HOUSTONLiposomal encapsulated tretinoin (Atragen) is
active in relapsed aggressive T-cell and B-cell non-Hodgkin’s lymphomas (NHL)
as well as in cutaneous T-cell lymphomas (CTCL), and strikingly effective in
patients with primary refractory disease. Andreas H. Sarris, MD, PhD, associate
internist and associate professor of medicine at the University of Texas M. D.
Anderson Cancer Center in Houston, reported these results in a poster
presentation. Liposomal tretinoin is more active than the oral formulation when
tested against lymphoma cell lines and also down regulates expression of
bcl-2, Dr. Sarris said.
His presentation was an interim analysis of an ongoing phase II
study and included data on 57 patients. Patients had refractory or relapsed NHL
or CTCL with normal liver function, platelets, and neutrophils, and no central
nervous system disease. Half of the patients had elevated serum LDH levels, and
75% had serum beta-2 microglobulin over 3.0 mg/L.
Liposomal tretinoin was given at 120 mg/m2 IV every other day
in 28-day courses for up to 6 courses. Overall response rates, including
complete response (CR) plus partial response (PR), were 40% in patients with
refractory aggressive B-cell lymphomas and 38% in patients with refractory
aggressive T-cell lymphomas (see Table 1). Response rates were 8% in patients
with relapsed aggressive B-cell lymphomas and 27% in patients with relapsed
aggressive T-cell lymphomas.
Range of Responses
Analysis of response by clinical grade ranged from 0% response
in indolent B-cell lymphomas, to 17% in aggressive B-cell lymphomas, 30%
response in aggressive T-cell lymphomas, and 40% in cutaneous T-cell lymphomas.
Median progression-free survival for responders was 6 months.
"Refractory T-cell lymphomas have a particularly bad
prognosis, but 3 of our 8 patients with this disease who were refractory to
CHOP (cyclophosphamide, doxorubicin, Oncovin [vincristine], prednisone) had
complete or partial remissions lasting a median of 6 months with liposomal
tretinoin," Dr. Sarris said.
Dr. Sarris told ONI he was surprised to find response rates in
patients with refractory disease higher than in those with relapsed disease.
"The fact that the relapsed patients had more previous cycles of treatment
might be a factor in this difference," he said.
Adverse Prognostic Factors
The most important adverse prognostic factors were levels of
LDH and beta-2 microglobulin. "We suspect that the efficacy of liposomal
tretinoin is due to its ability to down-regulate bcl-2 expression and also to
induce apoptosis," Dr. Sarris said. "The intravenous formulation does
not suffer from the hepatic first-pass phenomenon that occurs with oral
formulations, and the liposomes preferentially pass through the leaky blood
vessels characteristic of cancers and into the target tissues."
The investigators concluded that liposomal tretinoin can be
safely administered at 120 mg/m2 to patients with relapsed or refractory NHL or
CTCL and that it causes no severe toxicities. Grade 3 toxicities were headache
(n = 7) and arthralgia (n = 1).