A phase I study of T101-ricin A chain immunotoxin in refractory chronic lymphocytic leukemia.
Four patients with chronic lymphocytic leukemia refractory to alkylating agents were treated with T101-ricin A chain immunotoxin (T101-RTA) as part of a phase I study. Over a 4-week period, each patient received eight intravenous infusions of 3 mg/m2 T101-RTA over 1 h. All infusions were well tolerated. Patients had mild fevers but no other systemic toxicities. In vivo binding of T101-RTA was detected by FACS analysis using anti-mouse Ig-FITC or anti-A chain-FITC antibody conjugates. Saturation of circulating leukemic cell-associated target antigen was achieved in three of the patients. Available CD5 sites per cell dropped precipitously at the completion of infusions in all four patients, returning to within 30% of baseline by 24 h. Pharmacokinetic studies revealed rapid clearance of T101-RTA, with wide interpatient variability in peak serum levels (the highest levels in those patients who saturated their circulating CD5 antigen with immunotoxin). Although no patient developed detectable levels of antimurine antibodies, one patient did have a rising titer of anti-ricin A chain antibody associated with declining peak serum levels of immunotoxin. All patients had a rapid fall in WBC count of less than 24-h duration after each T101-RTA infusion, most likely secondary to the antibody portion of immunotoxin. No sustained benefit could be demonstrated in any patient, possibly because in the absence of an enhancing agent the leukemic cells of all four patients were resistent to T101-RTA at concentrations up to 2,000 ng/ml in vitro.
Hertler
A A
AA
Division of Hematology/Oncology, Duke University Medical Center, Durham, NC 27710.
Schlossman
D M
DM
Borowitz
M J
MJ
Laurent
G
G
Jansen
F K
FK
Schmidt
C
C
Frankel
A E
AE
D000368:Aged; D000906:Antibodies / Q000097:blood; D000951:Antigens, Neoplasm / Q000276:immunology; D002469:Cell Separation; D004341:Drug Evaluation; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy; D066298:In Vitro Techniques; D007945:Leukemia, Lymphoid / Q000276:immunology / Q000628:therapy*; D007962:Leukocytes / Q000166:cytology; D008297:Male; D008875:Middle Aged; D012276:Ricin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014057:Tomography, X-Ray Computed; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000906:Antibodies; D000951:Antigens, Neoplasm; D012276:Ricin