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

   

Authors:	Rosenblat, T. L.; McDevitt, M. R.; Mulford, D. A.; Pandit-Taskar, N.; Divgi, C. R.; Panageas, K. S.; Heaney, M. L.; Chanel, S.; Morgenstern, A.; Sgouros, G.; Larson, S. M.; Scheinberg, D. A.; Jurcic, J. G.
Article Title:	Sequential cytarabine and α-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 (213Bi) was conjugated to lintuzumab. This phase I/II trial was conducted to determine the maximum tolerated dose (MTD) and antileukemic effects of 213Bi- 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/m2/d) for 5 days followed by 213Bi-lintuzumab (18.5-46.25 MBq/kg). Results: The MTD of 213Bi-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 213Bi- lintuzumab was achieved after partial cytoreduction with cytarabine. Conclusions: Sequential administration of cytarabine and 213Bi- lintuzumab is tolerable and can produce remissions in patients with AML. ©2010 AACR.
Keywords:	adult; clinical article; controlled study; treatment outcome; aged; aged, 80 and over; middle aged; unclassified drug; acute granulocytic leukemia; leukemia, myeloid, acute; clinical trial; drug tolerability; neutropenia; gastrointestinal hemorrhage; side effect; cytarabine; antineoplastic agent; cancer immunotherapy; controlled clinical trial; liver toxicity; phase 2 clinical trial; antimetabolites, antineoplastic; thrombocytopenia; drug administration schedule; antineoplastic activity; continuous infusion; chill; drug fever; febrile neutropenia; pneumonia; cancer regression; antibodies, monoclonal; rigor; drug distribution; remission induction; maximum tolerated dose; phase 1 clinical trial; radioimmunotherapy; drug dose regimen; radioisotopes; bacterial infection; drug dose sequence; alpha radiation; immunoconjugates; bismuth; hum 195; lintuzumab bi 213; candidemia; alpha particles
Journal Title:	Clinical Cancer Research
Volume:	16
Issue:	21
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2010-11-01
Start Page:	5303
End Page:	5311
Language:	English
DOI:	10.1158/1078-0432.ccr-10-0382
PUBMED:	20858843
PROVIDER:	scopus
PMCID:	PMC2970691
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-78049456138&partnerID=40&md5=243f691764825a90fde776255ecf2e5c
Notes:	--- - "Cited By (since 1996): 1" - "Export Date: 20 April 2011" - "CODEN: CCREF" - "Source: Scopus"