Germline polymorphisms in MGMT associated with temozolomide-related myelotoxicity risk in patients with glioblastoma treated on NRG Oncology/RTOG 0825

We sought to identify clinical and genetic predictors of temozolomide-related myelotoxicity among patients receiving therapy for glioblastoma. Patients ( = 591) receiving therapy on NRG Oncology/RTOG 0825 were included in the analysis. Cases were patients with severe myelotoxicity (grade 3 and highe...

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Published in:Neuro-oncology advances 2022-01, Vol.4 (1), p.vdac152
Main Authors: Scheurer, Michael E, Zhou, Renke, Gilbert, Mark R, Bondy, Melissa L, Sulman, Erik P, Yuan, Ying, Liu, Yanhong, Vera, Elizabeth, Wendland, Merideth M, Youssef, Emad F, Stieber, Volker W, Komaki, Ritsuko R, Flickinger, John C, Kenyon, Lawrence C, Robins, H Ian, Hunter, Grant K, Crocker, Ian R, Chao, Samuel T, Pugh, Stephanie L, Armstrong, Terri S
Format: Article
Language:English
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Clinical Investigations
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Summary:We sought to identify clinical and genetic predictors of temozolomide-related myelotoxicity among patients receiving therapy for glioblastoma. Patients ( = 591) receiving therapy on NRG Oncology/RTOG 0825 were included in the analysis. Cases were patients with severe myelotoxicity (grade 3 and higher leukopenia, neutropenia, and/or thrombocytopenia); controls were patients without such toxicity. A risk-prediction model was built and cross-validated by logistic regression using only clinical variables and extended using polymorphisms associated with myelotoxicity. 23% of patients developed myelotoxicity ( = 134). This toxicity was first reported during the concurrent phase of therapy for 56 patients; 30 stopped treatment due to toxicity. Among those who continued therapy ( = 26), 11 experienced myelotoxicity again. The final multivariable clinical factor model included treatment arm, gender, and anticonvulsant status and had low prediction accuracy (area under the curve [AUC] = 0.672). The final extended risk prediction model including four polymorphisms in had better prediction (AUC = 0.827). Receiving combination chemotherapy (OR, 1.82; 95% CI, 1.02-3.27) and being female (OR, 4.45; 95% CI, 2.45-8.08) significantly increased myelotoxicity risk. For each additional minor allele in the polymorphisms, the risk increased by 64% (OR, 1.64; 95% CI, 1.43-1.89). Myelotoxicity during concurrent chemoradiation with temozolomide is an uncommon but serious event, often leading to treatment cessation. Successful prediction of toxicity may lead to more cost-effective individualized monitoring of at-risk subjects. The addition of genetic factors greatly enhanced our ability to predict toxicity among a group of similarly treated glioblastoma patients.
ISSN:2632-2498
2632-2498
DOI:10.1093/noajnl/vdac152