TALLIMUSTINE, AN EFFECTIVE ANTILEUKEMIC AGENT IN A SEVERE COMBINED IMMUNODEFICIENT MOUSE MODEL OF ADULT MYELOGENOUS LEUKEMIA, INDUCES REMISSIONS IN A PHASE-I STUDY

Despite progress in leukemia therapy, only 20-30% of patients with acu te myelogenous leukemia (AML) are cured, 1-beta-D-arabinofuranosylcyto sine- and topoisomerase II-reactive drugs are the primary therapeutic agents used, The aim of this study was to evaluate the potential activ ity of tallimustine in leukemia.In this study, we first investigated t he efficacy and toxic effects of tallimustine, a distamycin-h derivati ve, in a human leukemia model in severe combined immunodeficient (SCID ) mice, On the basis of its dramatic activity in this preclinical stud y, a Phase I study of tallimustine at a starting dose of 300 mu g/m(2) /day for 3 days every 3-4 weeks was conducted in patients with refract ory or relapsed leukemia. In SCID mice grafted with a human myelomonoc ytic leukemia cell line, tallimustine resulted in complete remission o f disease in most mice at tolerable dosages ranging from 0.86 to 3.0 m g/kg/day for 3 days and was combined effectively and safely with a 2-d ay schedule of high-dose ara-C. In the Phase I study, 26 patients with refractory or relapsed leukemia were treated, The maximum tolerated d ose was 900 mu g/m(2)/day for 3 days every 3-4 weeks, This dose was 3 times higher than the maximum tolerated dose in solid tumors and was l imited by severe mucositis, Magnesium and potassium wasting were also observed, but other side effects (fatigue and gastrointestinal) were m inor, Two (8%) patients with AML achieved complete remission and two a chieved hematological improvement with persistent thrombocytopenia. Th e results of this study indicate that tallimustine has promising activ ity in AML. Future studies may combine tallimustine with other agents known to be active against AML, and investigate its activity in other hematological malignancies, The recommended Phase II single-agent dose of tallimustine is 750-900 mu g/m(2)/day for 3 days, and combination studies may start at 50-66% of this dose schedule, The SCID mouse mode l of human leukemia may be promising in the preclinical evaluation and selection of potential antileukemic agents.