Phase I study of bryostatin 1 and fludarabine in patients with chronic lymphocytic leukemia and indolent (non-Hodgkin's) lymphoma.
OBJECTIVE
Preclinical studies suggested that bryostatin 1 might potentiate the therapeutic effects of fludarabine in the treatment of hematologic malignancies. We undertook a phase I study to identify appropriate schedules and doses of bryostatin 1 and fludarabine to be used in phase II studies.


METHODS
Patients with chronic lymphocytic leukemia (CLL) or indolent lymphoma received fludarabine daily for 5 days and a single dose of bryostatin 1 via a 24-hour continuous infusion either before or after the fludarabine course. Doses were escalated in successive patients until recommended phase II doses for each sequence were identified on the basis of dose-limiting toxic events.


RESULTS
Bryostatin 1 can be administered safely and tolerably with full dose fludarabine (25 mg/m(2)/d x 5). The recommended bryostatin 1 phase II dose is 50 microg/m(2) for both sequences, bryostatin 1 --> fludarabine and fludarabine --> bryostatin 1. The combination is active against both CLL and indolent lymphomas with responses seen in patients who had been previously treated with fludarabine. Correlative studies do not support the hypothesis that bryostatin 1 potentiates fludarabine activity through down-regulation of protein kinase C in target cells.


CONCLUSIONS
Bryostatin 1 can be administered with full dose fludarabine, and the combination is moderately active in patients with persistent disease following prior treatment. In view of the activity of monoclonal antibodies such as the anti-CD20 monoclonal antibody rituximab in the treatment of CLL and indolent lymphomas, the concept of combining bryostatin 1 and fludarabine with rituximab warrants future consideration.
Roberts
John D
JD
Massey Cancer Center, Virginia Commonwealth University, Medical College of Virginia, Richmond, VA 23298, USA.
Smith
Mitchell R
MR
Feldman
Eric J
EJ
Cragg
Louise
L
Millenson
Michael M
MM
Roboz
Gail J
GJ
Honeycutt
Connie
C
Thune
Rose
R
Padavic-Shaller
Kristin
K
Carter
W Hans
WH
Ramakrishnan
Viswanathan
V
Murgo
Anthony J
AJ
Grant
Steven
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D054713:Bryostatins; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018942:Macrolides / Q000008:administration & dosage; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011379:Prognosis; D015996:Survival Rate; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
D054713:Bryostatins; D018942:Macrolides; C046785:bryostatin 1; D014740:Vidarabine; C024352:fludarabine