Treatment of therapy-refractory B-lineage acute lymphoblastic leukemia with an apoptosis-inducing CD19-directed tyrosine kinase inhibitor

Seven children and eight adults with CD19(+) B-lineage acute lymphoblastic leukemia, as web as one adult with chronic lymphocytic leukemia, were treat ed with the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein. All patients had faded previous chemotherapy regimens, and six patients ha d relapsed after bone marrow transplantation. B43-Genistein was administere d as a 1-hour i.v. infusion at 0.1-0.32 mg/kg/day dose levels for 10 consec utive days or 3 consecutive days weekly for a total of nine doses. B43-Geni stein was well tolerated by all patients with no life-threatening side effe cts. 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 tachycardi a, and grade 2 vascular leak syndrome. There was one durable complete remis sion and two transient responses. Pharmacokinetic analyses in 12 patients r evealed 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 hum an 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 ab ility to elicit objective responses at nontoxic dose levels, B43-Genistein may provide the basis for an effective treatment strategy for B-lineage acu te lymphoblastic leukemia patients who have failed standard therapy.