7068 The recombinant diphtheria toxin fusion protein, DT388IL3, composed of the catalytic and translocation domains of diphtheria toxin (DT388) fused to human interleukin-3 (IL3) showed selective cytotoxicity to acute myeloid leukemia (AML) stem cells both in vitro and in vivo and was prepared for a phase I clinical study (Urieto, Protein Exp Purif 33, 123, 2004). FDA approval (BB IND#11314) and IRB approvals were obtained. Seventy-five AML patients were screened and thirty-one patients treated. The median age of treated patients was 62 years (range, 25- 81 years). There were sixteen males and fifteen females. Disease was de novo in three, first relapse in ten, second relapse in eight, and refractory in ten patients. Four patients had a history of MDS, and one had a history of secondary AML. One patient each had previously received an autologous or allogeneic stem cell transplant. Cytogenetics were unfavorable in ten, intermediate in nineteen, and not done in two. Seven patients were treated with 4 μg/kg, eight patients were treated with 5.3 μg/kg, thirteen patients treated with 7.1 μg/kg, and three patients treated with 9.4 μg/kg DT388IL3. Drug-related toxicities were mild to moderate and transient including fever, chills, hypotension, hypoxemia, and hypoalbuminemia. Consistent with an absence of toxicity to normal hematopoietic progenitors, responses occurred in the absence of prolonged myelosuppression. Among thirty evaluable patients, we have observed one CR of 8 months duration, two partial remissions (PRs) lasting one and three months and three minimal responses with clearance of peripheral blasts and marrow blast cytoreductions of 89%, 90% and 93% lasting one to two months. Dose escalation is proceeding. No significant financial relationships to disclose.
Variant diphtheria toxin-interleukin-3 fusion proteins with increased receptor affinity have enhanced cytotoxicity against acute myeloid leukemia progenitors.