Cytarabine and neurologic toxicity.

Abstract

Cytarabine is an effective drug in the treatment of certain hematologic malignancies and its common toxicities are myelosuppression and gastrointestinal disturbance. In the past decade, neurotoxicity has been an increasingly recognized cytarabine effect. Intrathecal (IT) cytarabine may result in myelopathy that is incompletely reversible. Combined IT drug and cranial irradiation may lead to necrotizing leukoencephalopathy. Intravenous (IV) therapy may cause a peripheral neuropathy that varies greatly in its severity. The high IV cytarabine doses now commonly used can cause seizures, cerebral dysfunction, or an acute cerebellar syndrome with an incidence up to 14%. Patient age (greater than 60 years) appears to be the most important risk factor, but drug dose/schedule, cumulative drug dose, renal and hepatic dysfunction, and concomitant use of neurotropic antiemetic agents may also influence the risk of neurotoxicity. A better understanding of the pathophysiology and pharmacology of such cytarabine-induced neuronal injury will allow this drug to be used with greater efficacy and safety.

Nucleoside analogues: mechanisms of drug resistance and reversal strategies

“…A potential consequence related to NA modulation therapy may be the increased risk of secondary malignancies in a group of patients whose disease already places them at a great risk of second cancers, and dose-related effects like severe neurotoxicity. 210,211 Apparently, the frequency and severity of neurotoxicity may be greater with the combination therapy than with either drug used alone.…”

Gemcitabine-Induced Reversible Posterior Leukoencephalopathy Syndrome: A Case Report and Review of the Literature

“…Although more lipophilic, it is unclear if gemcitabine can cross the blood-brain barrier [9]. Both agents are rapidly metabolized by cytadine deaminase, which is absent in the CNS [8].…”

“…Ara-C rapidly distributes i.v. and concentrations in cerebrospinal fluid may reach 20%-50% of plasma levels [8]. Although more lipophilic, it is unclear if gemcitabine can cross the blood-brain barrier [9].…”

Unrelated donor bone marrow transplantation using a chemotherapy‐only preparative regimen for adults with high‐risk acute myelogenous leukemia

“…Resistance to standard dose cytarabine can be multifactorial, including decreased membrane transport, increased catabolism of the parent compound, and decreased formation of phosphorylated derivatives [16][17][18]. High-dose cytarabine can overcome resistance by altering drug transport into cells [16]. As cytarabine is one of the most effective agents used for treatment of AML, the addition of high-dose cytarabine to BU/CY might enhance cytoreduction with manageable regimen-related toxicity.…”

“…The BAC regimen, previously described by our group in allogeneic related BMT, incorporates high-dose cytarabine with BU/CY-2 [15]. Resistance to standard dose cytarabine can be multifactorial, including decreased membrane transport, increased catabolism of the parent compound, and decreased formation of phosphorylated derivatives [16][17][18]. High-dose cytarabine can overcome resistance by altering drug transport into cells [16].…”