Liposomal Tretinoin Produces Impressive Responses in Refractory B-cell and T-cell Lymphomas

HOUSTON—Liposomal 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).