Introduction: Glioblastoma (GBM) is a highly aggressive malignancy which requires a multi-disciplinary therapeutic approach of surgery, chemotherapy and radiation therapy, but is frequently limited by treatment-related side-effects. The most common adverse effect of chemotherapy with temozolomide (TMZ) is myelosuppression. It remains unclear whether the degree of bone marrow suppression might serve as a biomarker for treatment outcome. The aim of the current study was to investigate whether the degree of bone-marrow toxicity in patients treated with TMZ correlates with overall survival (OS) and MRI-based time to progression (PFS).

Methods: Complete blood counts and clinical and radiographic information were collected retrospectively from 86 malignant glioma patients who had completed both radiation therapy and at least 6 monthly cycles of chemotherapy with TMZ.

Results: Using a multivariate cox proportional hazard model, it was observed that treatment-induced leukopenia, MGMT promotor methylation, wild-type EGFR, and younger patient age at diagnosis were associated with improved OS. The 2-year survival rate was 25% and 58% for patients with leukocytosis and leukopenia, respectively, over 6 months of TMZ treatment. Consistent with the literature, IDH mutation and MGMT promotor methylation were associated with better PFS and OS. IDH mutation and MGMT promotor methylation were not correlated with changes in peripheral red blood cell or white blood cell counts.

Conclusions: Bone marrow suppression, specifically leukopenia, might serve as a potential biomarker for OS and PFS in malignant glioma patients treated with chemoradiation and temozolomide. It remains unclear whether treatment induced leukopenia correlates with drug induced anti-tumor activity, or represents an independent factor of altered systemic and tumor microenvironment. Additional studies will be needed to determine a dose-dependence for chemotherapy based upon peripheral blood counts.

Patient Care: Given the routine and reliable sampling of peripheral blood counts in GBM patients receiving conventional therapies, leukopenia could serve as a valuable biomarker for monitoring of treatment response and predicting clinical outcomes. It could enhance the clinical utility of emerging liquid biopsy techniques that monitor circulating tumor cells and tumor DNA. If changes in white blood cell counts can serve as a correlate marker for in vivo TMZ levels and efficacy, this could help in the optimization of dosing and scheduling of chemotherapy, accounting for variability in drug metabolism. This study sets the foundation for a larger prospective study to validate and characterize the prognostic and predictive value of alterations in white blood cell counts in GBM patients treated with TMZ.

Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the importance of leukopenia as an independent prognostic marker associated with improved OS in GBM patients receiving TMZ. 2) Discuss, in small groups, whether the temporal relationship between changes in peripheral white blood cell counts during adjuvant TMZ treatment and clinical outcomes may be a reflection of plasma TMZ levels, and thus a surrogate marker of therapeutic efficacy. Currently, TMZ dosing is based solely on patient BSA and does not account for variability in resistance mechanisms and drug metabolism, raising the possibility that some patients may be dosed sub-therapeutically. Inadequate dosing may partially contribute to the observed resistance to cytotoxic treatment and ultimately tumor recurrence. If changes in white blood cell counts can serve as a correlate marker for in vivo TMZ levels and efficacy, this could help in the optimization of dosing and scheduling of chemotherapy, accounting for variability in drug metabolism. 3) Identify an effective treatment protocol for GBM patients in which TMZ dosing accounts for inter-patient differences in resistance mechanisms or drug metabolism. Adequate dosing, guided by changes in white blood cell counts, may overcome causes of treatment failure and improve survival.

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