The impact of thrombocytopenia from temozolomide and radiation in newly diagnosed adults with high-grade gliomas

Abstract

Temozolomide (TMZ) administered daily with radiation therapy (RT) for six weeks, followed by adjuvant TMZ for six months, has become standard therapy for patients with glioblastoma multiforme (GBM). After several newly diagnosed patients at our institution developed severe (grade 3-4), prolonged thrombocytopenia, we conducted a retrospective review to define the incidence, depth, and duration of thrombocytopenia associated with this therapy. We reviewed the medical records and laboratory data of all adult patients with newly diagnosed high-grade gliomas who started treatment with this regimen between June 2004, when the regimen was first used at our institution, and August 2005. Of the 52 patients who met the criteria for this review, grade 3-4 thrombocytopenia occurred in 10 (19%; 95% CI, 10%-33%). In eight patients, the thrombocytopenia was attributable to concurrent daily TMZ and RT. The median duration of grade 3-4 thrombocytopenia was 32 days (range, 1-389 days). Five patients (10%) required platelet transfusions, two (4%) have required continued biweekly platelet transfusions for over six months, and nine (17%) discontinued therapy because of thrombocytopenia. Grade 3-4 thrombocytopenia occurred in 25% of women and 14% of men. Grade 3-4 neutropenia and anemia were noted in 10% and 8% of patients, respectively, and were not clinically significant. Between 15% and 20% of our newly diagnosed patients receiving TMZ and RT developed severe (grade 3-4) and potentially irreversible thrombocytopenia. The factors that predispose patients to this toxicity have yet to be determined. This toxicity should be considered when (1) prescribing this regimen to patient populations where a clinical benefit has yet to be shown, (2) contemplating empirical escalations of the dose or duration of TMZ, or (3) combining it with other potentially myelosuppressive therapies.

Fig. 1

Platelet counts of the 10 patients who developed grade 3–4 thrombocytopenia. The vertical line at day 42 indicates the point at which concomitant daily TMZ and RT are typically completed. The vertical line at day 70 indicates the point at which adjuvant TMZ cycles are usually started. The upper horizontal line (at platelet count 100,000/mm3) indicates the level below which TMZ is no longer administered. The lower horizontal line (at platelet count 50,000/mm3) indicates the level below which patients are classified as having grade 3–4 thrombocytopenia. To display underlying platelet trends more clearly, immediate posttransfusion platelet counts have not been displayed.

Fig. 2

Duration of grade 3–4 thrombocytopenia for the 10 patients who developed grade 3–4 thrombocytopenia.

Fig. 3

The imidazotetrazinone group of alkylating agents. Both dacarbazine (DTIC) and mitozolomide have been associated with severe hematologic toxicity.