Treatment of therapy-refractory B-lineage acute lymphoblastic leukemia with an apoptosis-inducing CD19-directed tyrosine kinase inhibitor. Clin Cancer Res 1999 Dec;5(12):3906-13
Date
01/13/2000Pubmed ID
10632319Scopus ID
2-s2.0-0033387144 (requires institutional sign-in at Scopus site) 71 CitationsAbstract
Seven children and eight adults with CD19+ B-lineage acute lymphoblastic leukemia, as well as one adult with chronic lymphocytic leukemia, were treated with the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein. All patients had failed previous chemotherapy regimens, and six patients had relapsed after bone marrow transplantation. B43-Genistein was administered as a 1-hour i.v. infusion at 0.1-0.32 mg/kg/day dose levels for 10 consecutive days or 3 consecutive days weekly for a total of nine doses. B43-Genistein was well tolerated by all patients with no life-threatening side effects. There were six episodes of grade 2-3 fever, two of which were clearly drug related, one episode each of grade 3 myalgia, grade 2 sinus tachycardia, and grade 2 vascular leak syndrome. There was one durable complete remission and two transient responses. Pharmacokinetic analyses in 12 patients revealed a plasma half-life of 20 +/- 5 h, mean residence time of 24 +/- 5 h, and a systemic clearance rate of 20 +/- 3 ml/h/kg. Moderate levels of human antimouse antibody (HAMA) ranging from 20-87 ng/ml were detected in the day 28 blood samples from three of nine cases examined. Treatment of these three HAMA-positive patients with a second course of B43-Genistein did not yield measurable immunoconjugate levels in the plasma, indicating that the administered B43-Genistein molecules were rapidly cleared from circulation due to the HAMA. On the basis of its acceptable toxicity profile and its ability to elicit objective responses at nontoxic dose levels, B43-Genistein may provide the basis for an effective treatment strategy for B-lineage acute lymphoblastic leukemia patients who have failed standard therapy.
Author List
Uckun FM, Messinger Y, Chen CL, O'Neill K, Myers DE, Goldman F, Hurvitz C, Casper JT, Levine AMESH terms used to index this publication - Major topics in bold
AdolescentAdult
Antibodies, Monoclonal
Antibodies, Neoplasm
Antigens, CD19
Antineoplastic Agents
Apoptosis
Burkitt Lymphoma
Child
Child, Preschool
Enzyme Inhibitors
Female
Genistein
Humans
Immunotoxins
Male
Middle Aged
Pilot Projects
Protein-Tyrosine Kinases
