temozolomide ( tmz ) is an oral dna alkylating agent used to treat high - grade gliomas such as glioblastoma multiforme and anaplastic astrocytoma . it results in a depletion of the dna repair enzyme o - methylguanine - dna methyltransferase ( mgmt ) . as it improves median survival by 2.5 months and 2-year survival rates by 16% compared to radiotherapy alone in glioblastoma patients after surgery , it has become part of the standard care of brain cancer . daily dosage of 75 mg / m for up to 6 weeks is given concomitantly with radiation therapy . in adjuvant therapy , a daily dose of 150200 mg / m of body surface area is given for 5 days of every 28-day cycle . alternatively , an extended dose - dense regimen , in which the dose density over the 28-day cycle is 210% higher , can be administered . such regimens are believed to be more efficient as they deplete the mgmt enzyme more profoundly , but to date no significant benefit in survival has been demonstrated . the incidence of grade 34 hematological events is believed to be less than 10% [ 3 , 4 ] . however , as tmz is a relatively new agent that is administered to patients with poor prognosis , possible hematological adverse events may not have been fully characterized yet . a 58-year - old male was admitted to the emergency department in may 2010 with a right motor hemiparesis and a speech disorder . medical history was unremarkable except for a vasectomy and nephrolithiasis . an mri scan showed a contrast - enhancing nodule in the left crus posterior capsulae internae of the brain . the patient received chemoradiation with external beam radiotherapy ( 60 gray in 30 fractions ) and concomitant tmz ( 75 mg / m / day ) . adjuvant tmz was started in september 2010 , using a standard regimen ( 150 mg / m / day for 5 days of a 28-day cycle , or 300 mg per cycle ) . two days after the first administration , he developed epilepsy which was treated with levetiracetam ( keppra ) . mri evaluation after 2 cycles showed tumor growth . it was then decided to start with an extended dosing schedule ( 100 mg / m / day for 21 consecutive days every 28-day cycle ) . from november 2010 until december 2011 , 14 cycles of extended dosing tmz were completed . repeated imaging by mri consistently showed good tumor control . on clinical evaluation , there was a stable dysarthria , progressive loss of memory and a tolerable headache . there was very little delay in administration of subsequent cycles , indicating low overall myelotoxicity , although a marked lymphopenia ( grade 3 and sometimes grade 4 ) was present very early in treatment ( 11/2010 ) . the administration of a 15th cycle , scheduled for january 2012 , was delayed because of leuko- and neutropenia ( grade 1 ) . on consultation 1 month later , persisting neutropenia was seen . the patient then complained of a possible infection of the left eye , for which local oxytetracycline hydrochloride ( terramycin ) was prescribed . one week later , he presented to the emergency unit with fever , green rhinorrhea , headache and an infection of the left eye . , pneumonia was diagnosed and antibiotics were started ( amoxicillin / clavulanic acid together with trimethoprim / sulfamethoxazole ) . as the patient did not improve , a ct scan was performed and showed pansinusitis with an abscess breaking through the transethmoidal sinus and causing proptosis ( fig . surprisingly , the histological diagnosis was a second tumor , a high - grade b - cell lymphoma , as seen in immunodeficient patients ( fig . cytomegalovirus and epstein - barr virus ( ebv ) serology was positive , consistent with an old infection . pet - ct scanning showed involvement extending from the left ethmoid and maxillary sinuses to the naso- and oropharynx . bone marrow investigation showed dysplasia in all 3 lineages , due to tmz toxicity ; there were no signs of invasion . systemic therapy [ rituximab , cyclophosphamide , doxorubicin , vincristine and prednisone ( r - chop ) at 50% ] was proposed ; 68 cycles , depending on tolerance and response . in the meantime , there was a further progression of the glioblastoma for which the patient underwent stereotactic radiosurgery of 2 tumoral localizations in the brain . the first administration of r - chop was not well tolerated and the patient developed disseminated zona . although alkylating agents have been associated with an increased risk of secondary neoplasms ( both hematological malignancies and solid tumors ) , tmz was thought to have a rather favorable myelotoxic profile , with a relatively low incidence of grade 