Drug Interactions between cytarabine and nelarabine

MONITOR CLOSELY: Administration of nelarabine in the setting of previous or concurrent intrathecal chemotherapy may increase the risk of severe neurologic events. Fatal neurologic outcomes have been reported. Neurological adverse reactions reported with nelarabine are considered dose-dependent, dose-limiting, and may not be completely reversible with cessation of therapy. It has been suggested that nelarabine and its active metabolite Ara-G, have good penetration and a longer half-life in the cerebrospinal fluid (CSF) than in plasma; however, a causal relationship between its CSF concentration and neurotoxicity has not been established. Intrathecal chemotherapy has also been independently associated with neurologic toxicity. A case report describes severe neurotoxicity in a 37-year-old Caucasian female with relapsed T-cell lymphoblastic lymphoma. Her treatment included re-induction with nelarabine 1500 mg/m2 on days 1, 3, and 5 with intrathecal cytarabine 100 mg administered on day 2, followed by a second cycle of nelarabine at the same dose as cycle 1 without intrathecal cytarabine starting on day 32. Ten days after completing her second course of nelarabine, she was admitted with bilateral lower extremity numbness which progressed to the mid-thoracic region, along with gait instability, lower extremity weakness, urinary incontinence, and impaired coordination of the bilateral upper extremities. These symptoms were attributed to an additive neurotoxic effect from the single intrathecal cytarabine dose administration close to nelarabine. Other case reports describe the development of progressive muscle weakness, in some cases leading to significant paraplegia with paresis of the upper limbs, dysautonomia, and a Guillain-Barre-like syndrome of acute polyradiculopathy of the lower limbs. However, those cases included prior treatments with neurotoxic potential in addition to intrathecal chemotherapy. It has also been suggested that the number of doses of intrathecal chemotherapy may increase the severity of neurotoxicity. A study in seven pediatric and adolescent patients with refractory or relapsed T-cell lymphoblastic leukemia or lymphoma reported that 75% of who developed grade 3 neurotoxicity following nelarabine therapy have received two to four doses of intrathecal chemotherapy. The risk of neurotoxicity may also be influenced by concurrent CNS disease at baseline, as well as polymorphisms in genes responsible for DNA repair or inflammation.

MONITOR CLOSELY: The concomitant or sequential administration of multiple antineoplastic agents may result in additive hematologic toxicities. Chemotherapy administered via the intrathecal route may appear in significant concentrations in the systemic circulation and result in hematologic adverse events.

MANAGEMENT: Caution and close monitoring for neurotoxicity is advised if nelarabine is to be used concurrently with intrathecal chemotherapy or in patients who have been previously treated with intrathecal chemotherapy. Close monitoring for neurologic and hematologic adverse events is recommended. Monitoring for signs and symptoms of neurologic toxicity is particularly recommended during and for at least 24 hours after treatment with nelarabine. Nelarabine therapy should be discontinued in the event of neurologic adverse reactions of NCI CTCAE Grade 2 or more. Patients should be advised to contact their physician immediately in the event of signs and symptoms of neurotoxicity such as severe somnolence, confusion and coma, convulsions, ataxia, status epilepticus, and hypoesthesia ranging from numbness and paresthesias to motor weakness and paralysis. The manufacturers' recommendations and/or institutional protocols should also be consulted for specific guidance concerning monitoring and management of non-hematologic and hematologic toxicities.