Neurologic complications associated with intrathecal liposomal cytarabine given prophylactically in combination with high-dose methotrexate and cytarabine to patients with acute lymphocytic leukemia

Abstract

Neurologic complications associated with intrathecal liposomal cytarabine given prophylactically in combination with high-dose methotrexate and cytarabine to patients with acute lymphocytic leukemiaElias Jabbour and colleagues reported on the novel use of intralumbar liposomal extended-release ara-C (DepoCyt; SkyePharma, San Diego, CA) administered in lieu of standard central nervous system (CNS) prophylaxis for adult patients with acute lymphocytic leukemia (ALL). 1 Concerningly, 5 of the 31 patients receiving DepoCyt (16%) developed neurologic complications attributed by the investigators to intralumbar DepoCyt. We would like to comment on the neurologic syndromes observed in this patient cohort and attributed to DepoCyt.In one instance, an unprovoked, uncomplicated seizure was reported. Seizures occasionally occur (more than 1%) with intracerebrospinal fluid (intra-CSF) chemotherapy and in particular following intraventricular drug instillation. However, in the authors' experience, seizures occur in relation to acute drug administration (ie, either at time of drug injection or as a complication of drug-induced chemical meningitis). 2 A seizure occurring 10 days after intralumbar therapy seems unlikely to be related to intra-CSF chemotherapy and more likely metabolic in etiology or cryptogenic and occurring in a genetically predisposed patient.Patient 2 developed "pseudotumor cerebri" characterized by progressive visual loss and increased opening pressure on lumbar puncture. 3 Treatment with ventriculoperitoneal (VP) shunting resulted in partial visual restoration. Intra-CSF chemotherapy often produces transient chemical meningitis, which, rarely, gives rise to an adhesive arachnoiditis and, as a result, CSF flow disturbances. This sequence of events, culminating in communicating hydrocephalus, has only previously been described following intraventricular drug administration. The risk factors for this poorly understood disorder likely include female sex and corticosteroid administration.The third patient was described as having a cauda equina syndrome with isolated incontinence and saddle anesthesia. Cauda equina syndromes are characterized by lower motor neuron asymmetric paraparesis and dermatomal lower-extremity sensory loss with the late appearance of incontinence. The symptoms in this patient suggest instead a conus medullaris syndrome typified by early incontinence and sacral sensory disturbance. Unfortunately, this is a rare complication of intralumbar chemotherapy regardless of drug administered.The fourth patient was also described as having a cauda equina syndrome though the clinical findings were incontinence only. Incontinence as the sole manifestation of spinal cord dysfunction is rarely seen. The fact that this symptom did not progress (or new symptoms develop) despite continued intralumbar DepoCyt seems unusual and unlikely to represent spinal cord injury.The final patient developed what was characterized as encephalitis; however, encephalopathy seems more precise. Again, a relation between the ...

Intrathecal liposomal cytarabine for treatment of leptomeningeal involvement in transformed (Richter’s syndrome) and non‐transformed B‐cell chronic lymphocytic leukaemia in Spain: a report of seven cases

“…Tolerability was good, and mild headache was the only adverse effect, similar to other case reports (Miller et al, 1997;Knop et al, 2005). It is interesting that there were no neurological side effects in the three patients who received concurrent high-dose systemic chemotherapy, contrary to other authors' findings (Chamberlain & Glantz, 2007;Jabbour et al, 2007;McClune et al, 2007). In summary, these are the first results on the effectiveness of the sustained-release formulation of liposomal cytarabine for CNS involvement in B-CLL and RS.…”

“…Although several studies have demonstrated the efficacy of the IT formulation of liposomal cytarabine in the treatment of neoplastic meningitis in acute leukaemia and lymphoma (Glantz et al, 1999;Sancho et al, 2007;Garcia-Marco et al, 2009), no reports on its effectiveness for leptomeningeal involvement in B-CLL or RS have been published. To the best of our knowledge, of all reported cases of CLL with CNS involvement, only one patient received treatment with IT depot liposomal cytarabine.…”

“…Depot formulation of liposomal cytarabine has proven to be useful in intrathecal (IT) treatment of leukaemic and lymphomatous meningitis (Glantz et al, 1999;Garcia-Marco et al, 2009), but has scarcely been used for central nervous system (CNS) involvement in B-cell chronic lymphocytic leukaemia (B-CLL) or transformed B-CLL (Richter syndrome) (RS). We report the results of compassionate therapy with IT depot liposomal cytarabine in seven patients diagnosed with B-CLL or RS with CNS involvement.…”

Treatment of lymphomatous and leukemic meningitis with liposomal encapsulated cytarabine

“…Admittedly, it is diffi cult to distinguish symptoms by infi ltration of CNS from side effects observed after administration of any substance available for intrathecal use alone or in combination with systemic chemotherapy (Weiss et al 1974;Resar et al 1991;Schiller et al 1992;Benesch and Urban 2008). Nevertheless, these observations have led to a discussion among clinicians about the safety of DepoCyte ® (Chamberlain and Glantz 2007;Pui 2007). …”

Preparation, Characterization, and Optimization of Folic Acid-Chitosan-Methotrexate Core-Shell Nanoparticles by Box-Behnken Design for Tumor-Targeted Drug Delivery

“…Methotrexate is known as a strong classic anticancer agent and used as monotherapy or in combination with other anticancer drugs in multidrug chemotherapy regimens (3). It has a wide range of activities in cytostatic activities, especially when high doses are associated with the release of folinic acid (4)(5)(6). Serum concentrations of methotrexate quickly drop when it is directly injected into the bloodstream (7).…”