Originally published as JCO Early Release 10.1200/JCO.2005.09.118 on April 11 2005

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Phase I Study of Oblimersen Sodium, an Antisense to Bcl-2, in Untreated Older Patients With Acute Myeloid Leukemia: Pharmacokinetics, Pharmacodynamics, and Clinical Activity

From the Division of Hematology-Oncology, Department of Medicine, and Division of Pharmaceutics, College of Pharmacy, the Comprehensive Cancer Center and The Ohio State University, Columbus, OH; Department of Medicine and Cancer Research Center, University of Chicago, Chicago, IL; National Cancer Institute, Bethesda, MD; and Genta Inc, Berkeley Heights, NJ

Address reprint requests to Guido Marcucci, MD, Division of Hematology-Oncology, The Comprehensive Cancer Center, The Ohio State University, 433A Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210; email: marcucci-1{at}medctr.osu.edu

PURPOSES: Pharmacologic downregulation of Bcl-2, an antiapoptotic protein overexpressed in cancer, might increase chemosensitivity in acute myeloid leukemia (AML). Herein, we investigated the feasibility of this approach in untreated elderly AML patients by administering oblimersen sodium (G3139), an 18-mer phosphorothioate antisense to Bcl-2, during induction and consolidation treatments.

PATIENTS AND METHODS: Untreated patients with primary or secondary AML (stratified to cohort 1 or 2, respectively) who were 60 years received induction with G3139, cytarabine, and daunorubicin at one of two different dose levels (45 and 60 mg/m²) and, on achievement of complete remission (CR), consolidation with G3139 and high-dose cytarabine. An enzyme-linked immunosorbent assay (ELISA) –based assay was used to measure plasma and intracellular concentrations (IC) of G3139. Bcl-2 mRNA and protein levels were quantified by real-time reverse transcriptase polymerase chain reaction and ELISA, respectively, in bone marrow samples collected before induction treatment and after 72 hours of G3139 infusion, prior to initiation of chemotherapy.

RESULTS: Of the 29 treated patients, 14 achieved CR. With a median follow-up of 12.6 months, seven patients had relapsed. Side effects of this combination were similar to those expected with chemotherapy alone and were not dose limiting at both dose levels. After 72-hour G3139 infusion, Bcl-2/ABL mRNA copies were decreased compared with baseline (P = .03) in CR patients and increased in nonresponders (NRs; P = .05). Changes in Bcl-2 protein showed a similar trend. Although plasma pharmacokinetics did not correlate with disease response, the median IC of the antisense was higher in the CR patients compared with NRs (17.0 v 4.4 pmol/mg protein, respectively; P = .05).

CONCLUSION: G3139 can be administered safely in combination with intensive chemotherapy, and the degree of Bcl-2 downmodulation may correlate with response to therapy.

Supported by grant Nos. P30-CA16058, U01-CA76576, K08-CA90469, R01-CA102031, and R21-CA 094552 from the National Cancer Institute, Bethesda, MD; The Sidney Kimmel Cancer Research Foundation; The Leukemia and Lymphoma Society of America; The D. Warren Brown Foundation; and The Coleman Leukemia Research Foundation.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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