Compound 506 Shows Promise in Mature Lymphoid Leukemias

HOUSTON—A novel nucleoside analog, known as compound 506U78, has significant activity in mature B-cell and T-cell leukemias, producing responses in patients whose disease is refractory to fludarabine (Fludara) and alkylating agents, investigators from M.D. Anderson Cancer Center and Glaxo Wellcome, Inc. reported at the ASH meeting.

Susan O’Brien, MD, of M.D. Anderson, presented the collective experience from two phase I trials and one biochemical modulation trial. She said that compound 506, a derivative of arabinosyl guanosine (ara-G), produced clinically impressive responses in several of the 37 patients in the trials.

The initial phase I study had six patients receiving compound 506 as a 1-hour infusion daily for 5 days. In the second phase I study, 22 patients received the drug on days 1, 3, and 5. The nine patients in the third trial received compound 506, 1.2 g/m², on days 1, 3, and 5, in conjunction with fludarabine on days 3 and 5.

All of the study patients with B-cell disease had received prior therapy with alkylating agents and fludarabine, as had many of the T-cell patients. In 68% of the patients, their disease had been refractory to their last regimen, and most of the patients had advanced-stage disease with anemia, thrombocytopenia, and high beta2-microglobulin levels.

Overall, 5 (31%) of 16 patients with B-cell chronic lymphocytic leukemia (CLL) responded to treatment with compound 506, and 3 (25%) of 12 patients with T-cell disease responded. However, no responses were seen among patients with transformed CLL. The investigators found no correlation of response with refractoriness to previous regimens, T-cell phenotype, or dose.

Possible Synergism?

Patients treated in the combination study had a higher response rate than did those in the two phase I studies, “albeit with very limited numbers of patients in each group and overlapping confidence intervals,” Dr. O’Brien said. “If you exclude the patients with transformed CLL, the data are even more suggestive that the combination might have synergistic efficacy,” she added.

Of the eight patients who responded to compound 506, three have relapsed. The median time to disease progression was 9 months. “The number of responders is so small that it’s really difficult to get a feel for how long their remissions will last, but the longest to date is 14 months,” Dr. O’Brien said.

The dose-limiting toxicity in both phase I studies was neurotoxicity, and the main side effect of compound 506 overall was somnolence, which was seen in almost half the patients, generally during chemotherapy and resolving within a few days of discontinuation. Other acute neurotoxicities were seen in a smaller percentage of patients but were generally mild and, when severe, were always reversible.

“Of note was the fact that patients exposed to multiple cycles of therapy developed peripheral neuropathy, which tended to be mild,” Dr. O’Brien said. “But no patient who received less than three cycles of therapy developed peripheral neuropathy.” Myelosuppression with compound 506 was modest, especially given the fact that most of these patients had bone marrow failure at the start of therapy, she said.

“Further exploration of alternative schedules that may minimize neurotoxicity is warranted, given this impressive activity in both acute and chronic leukemias,” Dr. O’Brien concluded.