Factors predicting temozolomide induced clinically significant acute hematologic toxicity in patients with high-grade gliomas: a clinical audit

Abstract

Introduction: Myelo-suppression, the dose-limiting toxicity of alkylating cytotoxic agents is generally perceived to be uncommon with temozolomide (TMZ), a novel oral second generation imidazotetrazinone prodrug, with a reported incidence of 5-10% of grade 3-4 acute hematologic toxicity. We were observing a higher incidence of clinically significant myelo-toxicity with the standard schedule of TMZ, particularly in females, prompting us to do a clinical audit in our patient population.

Methods: One hundred two adults (>18 years of age) treated with TMZ either for newly diagnosed or recurrent/progressive high-grade glioma constituted the study cohort. Clinically significant acute hematologic toxicity was defined as any one or more of the following: any grade 3-4 hematologic toxicity; omission of daily TMZ dose for ≥ 3 consecutive days during concurrent phase; deferral of subsequently due TMZ cycle by ≥ 7 days during adjuvant phase; dose reduction or permanent discontinuation of TMZ; use of growth factors, platelets or packed-cell transfusions during the course of TMZ. Uni-variate and multi-variate analysis was performed to correlate incidence of acute hematologic toxicity with baseline patient, disease, and treatment characteristics.

Results: The incidence of clinically significant neutropenia and thrombocytopenia was 7% and 12% respectively. Seven (7%) patients needed packed-cells, growth factors, and/or platelet transfusions. Grade 3-4 lymphopenia though common (32%) was self-limiting and largely asymptomatic. Two (2%) patients, both women succumbed to community acquired pneumonia during adjuvant TMZ. Multi-variate logistic regression analysis identified female gender, grade IV histology, baseline total leukocyte count <7700/mm(3) and baseline serum creatinine ≥1mg/dl as factors associated with significantly increased risk of clinically significant acute hematologic toxicity.

Conclusion: The incidence of TMZ induced clinically significant neutropenia and thrombocytopenia was low in our patient population. Severe lymphopenia though high was largely asymptomatic and self-limiting. Gender, grade, leukocyte count, and serum creatinine were significant independent predictors of severe acute myelo-toxicity.

Keywords: Glioma; Myelo-toxicity; Neutropenia; Temozolomide; Thrombocytopenia.