HOUSTONA 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 OBrien, 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
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.
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. OBrien 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 its really
difficult to get a feel for how long their remissions will last, but
the longest to date is 14 months, Dr. OBrien 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. OBrien 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. OBrien concluded.