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1460 Phase I Trial Of The Targeted Alpha-Particle Nano-Generator Actinium-225 (225Ac)-Lintuzumab (Anti-CD33) In Combination With Low-Dose Cytarabine (LDAC) For Older Patients With Untreated Acute Myeloid Leukemia (AML)

Program: Oral and Poster Abstracts
Session: 615. Acute Myeloid Leukemia: Therapy, excluding Transplantation: Poster I
Saturday, December 7, 2013, 5:30 PM-7:30 PM
Hall E (Ernest N. Morial Convention Center)

Joseph G. Jurcic, MD1, Farhad Ravandi, MD2, John Pagel, MD, PhD3, Jae H Park, MD4, Dan Douer, MD5, Elihu H. Estey, MD6, Hagop M. Kantarjian, MD7, Dragan Cicic, MD8* and David A. Scheinberg, MD, PhD9

1Columbia University Medical Center, New York, NY
2Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, TX
3Fred Hutchinson Cancer Center, Seattle, WA
4Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY
5Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY
6University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA
7Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
8Actinium Pharmaceuticals, Inc., New York, NY
9Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY

Background: Lintuzumab, a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest activity against AML. To increase the antibody’s potency yet avoid nonspecific cytotoxicity seen with β-emitting isotopes, the isotope generator 225Ac (t½=10 days), which yields 4 α-particles, was conjugated to lintuzumab. A phase I trial demonstrated that 225Ac-lintuzumab is safe at doses ≤ 3 μCi/kg and has anti-leukemic activity across all dose levels studied (Jurcic et al. ASH, 2011). We are conducting a multicenter, phase I dose escalation trial to determine the maximum tolerated dose (MTD), toxicity, and biological activity of fractionated-dose 225Ac-lintuzumab in combination with LDAC. Patients and Methods: Patients ≥ 60 yrs who had untreated AML with poor-prognostic factors, such as an antecedent hematologic disorder (AHD), unfavorable cytogenetic or molecular abnormalities, and significant comorbidities, were eligible. Patients received LDAC 20 mg bid for 10 days every 4-6 weeks. During cycle 1, beginning 4-7 days after LDAC, two doses of 225Ac-lintuzumab were given approximately one week apart. Results: Seven patients (median age, 76 yrs; range, 72-80 yrs) were treated, all of whom had AHDs. Five (71%) had intermediate-risk cytogenetics, and two (29%) had unfavorable cytogenetics. The median CD33 expression was 76% (range, 69-95%). Prior therapy for myelodysplastic syndrome included hypomethylating agents (n=4) and allogeneic hematopoietic cell transplantation (n=1). Patients received 225Ac-lintuzumab at doses of 0.5 (n=3) or 1 (n=4) μCi/kg/fraction, two fractions per patient (total administered activity, 68-199 μCi). Dose-limiting toxicity was seen in one patient receiving 1 μCi/kg/fraction who had grade 4 thrombocytopenia in the setting of an aplastic bone marrow that persisted > 6 wks after completing the second fraction of 225Ac-lintuzumab. Other toxicities included grade 3 febrile neutropenia (n=5), bacteremia (n=1), pneumonia (n=1), cellulitis (n=1), transient increase in creatinine (n=1), and generalized weakness (n=1). Bone marrow blast reductions were seen in 4 of 6 evaluable patients (67%) after cycle 1 (mean blast reduction, 58%; range, 34-100%). No CRs, however, were observed. The median number of cycles administered was 2 (range, 1-4), and the median time to progression was 2.5 months (range, 2-7+ months). Conclusions: Fractionated-dose 225Ac-linutuzmab in combination with LDAC is feasible, safe, and has anti-leukemic activity. 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.

Disclosures: Jurcic: Actinium Pharmaceuticals, Inc.: Membership on an entity’s Board of Directors or advisory committees . Ravandi: Actinium Pharmaceuticals, Inc.: Research Funding . Pagel: Actinium Pharmaceuticals, Inc.: Equity Ownership , Membership on an entity’s Board of Directors or advisory committees , Research Funding . Park: Actinium Pharmaceuticals, Inc.: Research Funding . Douer: Actinium Pharmaceuticals, Inc.: Research Funding . Estey: Actinium Pharmaceuticals, Inc.: Membership on an entity’s Board of Directors or advisory committees . Cicic: Actinium Pharmaceuticals, Inc.: Employment , Equity Ownership . Scheinberg: Actinium Pharmaceuticals, Inc.: Ac-225-Lintuzumab , Equity Ownership , Membership on an entity’s Board of Directors or advisory committees , Patents & Royalties: Ac-225-Lintuzumab .

*signifies non-member of ASH