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| |  ASH: Bryostatin Less Than Impressive in Chronic Lymphocytic Leukemia and Indolent Non-Hodgkin's Lymphoma By Robert H. Carlson PHILADELPHIA, PA -- December 16, 2002 -- In-vitro evidence of synergy between bryostatin and fludarabine has not been borne out in clinical phase-I studies of the combination in chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin's lymphoma (NHL). Bryostatin, a cytotoxic agent derived from a single-cell sea organism, has both cytotoxic and immunomodulatory properties in in-vivo and in-vitro models. But in parallel phase-I trials in CLL and NHL, the combination of bryostatin and fludarabine produced only a 30 percent response rate among 53 patients, including a 25 percent response rate in patients who had prior fludarabine exposure First author John D. Roberts, MD, professor, internal medicine, and associate director of clinical research, Massey Cancer Center, Virginia Commonwealth University, in Richmond, Virginia, United States, stated that these response rates are probably no higher than those that would be seen with fludarabine alone in this patient population. Response rates were 32 percent for patients with NHL and 31 percent for those with CLL. Response rates in patients with prior fludarabine exposure were 29 percent and 25 percent, respectively. "We found that we can combine the drugs and that we do see activity in B-cell disorders," Dr. Roberts reported in a presentation here at the 44th annual meeting of the American Society of Hematology. "The problem is, at this meeting we see combinations of fludarabine and rituximab with response rates of 60 and 80 percent in CLL." Though it never showed much activity as a single agent, bryostatin has been of interest to scientists as a potential modulator of other cytotoxic drugs, Dr. Roberts said. In-vitro studies showed a very dramatic synergistic interaction between bryostatin and fludarabine in CLL and NHL cell cultures. The parallel CLL and NHL phase-I studies reported on here started with low doses of both drugs, 16 micrograms/m2 of bryostatin and 12.5 mg/m2 of fludarabine. The trials continued escalation to 50 micrograms/m2 of bryostatin followed by 25 mg/m2 of fludarabine. These were heavily pretreated patients, Dr. Roberts said, with a median of three prior treatments, and 23 of the patients had prior fludarabine therapy. Toxicities in the trials were as expected for either drug alone, he added. Dr. Roberts said that he was not optimistic about future bryostatin-fludarabine trials. "How do you get people excited about this when combinations of cytotoxics and monoclonal antibodies are doing very well?" Dr. Roberts posed. "This is not a home run -- this response rate is what might have been expected in this patient population with fludarabine alone," he concluded.
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