Recurrent Hematological Toxicity After Second-Line Treatment in Patients with Glioblastoma: Indication of a Potential Predisposition

PURPOSE: Myelotoxicity is a well-known adverse effect of alkylating chemotherapy for glioblastoma. While risk factors during first-line therapy are established, little is known about myelotoxicity recurrence in second-line treatment. This study investigates whether first-line myelotoxicity therapy predisposes patients to recurrence in the second-line setting.

PATIENTS AND METHODS: We conducted a retrospective cohort study of 589 patients with glioblastoma treated at the Brain Tumor Centre Amsterdam (2005-2022). Of these, 178 received second-line lomustine or rechallenge temozolomide. Myelotoxicity severity was predominantly assessed using nadir hematological values and its duration. A log-link generalized linear model evaluated associations between first-line and second-line myelotoxicity severity, adjusting for covariates. Cox proportional hazards models assessed time to myelotoxicity onset.

RESULTS: We included 151 patients (mean age 57.1 ± 11.8 years; 66.9% male). Lomustine was given to 66.9%. Myelotoxicity occurred in 73.5% of patients, with 19.9% developing severe toxicity. First-line myelotoxicity severity was significantly associated with second-line severity (β = 1.3, p<.001). Lomustine correlated with higher myelotoxicity severity than temozolomide (β = 1.4, p=.002). Higher first-line myelotoxicity scores predicted earlier onset of any-grade (HR = 1.4, p<.001) and severe (HR = 2.1, p<.001) myelotoxicity in second-line therapy.

CONCLUSION: First-line myelotoxicity for glioblastoma predicts its recurrence and earlier onset in second-line therapy. Patients with toxicity in first-line have an increased risk of severe hematological toxicity upon re-exposure. Lomustine carries a higher risk for myelotoxicity than temozolomide. These findings suggest an inherent predisposition to alkylating chemotherapy-induced myelotoxicity for a subgroup of patients. Integrating prior myelotoxicity history into second-line treatment decisions may improve risk stratification and guide monitoring.