Alpha-Particle Radiopharmaceuticals Moving Forward as AML Therapy

Joseph G. Jurcic, MD
Published: Monday, Sep 08, 2014
ColumbiaJoseph G. Jurcic, MD
Joseph G. Jurcic, MD
Professor, Medicine
Columbia University Medical Center
Director, Hematologic Malignancies Section
Attending Physician, New York-Presbyterian Hospital
Member, Herbert Irving Comprehensive Cancer Center
New York, NYStrategic Partners
Although standard induction therapy produces complete remissions in 50% to 70% of patients with acute myeloid leukemia (AML), long-term survival is seen in only 20% to 40% of patients. The prognosis for older patients is even worse, with a 5-year survival rate of 5% for patients older than 65 years.1 Therefore, new therapies are needed to improve survival and reduce therapy-related toxicity.

By targeting specific cell types, monoclonal antibodies (mAbs) offer the possibility of improved efficacy and decreased toxicity compared with conventional chemotherapy. The use of mAbs to deliver radiation selectively to tumor cells is an attractive strategy to increase their potency.

Early studies showed that β particle–emitting anti-CD33 constructs labeled with iodine-131 (131I) could eliminate large leukemic burdens but resulted in prolonged myelosuppression requiring hematopoietic cell transplantation (HCT).2 131I-labeled anti-CD45 mAbs3 as well as rhenium-188 (188Re)- and 90Y-labeled anti-CD66 mAbs4 have subsequently been used to intensify conditioning before HCT.

The unique physical and radiobiological properties of α-particles may provide more efficient tumor cell killing with fewer nonspecific cytotoxic effects than β-emitters. Compared with β-particles, α-particles have a shorter range (50-80 μm vs 800-10,000 μm) and a higher linear energy transfer (LET) (100 keV/μm vs 0.2 keV/ μm). As few as one or two α-particles can kill a target cell. Clinical studies using α-particle emitters for AML have targeted CD33, a cell surface glycoprotein expressed on most myeloid leukemia cells, using the humanized mAb lintuzumab (Table 1).

First Agent Establishes Concept

Initial trials were performed with the first-generation construct, bismuth-213 (213Bi)-lintuzumab.5

213Bi is a radiometal that emits a single α-particle and has a half-life of 45.6 min. It is prepared using a generator that consists of its parent isotope actinium- 225 (225Ac) dispersed onto a cation exchange resin from which 213Bi is eluted.

In a phase I trial of 213Bi-lintuzumab in advanced myeloid leukemia, doses up to 1 mCi/kg were administered safely, although myelosuppression and transient minor liver function abnormalities were seen. Nearly all the 213Bi-lintuzumab rapidly localized to and was retained in areas of leukemic involvement, including the bone marrow, liver, and spleen. Despite avidity for free bismuth, the kidneys were not visualized, suggesting that no significant catabolism of the drug occurred. Bone marrow blasts were reduced in 14 of 18 patients, but no complete remissions were seen, likely due to large tumor burdens in heavily pretreated patients. Nevertheless, this study demonstrated proof of concept for systemic targeted α-particle immunotherapy in humans.

Table 1. Clinical Trials Using Alpha-Particle Radiopharmaceuticals for AML

Reference Phase of Study Agent Dose Additional Therapy Disease Status No. of Patients Outcomes
Jurcic (2002)5 I 213Bi-lintuzumab 0.28-1 mCi/kg None Relapsed/refractory 18 14 patients with reductions in marrow blasts
Rosenblat (2010)6 I/II 213Bi-lintuzumab 0.5-1.25 mCi/kg Cytarabine Untreated Untreated >60 y; Relapsed/refractory 31 2 CRs, 2 CRp, 2 PRs
Jurcic (2011)7 I 225Ac-lintuzumab 0.5-4 μCi/kg None Relapsed/refractory 18 10 patients with reductions in marrow blasts; 3 with ≤5%
Jurcic (2013)8 I/II 225Ac-lintuzumab 1-2 μCi/kg (in 2 fractions) LDAC Untreated ≥60 y 7 4 patients with reductions in marrow blasts after cycle 1

AML indicates acute myeloid leukemia; CR, complete remission; CRp, CR with incomplete platelet recovery; LDAC, low-dose cytarabine; PR, partial remission.




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