Targeted Alpha-Particle Therapy for Hematologic Malignancies.

INTRODUCTION

The 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.

METHODS

A 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 (Bi) and actinium-225 (Ac) in patients with acute myeloid leukemia (AML).

RESULTS

Initial studies showed that Bi-lintuzumab had antileukemic activity and could produce remissions after partial cytoreduction with cytarabine. A phase I trial demonstrated that a single infusion of Ac-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 Ac-lintuzumab and low-dose cytarabine. A phase II study of Ac-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.

CONCLUSIONS

Studies with Bi-lintuzumab provided proof of principle for systemically administered α-particle therapy. Ac-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 Ac-lintuzumab in combination with a variety of agents in AML and in other hematologic malignancies such as myelodysplastic syndrome and multiple myeloma.