Alpha-Particle Radiopharmaceuticals Moving Forward as AML Therapy

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

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).^{2 131}I-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.

Subsequently, a phase I/II trial was undertaken to assess the effects of ²¹³Bi-lintuzumab against residual disease.⁶ Patients with both relapsed/refractory AML and older patients with poor-risk AML were included.

After receiving nonremittive doses of cytarabine, patients were treated with 213Bi-lintuzumab (0.5-1.25 mCi/kg). Prolonged myelosuppression was seen in two of four patients treated with 1.25 mCi/kg, and the maximum tolerated dose (MTD) was 1 mCi/kg. Clinical responses were observed in six of the 25 patients (24%) who received doses of ≥1 mCi/kg. All responders had poor-risk features, including age ≥70 years or secondary AML; however, none of the seven patients with primary refractory AML or multiply treated relapsed disease responded, indicating that effective cytoreduction was necessary to achieve remission after administration of ²¹³Bi-lintuzumab.

Second-Generation Lintuzumab Advances

The major obstacles to the widespread use of ²¹³Bi are its short half-life and the requirement of an onsite 225Ac/213Bi generator. Therefore, a secondgeneration construct was developed by directly conjugating ²²⁵Ac to lintuzumab. ²²⁵Ac has a 10-day half-life and emits four α-particles in its decay to stable isotopes.

Table 2. Lintuzumab Study at a Glance

Patient population

• ≥60 years
• Untreated acute myeloid leukemia
• Unwilling to undergo intensive chemotherapy, presence of poor-risk prognostic factors, presence of significant comorbidities, or age ≥70 years

Estimated enrollment

• 77 patients in 2 phases

Intervention

• Cytarabine 20 mg injected subcutaneously every 12 hours on days 1 to 10 of every cycle
• Lintuzumab-Ac 225 with starting dose level of 1.0 μCi/kg and 15 μg/kg unlabeled HuM195 divided into 2 equal fractionated doses (0.5 μCi/kg and 7.5 μg/kg + 0.5 μCi/kg and 7.5 μg/kg)
• Furosemide and spironolactone at various points in cycle

Goals

• Phase I seeks to find highest tolerable dose
• Phase II aims to evaluate disease control and safety

Industry sponsor

• Actinium Pharmaceuticals

Source: NIH Registry. www.ClinicalTrials.gov. Identifier: NCT01756677.

In a phase I trial conducted in patients with relapsed or refractory AML, a single infusion of ²²⁵Ac-lintuzumab was administered at doses of 0.5-4 μCi/kg.⁷ Dose-limiting toxicities included prolonged myelosuppression in one patient treated at the highest dose level. No evidence of radiation nephritis was seen. Peripheral blasts were eliminated in 10 of 16 evaluable patients (63%). Bone marrow blast reductions were seen in 10 of 15 evaluable patients (67%) at 4 weeks, and three patients achieved marrow blasts of ≤5%.

Based on these findings, a multicenter, phase I/II trial is now under way to determine the MTD and efficacy of fractionated-dose ²²⁵Ac-lintuzumab (lintuzumab-Ac 225) in combination with low-dose cytarabine (LDAC) in patients ≥60 years with untreated AML (Table 2).⁸

An earlier study showed that repetitive cycles of LDAC resulted in improved 12-month survival compared with hydroxyurea in this population, but produced remissions in only 18% of patients.⁹

In the current study, patients receive LDAC twice daily for 10 days every 4 to 6 weeks.⁸ During the first cycle, two doses of ²²⁵Ac-lintuzumab are given approximately 1 week apart following completion of LDAC. Seven patients, all of whom had prior myelodysplastic syndrome, were treated with 0.5 or 1 μCi/kg/fraction to date. Bone marrow blast reductions (mean, 58%) were seen in four patients (57%) after cycle 1. Accrual continues to define the MTD, with planned dose levels up to 2 μCi/kg/fraction. Additional patients will be treated at the MTD in the phase II portion of this trial to determine response rate, progression-free survival, and overall survival.

Additional Studies Warranted

Early studies of systemically administered targeted α-particle immunotherapy for AML have shown significant antitumor activity. The shorter range and higher energy of α-particles compared with β-particles potentially allow for more efficient and selective killing of individual tumor cells. Reductions in leukemic blasts were seen with both ²¹³Bi- and ²²⁵Ac-lintuzmab in phase I trials, but the use of ²²⁵Ac overcomes the logistical difficulties associated with short-lived radionuclides such as ²¹³Bi. The ongoing phase I/II trial of ²²⁵Ac-lintuzumab in combination with LDAC for older patients with untreated AML builds on the encouraging results seen with ²¹³Bi-lintuzumab for cytoreduced leukemia. These studies provide the rationale for the further investigation of targeted α-particle therapy in patients with residual disease.

References

1. Döhner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet [published online October 30, 2009]. Blood. 2010;115(3):453-474.
2. Burke JM, Caron PC, Papadopoulos EB, et al. Cytoreduction with iodine-131-anti-CD33 antibodies before bone marrow transplantation for advanced myeloid leukemias. Bone Marrow Transplant. 2003;32(6):549-556.
3. Pagel JM, Gooley TA, Rajendran J, et al. Allogeneic hematopoietic cell transplantation after conditioning with 131I-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome [published online September 28, 2009]. Blood. 2009;114(27):5444-5453.
4. Ringhoffer M, Blumstein N, Neumaier B, et al. 188Re or 90Y-labelled anti-CD66 antibody as part of a dose-reduced conditioning regimen for patients with acute leukaemia or myelodysplastic syndrome over the age of 55: results of a phase I-II study. Br J Haematol. 2005;130(4):604-613.
5. Jurcic JG, Larson SM, Sgouros G, et al. Targeted alpha particle immunotherapy for myeloid leukemia. Blood. 2002; 100(4):1233-1239.
6. Rosenblat TL, McDevitt MR, Mulford DA, et al. Sequential cytarabine and alpha-particle immunotherapy with bismuth- 213-lintuzumab (HuM195) for acute myeloid leukemia [published online September 21, 2010]. Clin Cancer Res. 2010;16(21):5303-5311.
7. Jurcic JG, Rosenblat TL, McDevitt MR, et al. Phase I trial of the targeted alpha-particle nano-generator actinium-225-lintuzumab (anti-CD33; HuM195) in acute myeloid leukemia Blood. 2011;118(21):Abstract 768.
8. Jurcic JG, Ravandi F, Pagel JM, et al. Phase I trial of the targeted alpha-particle nano-generator actinium-225-lintuzumab (anti-CD33) in combination with low-dose cytarabine for older patients with untreated acute myeloid leukemia [published online December 6, 2013]. Blood. 2013;122(21):Abstract 1460.
9. Burnett AK, Milligan D, Prentice AG, et al. A comparison of low-dose cytarabine and hydroxyurea with or without alltrans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer. 2007;109(6):1114-1124.