MIAMI BEACH-Histone deacetylase (HDAC) inhibitors have emerged as promising new candidates in T-cell lymphoma therapy. Phase I data reported by National Cancer Institute (NCI) investigators showed responses in all patients treated with
MIAMI BEACHHistone deacetylase (HDAC) inhibitors have emerged as promising new candidates in T-cell lymphoma therapy. Phase I data reported by National Cancer Institute (NCI) investigators showed responses in all patients treated with depsipeptide (FR901228). One patient with peripheral T-cell lymphoma remains in complete remission after 2 years of continuing treatment.
The NCI group has recently begun a phase II trial of depsipeptide in patients with either cutaneous or peripheral T-cell lymphoma. Six of the needed 29 patients have already been enrolled in that study.
Antonio T. Fojo, MD, PhD, reported the phase I data at the Molecular Targets and Cancer Therapeutics meeting (abstract 360), sponsored by the American Association for Cancer Research, NCI, and European Organization for Research and Treatment of Cancer.
Dr. Fojo is senior investigator in the NCI’s Center for Cancer Research, Cancer Therapeutics Branch. Lead investigator for the study is Susan Bates, MD, chief and senior clinical investigator in the Cancer Therapeutics Branch.
Histones are proteins associated with DNA. They can be modified in various ways, including acetylation. HDAC blocks the removal of acetyl groups, with the net result of decreasing histone acetylation. "Abnormal activation of HDAC is implicated in tumorigenesis," Dr. Fojo said.
Following promising in vitro and in vivo studies, the NCI researchers opened a phase I trial in which patients received depsipeptide by 4-hour infusion on days 1 and 5 of a 21-day cycle. Patients received continuous cardiac monitoring due to concerns about cardiotoxicity seen in animal studies.
Dr. Fojo said that the maximum tolerated dose was 17.8 mg/m2 and that dose-limiting toxicities included grade 3 fatigue, grade 3 nausea and vomiting, grade 4 thrombocytopenia, and grade 4 atrial fibrillation (seen in one patient). Post-treatment electrocardiograms showed reversible ST/T changes, but there were no significant changes in cardiac function. He speculated that the heart rhythm disturbances could be related to previous doxorubicin, which most of these patients had received.
The first patient in the cohort enrolled at the maximum tolerated dose had peripheral T-cell lymphoma that had progressed on standard therapy. Dr. Fojo said that this patient had an early, dramatic, complete response and remains free of disease after 2 years and 22 cycles of treatment. The treatment interval was lengthened slightly in this patient to increase tolerability over the long term.
Nine more patients were enrolled in the phase I study. All had at least a partial response to treatment and remain on study after 4 to 11 cycles of treatment.
Dr. Fojo told ONI in an interview that patients were restaged after the second cycle of treatment but that responses in these peripheral and cutaneous T-cell lymphomas could be seen after the first cycle in most cases.
Thrombocytopenia was transient and typically resolved within a couple of days without intervention. The original schedule has been changed to treatment on days 1, 8, and 15 to permit time for platelet recovery.
Sézary Syndrome Patients
Two patients with high Sézary counts experienced dramatic decreases in circulating Sézary cells, he said, and the Sézary cells obtained after treatment had increased histone acetylation.
The circulating Sézary cells of two patients were CD25 negative at the start of treatment but CD25 positive after the second dose of depsipeptide in one patient and after several cycles of treatment in the other. "This is important because it suggests that depsipeptide may upregulate expression of CD25, which is a target for IL-2-receptor-directed therapies in cutaneous T-cell lymphoma," he said.
Depsipeptide is derived from Chromobacterium violaceum and is produced by the Fujisawa Pharmaceutical Company. Dr. Fojo told ONI that it is grown in "big vats" and that scaling up for industrial production should not be much of a problem if the drug proves useful in larger, randomized, controlled clinical trials.
"It is important to remember that this is a drug with HDAC effects but that there are likely to be a number of these compounds tested over the next few years," he said.