Discussion
HAE, hematologic adverse, toxicity, lymphopenia, glioma, hematotoxic, hematotoxicity
LYMPHOPENIA, EVENTS, GLIOMA
The present study provides a detailed comparative analysis of high grade hematotoxicity in the CeTeG/NOA-09 trial. No hematologic adverse event grade 5 was reported and the overall frequency of HAE showed a non-significant tendency to be higher with CCNU/TMZ as compared to TMZ [HAE patterns differed between the treatment arms: compared to TMZ, more patients developed HAE during later courses in the CCNU/TMZ arm. HAE in the TMZ arm lasted longest after concurrent treatment, while HAE from CCNU/TMZ were more prolonged during later courses. Most likely, the 6-week long exposure to TMZ during the concomitant phase of radiochemotherapy (employing > 1/3 of the total maximum temozolomide dose given during therapy) translates to a longer lasting nadir than the adjuvant 5/28 courses. On the other hand, CCNU/TMZ courses with increasing intensity of the CCNU/TMZ treatment scheme and potentially cumulative and prolonged toxicity of CCNU may explain the more frequent HAE onset in later courses. Consequently, more patients in the CCNU/TMZ arm compared to TMZ discontinued chemotherapy due to hematotoxicity or a resulting delay of > 6 weeks.In line with previous reports, the occurrence of HAE was not associated with shorter survival in our analysis [The duration of HAE was similar between treatment arms with the exception of lymphopenia, which lasted longer in CCNU/TMZ than in TMZ. However, this observation was based on a small number of observations and lymphopenia is often perceived as a less threatening HAE due to the possibility of chemoprophylaxis for pneumocystis jirovecii pneumonia [Comparing HAE rates to former studies, one has to consider the different follow up schemes for blood tests. The present study required mandatory weekly blood tests to attribute hematotoxic events to the suspected causative chemotherapeutic drug and guide dose adjustment. This careful follow-up could explain the higher rate of HAE during standard TMZ treatment of 29%, compared to 16% upon monthly examination in the landmark EORTC 22981/26981-NCIC CE3 trial [We also evaluated the prediction of hematotoxicity employing previously published baseline factors found to be predictive in glioma patients receiving TMZ chemotherapy [The association of female gender and increased risk of HAE has been reported for temozolomide in glioma treatment [In addition to clinical factors, little is known about the contribution of genetic factors to hematotoxicity susceptibility. Lombardi et al. found a methylated 