Acute lymphoblastic leukemia following temozolomide treatment in a patient with glioblastoma: A case report and review of the literature

Abstract

Abstract. Temozolomide (TMZ) is a second-generation oral alkylating agent that functions against a number of central nervous system neoplasms, and is generally used to treat high-grade gliomas, including anaplastic astrocytoma and glioblastoma multiforme. Therapy-related secondary myelodysplastic syndrome and acute myeloid leukemia have been reported in patients following prolonged exposure to TMZ. However, TMZ-related acute lymphoblastic leukemia (ALL) is extremely rare. The present study describes the case of an 11-year-old boy with a 3-day history of generalized tonic-clonic seizures and a contrast-enhanced lesion in the left temporooccipital region with focal cystic degeneration, as detected by magnetic resonance imaging. The patient underwent craniotomy and gross-total resection andpathological analysis confirmed the diagnosis of giant cell glioblastoma. Postoperatively, the patient received TMZ-based concurrent chemoradiation during radiotherapy, and developed B-cell ALL 6 months following TMZ treatment. A thorough literature search identified only six published cases of TMZ-related ALL. The chemotherapeutic efficacy of TMZ has been identified, however, its leukemogenic potential should be emphasized among practitioners and patients. Further studies are required to determine the specific pathogenic mechanism of TMZ-related ALL. Close hematological monitoring of patients following TMZ treatment is vital and a high index of suspicion is necessary. IntroductionTemozolomide (TMZ) is a second-generation oral alkylating agent with the ability to penetrate the blood-brain barrier, and is widely used in the management of high-grade brain neoplasms, including anaplastic astrocytoma and glioblastoma multiforme, in addition to brain metastasis from solid tumors (1,2). TMZ is a prodrug and imidazotetrazine analog that exerts its action following spontaneous conversion to its active form, 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (3). This active drug subsequently exerts its antitumor effect by methylating the purine bases of chromosomal DNA including O6-guanine, which results in the failure of DNA replication, cell cycle arrest and subsequent apoptosis (4,5). TMZ is generally considered effective and relatively safe (6-8); however, increased survival rates in certain patients have uncovered toxicities arising from the long-term use of alkylating agents, including TMZ (9). Treatment-related secondary myelodysplastic syndrome (t-MDS) and treatment-related acute myeloid leukemia (t-AML) have been recorded in patients following prolonged (5-10 years) exposure to alkylating agents (10-12).TMZ is a relatively new drug and glioblastoma is an aggressive neoplasm with poor prognosis, thus the types of secondary cancer arising due to TMZ treatment have not yet been fully characterized. A review of the existing literature demonstrated that only 7 cases of TMZ-related acute lymphoblastic leukemia (ALL) have been reported thus far (13-18). The current case describes an 11-year-old boy with glioblastoma multiforme, who develo...

Lymphoproliferative disorder during temozolomide therapy; a representative case of a formidable complication and management challenges

“…Combining both the above clinical and histopathological ndings, OIIA-LPD was diagnosed. Although hematologic malignancies such as leukemia and myelodysplastic syndrome secondary to temozolomide administration have already been described multiple times, [10][11][12][13] and a small number of cases of non-Hodgkin's lymphoma following temozolomide administration have also been reported, [21] the relationships of those pathologies to EBV were not described. Neither were any of those cases de ned as OIIA-LPD.…”

“…[8] The leukemogenic potential of temozolomide has also been noted, and development of acute myeloid leukemia, acute lymphoblastic leukemia or myelodysplastic syndrome has been reported as late as 5-10 years after exposure. [10][11][12][13] However, there is a paucity of evidence regarding the occurrence of LPD as a side effect of temozolomide therapy.…”

Letter to the Editor regarding “Clear-cell renal cell carcinoma and glioblastoma multiforme coexistence: Double primary malignancy, does it have a causal relationship?”

“…[ 4 ] In addition, temozolomide is classically linked to the development of hematologic malignancies, not RCC. [ 6 ] There is no clearly defined relationship linking the treatment of RCC or GBM to the subsequent development of the other malignancy type.…”

Postmortem study of organ-specific toxicity in glioblastoma patients treated with a combination of temozolomide, irinotecan and bevacizumab

“…However, there is concern that prolonged use of TMZ alone or with other chemotherapy drugs may produce more harm than bene t, including alkylating agent-related leukemia. 21,22 At Tufts Medical Center and Memorial Hermann Hospital (MHH)-Texas Medical Center (TMC)/UTHealth, the TIB regimen was offered to rGBM patients with normal bone marrow function. Treatment decisions were based upon the physician's best knowledge and judgment along with close monitoring of adverse events, balancing the need to control the aggressive tumor and manageable side effects.…”