Phase I study of oblimersen sodium, an antisense to Bcl-2, in untreated older patients with acute myeloid leukemia: Pharmacokinetics, pharmacodynamics, and clinical activity

Guido Marcucci, Wendy Stock, Guowei Dai, Rebecca B. Klisovic, Shujun Liu, Marko I. Klisovic, William Blum, Cheryl Kefauver, Dorie A. Sher, Margaret Green, Mollie Moran, Kati Maharry, Steven Novick, Clara D. Bloomfield, James A. Zwiebel, Richard A. Larson, Michael R. Grever, Kenneth K. Chan, John C. Byrd

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)3404-3411
Number of pages8
JournalJournal of Clinical Oncology
Volume23
Issue number15
DOIs
StatePublished - 2005

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    Marcucci, G., Stock, W., Dai, G., Klisovic, R. B., Liu, S., Klisovic, M. I., Blum, W., Kefauver, C., Sher, D. A., Green, M., Moran, M., Maharry, K., Novick, S., Bloomfield, C. D., Zwiebel, J. A., Larson, R. A., Grever, M. R., Chan, K. K., & Byrd, J. C. (2005). Phase I study of oblimersen sodium, an antisense to Bcl-2, in untreated older patients with acute myeloid leukemia: Pharmacokinetics, pharmacodynamics, and clinical activity. Journal of Clinical Oncology, 23(15), 3404-3411. https://doi.org/10.1200/JCO.2005.09.118