Phase II trial of bryostatin 1 in patients with relapsed low-grade non-Hodgkin's lymphoma and chronic lymphocytic leukemia.

Bryostatin 1 is a natural product isolated from the marine bryozoan Bugula neritina in 1982 and is currently undergoing evaluation in a number of malignancies. Twenty-five patients with relapsed, low-grade non-Hodgkin's lymphoma or chronic lyphocytic leukemia (CLL) received bryostatin 1 by 72-h continuous infusion every 2 weeks at a dose of 120 microg/m2 per course. Patients who progressed while receiving bryostatin 1 alone could participate in a feasibility study by receiving vincristine administered by bolus i.v. injection immediately after the completion of the bryostatin 1 infusion. The dose of vincristine was escalated in groups of three patients as follows: level 1, 0.5 mg/m2; level 2, 1.0 mg/m2; and level 3, 1.4 mg/m2 with vincristine doses capped at 2.0 mg for all patients. Bryostatin 1 alone resulted in one complete remission and two partial remissions. Nine patients received sequential treatment with bryostatin 1 and vincristine. The addition of vincristine at a dose of 2 mg was feasible and caused the expected dose-related sensory neuropathy. Phenotypic analysis by flow cytometric analysis on pre- and post-bryostatin 1-treated peripheral blood lymphocytes revealed up-regulation in the coexpression of CD11c/ CD22 on CD20+ B cells in two of four CLL patients studied, which is consistent with in vitro findings of differentiation of CLL cells to a hairy cell phenotype.

Phase I study of bryostatin 1 in patients with relapsed non-Hodgkin's lymphoma and chronic lymphocytic leukemia.

PURPOSE: To define, in a phase I study in relapsed non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL), the maximum-tolerated dose (MTD), major toxicities, and possible antitumor activity of bryostatin 1, a macrocyclic lactone. PATIENTS AND METHODS: Bryostatin 1 was delivered by 72-hour continuous infusion every 2 weeks to patients with relapsed NHL or CLL, at doses that ranged from 12 microg/m2 to 180 microg/m2 per course. Correlative investigations included evaluations of total protein kinase C (PKC) in peripheral blood and lymphoid differentiation in patient tumor tissue. RESULTS: Twenty-nine patients were treated, including three patients with CLL and 26 with NHL. Generalized myalgia was the dose-limiting toxicity (DLT) and occurred in two of three patients treated with bryostatin 1 at 180 microg/m2 per course. Myalgias were dose-related and cumulative, and often started in the thighs and calves, improved with activity, were somewhat responsive to analgesics, and often took weeks to resolve once taken off study. Six patients were treated at the MTD of 120 microg/m2 per course. Myalgia, headache, and fatigue were common. Hematologic toxicity was uncommon. Total cumulative doses of bryostatin 1 up to 1,134 microg/m2 have been administered without untoward toxicity. Eleven patients achieved stable disease for 2 to 19 months. An in vitro assay for total PKC evaluation in patient peripheral-blood samples demonstrated activation within the first 2 hours with subsequent downregulation by 24 hours, which was maintained throughout the duration of the 72-hour infusion. CONCLUSION: This phase I study defined the MTD and recommended phase II dose of bryostatin 1, when administered over 72 hours every 2 weeks, to be 120 microg/m2 (40 microg/m2/d for 3 days). Generalized myalgia was the DLT. Future studies will define the precise activity of bryostatin 1 in subsets of patients with lymphoproliferative malignancies and its efficacy in combination with other agents.