Sustained-Release Cytarabine for Lymphomatous Meningitis

ATLANTA—Administration of DepoCyt, a novel sustained-release formulation of cytarabine (ara-C), proved favorable with acceptable safety in the first randomized, controlled trial of any drug for lymphomatous meningitis, Stephen B. Howell, MD, said at the 35th annual meeting of the American Society of Clinical Oncology (ASCO).

About 6,000 people a year develop lymphomatous meningitis (7% to 15% of patients with lymphoma, including AIDS-related and non-Hodgkin’s lymphoma). An additional 15% of patients with solid tumors and leukemia can go on to develop neoplastic meningitis.

The most common treatment is delivery of local chemotherapy through a reservoir device placed in the lateral ventricle of the brain. “The problem is that the disease infiltrates the meninges, seeds the CSF, and spreads throughout the neuraxis,” said Dr. Howell, of the University of California, San Diego.

When free cytarabine is injected into the lateral ventricle, the drug is cleared so rapidly that it does not have time to spread evenly throughout the CSF, leaving some parts of the neuraxis undertreated. “The half-life is only about 3.4 hours. So following intrathecal administration of free cytarabine, there is inadequate duration of exposure,” he noted.

DepoCyt, Dr. Howell explained, is a slow-release formulation of cytarabine encapsulated in a novel drug delivery technology consisting of 20-micron multivesicular lipid particles made of phospholipids and cholesterol (Figure). This slow-release formulation maintains cytotoxic concentrations of free cytara-bine in the CSF for more than 14 days following intrathecal injection of 50 mg. The half-life is 5.8 days.

“The pharmacologic rationale for its development is that the cytotoxicity of cytarabine is a function of both concentration and duration of exposure. The hypothesis is that if one can maintain cytarabine at high concentrations for long periods of time in the CSF, one would do better with the treatment of this disease,” Dr. Howell said.

In the trial, lymphoma patients with a positive CSF cytology were randomized to DepoCyt (50 mg every 2 weeks) or free cytarabine (50 mg twice weekly) for 1 month; responding patients received 3 months consolidation and 4 months maintenance therapy. Dexamethasone was given on days 1 to 5 of each cycle.

Fourteen patients were randomized to each arm; 1 patient on the cytarabine arm never received the drug. Response was defined as conversion from a positive to negative CSF cytology at all sites known to be positive plus the absence of neurologic progression at the time the cytologic conversion was documented.

Patients receiving DepoCyt stayed on the study regimen for a total of 74 cycles (median, 5.5 per patient) whereas patients on the cytarabine arm stayed on study for 44.5 cycles (2.5 per patient). All patients on DepoCyt, but only 7 of 13 (54%) on cytarabine, were able to complete the planned 1-month induction.

The DepoCyt response rate, at 41% (7/17), with data from 5 additional subjects added into the tally, was significantly higher than that for free cytarabine (6%, 1/16; P = .04). Also, trends favoring DepoCyt were found for time to neurologic progression (median, 78.5 days vs 42 days), and survival (median, 99.5 days vs 63 days). “There was no difference in overall survival, but that was expected from the fact that only a minority of these patients die exclusively of the meningeal component of the disease,” he said.

While DepoCyt patients had an improved median Karnofsky score at the end of induction, cytarabine patients had a worse score (P = .041). “The drug can be delivered on a more patient-friendly dose schedule (once every 2 weeks). This results in an improved quality of life, not only because of the dose schedule, but also because of the higher Karnofsky score at the end of induction. Safety appears to be acceptable, given the life-threatening nature of the disease and the benefit afforded by the drug,” Dr. Howell said.