Sequential cytarabine and alpha-particle immunotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid leukemia

Abstract

Purpose: Lintuzumab (HuM195), a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest single-agent activity against acute myeloid leukemia (AML). To increase the potency of the antibody without the nonspecific cytotoxicity associated with β-emitters, the α-particle-emitting radionuclide bismuth-213 ((213)Bi) was conjugated to lintuzumab. This phase I/II trial was conducted to determine the maximum tolerated dose (MTD) and antileukemic effects of (213)Bi-lintuzumab, the first targeted α-emitter, after partially cytoreductive chemotherapy.

Experimental design: Thirty-one patients with newly diagnosed (n = 13) or relapsed/refractory (n = 18) AML (median age, 67 years; range, 37-80) were treated with cytarabine (200 mg/m(2)/d) for 5 days followed by (213)Bi-lintuzumab (18.5-46.25 MBq/kg).

Results: The MTD of (213)Bi-lintuzumab was 37 MB/kg; myelosuppression lasting >35 days was dose limiting. Extramedullary toxicities were primarily limited to grade ≤2 events, including infusion-related reactions. Transient grade 3/4 liver function abnormalities were seen in five patients (16%). Treatment-related deaths occurred in 2 of 21 (10%) patients who received the MTD. Significant reductions in marrow blasts were seen at all dose levels. The median response duration was 6 months (range, 2-12). Biodistribution and pharmacokinetic studies suggested that saturation of available CD33 sites by (213)Bi-lintuzumab was achieved after partial cytoreduction with cytarabine.

Conclusions: Sequential administration of cytarabine and (213)Bi-lintuzumab is tolerable and can produce remissions in patients with AML.

©2010 AACR.

Figures

Fig. 1

Percentage change in bone marrow blasts after treatment with sequential cytarabine and 213Bi-lintuzumab in 26 evaluable patients.

Fig. 2

Kaplan-Meier plot showing the probability of survival for patients with previously untreated AML and those with relapsed or refractory disease.

Fig. 3

Gamma camera images show targeting of isotope to marrow, liver, and spleen after the first injection (A) and blood pooling after the last (B). Rate images show uptake of 213Bi by target organs over 1 hour after the first injection (C) and clearance after the last (D). Time-activity curves demonstrate localization and retention of 213Bi in the marrow (E) and liver (F). (-○-), 1st injection; (-◆-), 4th injection.