Treatment of Patients with Acute Myeloid Leukemia with the Targeted Alpha-Particle Nanogenerator Actinium-225-Lintuzumab

Abstract

Purpose: The anti-CD33 antibody lintuzumab has modest activity against acute myeloid leukemia (AML). To increase its potency, lintuzumab was conjugated to actinium-225 (225Ac), a radionuclide yielding 4 α-particles. This first-in-human, phase I trial was conducted to determine the safety, pharmacology, and biological activity of 225Ac-lintuzumab.

Patients and methods: Eighteen patients (median age, 64 years; range, 45-80) with relapsed or refractory AML received a single infusion of 225Ac-lintuzumab at activities of 18.5 to 148 kBq/kg.

Results: The maximum tolerated dose was 111 kBq/kg. Dose-limiting toxicities included myelosuppression lasting > 35 days in one patient receiving 148 kBq/kg and death from sepsis in two patients treated with 111 and 148 kBq/kg. Myelosuppression was the most common toxicity. Significant extramedullary toxicities were limited to transient grade 3 liver function abnormalities. Pharmacokinetics were determined by gamma counting serial whole blood, plasma, and urine samples at energy windows for the 225Ac daughters, francium-221 and bismuth-213. Two-phase elimination kinetics were seen with mean plasma t1/2 - α and t1/2 - β of 1.9 and 38 hours, respectively. Peripheral blood blasts were eliminated in 10 of 16 evaluable patients (63%) but only at doses of ≥ 37 kBq/kg. Bone marrow blasts were reduced in 10 of 15 evaluable patients (67%), including 3 patients with marrow blasts ≤ 5% and one patient with a morphologic leukemia-free state.

Conclusions: Therapy for AML with the targeted α-particle generator 225Ac-lintuzumab was feasible with an acceptable safety profile. Elimination of circulating blasts or reductions in marrow blasts were observed across all dose levels.

Fig. 1.

²²⁵Ac decay scheme. ²²⁵Ac produces six predominant radionuclide daughters in the decay cascade to stable ²⁰⁹Bi. A single Ac decay yields net 4 alpha and 3 beta disintegrations, most of high energy, and 2 useful gamma emissions.

Fig. 2.

Percentage of injected dose per liter of ²²⁵Ac-lintuzumab in whole blood, plasma and urine over time. Data shown is for patient no. 1 following infusion of ²²⁵Ac-lintuzumab 1,110 kBq (18.5 kBq/kg). Similar pharmacokinetics were observed across all dose levels.

Fig. 3.

Percentage change in bone marrow blasts after treatment with ²²⁵Ac-lintuzumab in 15 evaluable patients.