ATLANTAAdministration 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-Hodgkins 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.