Targeted Alpha-Particle Therapy for Hematologic Malignancies

Abstract

IntroductionThe short range and high linear energy transfer of α-particles offer the potential for efficient tumor killing while sparing surrounding normal cells. Hematologic malignancies are ideally suited to targeted α-therapy because of easy accessibility of malignant cells in blood and bone marrow and their radiosensitivity. MethodsA series of clinical trials were conducted to assess the safety and antileukemic effects of lintuzumab, an anti-CD33 antibody, labeled with the α-emitters bismuth-213 (213Bi) and actinium-225 (225Ac) in patients with acute myeloid leukemia (AML). ResultsInitial studies showed that 213Bi-lintuzumab had antileukemic activity and could produce remissions after partial cytoreduction with cytarabine. A phase I trial demonstrated that a single infusion of 225Ac-lintuzumab could be given safely at doses up to 111 kBq/kg with antileukemic activity at all dose levels studied. A second phase I study showed that 28% of older patients with untreated AML had objective responses after receiving fractionated-dose 225Ac-lintuzumab and low-dose cytarabine. A phase II study of 225Ac-lintuzumab monotherapy in this population produced remissions in 69% of patients receiving two fractions of 74 kBq/kg and 22% of patients receiving two 55.5-kBq/kg fractions. ConclusionsStudies with 213Bi-lintuzumab provided proof of principle for systemically administered α-particle therapy. 225Ac-lintuzumab was active against advanced AML and produced remissions in older patients with untreated AML in combination with low-dose cytarabine and as a single agent. These studies provide the rationale for development of 225Ac-lintuzumab in combination with a variety of agents in AML and in other hematologic malignancies such as myelodysplastic syndrome and multiple myeloma.