Lucas A Salas1, Thomas G Stewart2, Bret C Mobley3, Chengwei Peng4, Jing Liu5, Sudan N Loganathan5, Jialiang Wang5, Yanjun Ma6, Mitchell S Berger7, Devin Absher8, Yang Hu9, Paul L Moots10, Brock C Christensen1,11, Stephen W Clark10,12. 1. Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH. 2. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN. 3. Department of Pathology, Vanderbilt University Medical Center, Nashville, TN. 4. Department of Medicine, Yale Medical School, New Haven, CT. 5. Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, TN. 6. Tennessee Oncology PLLC, Nashville, TN. 7. Department of Neurosurgery, UCSF, San Francisco, CA. 8. HudsonAlpha, Huntsville, AL. 9. CD Genomics, Shirley, NY. 10. Division of Neuro-Oncology, Vanderbilt-Ingram Cancer Center, Nashville, TN. 11. Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH. 12. Sir Gallahad Labs, Nashville, TN.
Abstract
Purpose: IDH mutations in low-grade gliomas (LGGs) results in improved survival and DNA hypermethylation compared to IDH wild-type LGGs. IDH-mutant LGGs become hypomethylated during progression. It's uncertain if methylation changes occur during IDH wild-type GBM progression and if the methylome can be reprogrammed. This phase I study evaluated the safety, tolerability, efficacy and methylome changes after L-methylfolate (LMF) treatment, in combination with temozolomide and bevacizumab in patients with recurrent high-grade glioma. Patients and Methods: Fourteen patients total, 13 with GBM, one with anaplastic astrocytoma, all IDH wild-type were enrolled in the study. All patients received LMF at either 15, 30, 60, or 90 mg daily plus temozolomide (75mg/m2 5 days per month) and bevacizumab (10mg/kg every two weeks). Results: No MTD was identified. LMF treated had mOS of 9.5 months (95% CI, 9.1-35.4) comparable to bevacizumab historical control 8.6 months (95% CI, 6.8-10.8). Six patients treated with LMF survived more than 650 days. Across all treatment doses the most adverse events were diarrhea (7%, 1 patient, grade 2), reflux (7%, 1 patient, grade 2), and dysgeusia (7%, 1 patient, grade 2). In the six brains donated at death, there was a 25% increase in DNA methylated CpGs compared to the paired initial tumor. Conclusions: LMF in combination with temozolomide and bevacizumab was well tolerated in patients with recurrent IDH wild-type high-grade glioma. This small study did not establish a superior efficacy with addition of LMF compared to standard bevacizumab therapy, however, this study did show methylome reprogramming in high-grade glioma.
Purpose: IDH mutations in low-grade gliomas (LGGs) results in improved survival and DNA hypermethylation compared to IDH wild-type LGGs. IDH-mutant LGGs become hypomethylated during progression. It's uncertain if methylation changes occur during IDH wild-type GBM progression and if the methylome can be reprogrammed. This phase I study evaluated the safety, tolerability, efficacy and methylome changes after L-methylfolate (LMF) treatment, in combination with temozolomide and bevacizumab in patients with recurrent high-grade glioma. Patients and Methods: Fourteen patients total, 13 with GBM, one with anaplastic astrocytoma, all IDH wild-type were enrolled in the study. All patients received LMF at either 15, 30, 60, or 90 mg daily plus temozolomide (75mg/m2 5 days per month) and bevacizumab (10mg/kg every two weeks). Results: No MTD was identified. LMF treated had mOS of 9.5 months (95% CI, 9.1-35.4) comparable to bevacizumab historical control 8.6 months (95% CI, 6.8-10.8). Six patients treated with LMF survived more than 650 days. Across all treatment doses the most adverse events were diarrhea (7%, 1 patient, grade 2), reflux (7%, 1 patient, grade 2), and dysgeusia (7%, 1 patient, grade 2). In the six brains donated at death, there was a 25% increase in DNA methylated CpGs compared to the paired initial tumor. Conclusions: LMF in combination with temozolomide and bevacizumab was well tolerated in patients with recurrent IDH wild-type high-grade glioma. This small study did not establish a superior efficacy with addition of LMF compared to standard bevacizumab therapy, however, this study did show methylome reprogramming in high-grade glioma.
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Authors: J L Roffman; L J Petruzzi; A S Tanner; H E Brown; H Eryilmaz; N F Ho; M Giegold; N J Silverstein; T Bottiglieri; D S Manoach; J W Smoller; D C Henderson; D C Goff Journal: Mol Psychiatry Date: 2017-03-14 Impact factor: 15.992
Authors: Ana C deCarvalho; Hoon Kim; Laila M Poisson; Mary E Winn; Claudius Mueller; David Cherba; Julie Koeman; Sahil Seth; Alexei Protopopov; Michelle Felicella; Siyuan Zheng; Asha Multani; Yongying Jiang; Jianhua Zhang; Do-Hyun Nam; Emanuel F Petricoin; Lynda Chin; Tom Mikkelsen; Roel G W Verhaak Journal: Nat Genet Date: 2018-04-23 Impact factor: 38.330
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