2HG functional spectroscopic maps (fSM). Univariate and multivariate regression were performed to correlate 2HG changes with Karnofsky performance score (KPS).

Results: We found that mean 2HG (2HG/Cre) levels decreased significantly (median = 48.1%; 95% confidence interval = 27.3%-56.5%;P= 0.007) in the posttreatment scan. The volume of decreased 2HG correlates (R(2)= 0.88,P= 0.002) with clinical status evaluated by KPS.

Conclusions: We demonstrate that dynamic measurements of 2HG are feasible by 3D fSM, and the decrease of 2HG levels can monitor treatment response in patients with IDH-mutant gliomas. Our results indicate that quantitative in vivo 2HG imaging may be used for precision medicine and early response assessment in clinical trials of therapies targeting IDH-mutant gliomas.

Figure 1

3D metabolic maps in a mutant IDH glioma patient (grade II, astrocytoma, R132C) before and after radiotherapy. The pre- and post-treatment maps of each metabolite are scaled to the same intensity scale. In the last column the mask of CRLB < 25% is shown for 2HG goodness of fit by LCModel.

Figure 2

Functional spectroscopic maps (fSM) of 2HG/Cre. fSM from three patients are shown: upper patient grade II (WHO) astrocytoma, middle patient grade III (WHO) anaplastic astrocytoma, and lower patient grade IV (WHO) glioblastoma. A threshold Δ2HG/Cre = 0.11 was used to classify voxels as decreased (blue), increased (red) or stable (green) 2HG/Cre. The fSM maps are masked by the CRLB < 25% mask.

Figure 3

Histograms for 2HG/Cre values within tumor ROI for all patients: post-treatment histograms (blue line) compared to pre-treatment histograms (red line). Bottom panel includes bar plots for: A) median 2HG/Cre, B) fractional tumor volume of 2HG/Cre (>0.1), and C) fractional volumes of decreased, stable and increased 2HG/Cre (Δ2HG/Cre = 0.11). Fractional volumes are calculated as the ratio of 2HG/Cre or Δ2HG/Cre volume within specified thresholds over the total volume of tumor outlined on FLAIR images and masked by CRLB < 25%.

Figure 4

Box plots of imaging biomarkers and clinical correlation. A) Fractional changes ((post-pre)/pre*100, %) of metabolite ratios, ADC mean tumor ROI values, and tumor volumes of 2HG/Cre (>0.1) and FLAIR. Vertical red lines indicate the variability of test-retest measurements. Stars indicate statistical significant change (P<0.05) between pre- and post-treatment scans. B) Fractional volumes of decreased, increased and stable 2HG/Cre and ADC, respectively. The hash symbol (#) indicates statistical significant correlation with KPS clinical outcome. C) Univariate linear regression of Karnofsky Performance Status (post-pre change) and the fractional tumor volume of decreased 2HG/Cre (PR = partial response, MR = minor response, SD = stable disease, PD = progressive disease by RANO criteria).