Aplastic anaemia in patient with glioblastoma multiforme treated with temozolomide

Temozolomide has received approval by the US Food and Drug Administration for use in combination with radiother apy as fi rst-line treatment for glioblastoma multiforme. Myelosuppression is the dose-limiting toxic eff ect of temozolomide. Stupp and colleagues reported that 19 (7%) of 284 patients had grade 3 or 4 haematological toxic eff ects with concomitant radiotherapy and temozol omide, and 32 (14%) of 223 with adjuvant temozolomide. Here, we report the occurrence of irreversible bone-marrow aplasia after treatment with temozolomide and radiotherapy given according to the regimen of Stupp and colleagues. A 45-year-old man with an unremarkable past medical history sought medical attention for insidious development of headaches, decreased short-term memory, and blurred vision. Brain MRI showed a large, enhancing mass in the left frontal lobe with surrounding oedema (fi gure 1A). He initially underwent a stereotactic biopsy, followed by optimum debulking surgery done with speech and motor mapping. Pathological analysis confi rmed glioblastoma multiforme (fi gure 2A). The patient received standard fractionated externalbeam radiotherapy at a dose of 60 Gy (given in 30 fractions of 2 Gy for 6 weeks) with concomitant temozolomide (75 mg/m2 a day). He tolerated chemotherapy well, and there were no changes or delays to the dose. He received 300 mg aerosolised pentamidine at the start and end of chemoradiotherapy for prophylaxis of Pneumocystis carinii. 4 weeks after concomitant treatment, the patient began temozolomide monotherapy (200 mg/m2 a day) for 5 days of a 28-day cycle. During the third cycle of treatment, he had a nadir absolute neutrophil count and white-blood-cell count of 1·6×109 cells/L (table). Before this time, the only haematological toxic eff ect was mild leucopenia. The dose of temozolomide was reduced to 150 mg/m2 for the fourth cycle, which was initiated on adequate recovery (table) of blood counts. After the fourth cycle of temozolomide, the patient developed profound and persistent pancytopenia (table). All drugs, including over-the-counter supplementation, were reviewed. Drugs preceding, and on-treatment with, temozolomide included ondansetron, prochlorperazine, para cetamol, ranitidine, dexamethasone, aerosolised pent amidine, phenytoin, carbamazepine, and gabapentin. On the basis of concern that the pancytopenia was secondary to drug eff ects, all drugs were discontinued except for the initiation of prophylactic antibiotics, fi lgrastim, epoetin alfa, and platelet transfusions. 8 weeks after adjuvant treatment with temozolomide, the pancytopenia worsened (table). Bone-marrow biopsy showed hypocellular bone marrow with nearly absent haemopoiesis, which was insuffi cient for cytogenetic studies (fi gure 2B). Supportive treatment and antibiotic prophylaxis were continued, and a repeat bone-marrow biopsy 2 weeks later confi rmed the absence of haemopoietic-cell progenitors; a diagnosis of aplastic anaemia was established. An HLA-identical sibling was identifi ed, and the patient underwent a T-cell-depleted allogeneic stem-cell trans plantation 3 months after the last treatment with Lancet Oncol 2006; 7: 436–38