34 events ( < 10% [ 3 , 4 ] ) . however , tmz is a relatively new agent and the prognosis of patients treated with tmz is usually short due to the underlying malignancy . consequently , severe hematological adverse events may not have been characterized yet . in this paper , we present a patient who developed a high - grade b - cell lymphoma after being treated with an extended dose - dense schedule of tmz . to our knowledge , there are only a few case reports of this type . this suggests that there might be an increased risk of non - hodgkin lymphoma after an extended dose - dense tmz treatment . in their study of severe hematologic adverse events associated with tmz reported between 1997 and 2008 , villano et al .   found reports of myelodysplastic syndromes , agranulocytosis , pancytopenia , leukemia ( both acute lymphoblastic and acute myeloid ) , and lymphoma . they also found a ( rather concerning ) high rate of aplastic anemia , which appears to be specifically associated with tmz . these authors conclude that tmz presents a profile of hematologic toxicity different from that of other alkylating agents . remarkable in the present case was the development of a grade 34 lymphopenia early in treatment . histological analysis indicated a high - grade b - cell lymphoma ( diffuse large b - cell lymphoma , dlbcl ) . sporadic dlbcl , is more consistent with post - transplant lymphoproliferative disorders , as corroborated by the presence of cd30-positive cells . the precise contribution of ebv to the pathogenesis is unclear , but ebv can cause abnormal growth of infected b - cells and some tumors are indeed known to be ebv associated ( e.g. burkitt 's lymphoma , hodgkin disease , nasopharyngeal carcinoma , post - transplant lymphoma ) . however , considering the high incidence of ebv infection , the finding of it might be random . the mechanism by which secondary ( hematological ) neoplasms occur after treatment with tmz remains largely unknown , though it is most likely related to treatment dose and duration . it might be possible that defective dna repair ( due to depletion of mgmt ) leads to genome instability and hypermutation , thereby predisposing leukemogenesis . alternatively , immunosuppressed patients ( post - transplant , hiv - infected ) are known to be at an increased risk of developing lymphoproliferative disorders , most of these being b - cell derived and ebv associated . this elicits a cytotoxic t - lymphocyte response which allows the transition into asymptomatic life - long infection . the persisting lymphopenia and thus the breakdown of ebv - specific immunity , may have contributed to the development of ebv - associated malignancy . there are also cases of high - grade b - cell lymphoma occurring at the site of a chronic inflammatory process ( pyothorax or osteomyelitis ) , where chronic inflammation results in a local defect of the ebv - specific immunity . thus , both the immunosuppressive and the possible mutagenic effect of tmz can explain why our patient developed non - hodgkin b - cell lymphoma . establishing a ( unequivocal ) causal relationship between tmz administration and secondary malignancies is difficult , since many patients receive additional therapies , including different alkylating agents and radiation therapy . nevertheless , this report of a patient developing non - hodgkin b - cell lymphoma after tmz treatment highlights the importance of regular ( hematological ) follow - up of patients and emphasizes the need of reporting major adverse events associated with tmz . as the use of tmz against various neoplasms associated with a better prognosis ( hence , a longer survival ) increases , the awareness that tmz may induce secondary malignancies through its cytotoxic and mutagenic properties should increase as well . based on this report , we would recommend a higher degree of vigilance in patients who develop grade 34 lymphopenia .
temozolomide ( tmz ) is an alkylating agent , used for the treatment of high - grade gliomas . 
 this case report describes the development of a non - hodgkin lymphoma in a patient treated with extended - dose temozolomide and radiotherapy . 
 in addition to the possible mutagenic effect of temozolomide  as described for all alkylating agents  there might have been an immunosuppressive effect of tmz . 
 the pathological appearance of the lymphoma as well as the presence of a grade 3 lymphopenia early in treatment supports this hypothesis . as the use of tmz increases , the awareness that tmz may induce secondary malignancies should increase as well .