Genase e? An Antise e to Bcl-2, Shows Promise in AML

Researchers from Ohio University, University of Chicago, the National Cancer I titute and Genta, Inc. have reported a promising phase I study of Genase e?(oblimersen) in untreated older patients with acute myeloid leukemia (AML). The details of this study a eared as an advanced on-line publication in the Journal of Clinical Oncology on April 11, 2005.<1>

Bcl-2 is a potent inhibitor of apoptosis which is a cause of cell death. Over-expre ion of this protein in patients with leukemia is a ociated with resistance to chemotherapy. The Bcl-2 antise e oligonucleotide, Genase e?down-regulates Bcl-2 and has been investigated in several hematological malignances where Bcl-2 has been implicated in disease resistance. In vitro studies have suggested that Genase e?can down-regulate Bcl-2 activity and inhibit cell viability. Thus, the targeting of Bcl-2 was a potential strategy for treatment of leukemia. These same researchers previously reported the results of treatment of patients with refractory AML with the combination of Fludara? cytarabine, Genase e?and Neupogen?<2> Seventeen patients in this study had rela ed or refractory AML and 3 had acute ALL, including 2 patients who had failed stem cell tra lantation. Five patients with AML and one patient with ALL achieved a complete re o e. Three other patients had disa earance of blasts but did not achieve full hematological recovery. In two patients, the re o e persisted for over one year before recurrence. Re o es were also seen in older patients. The researchers also reported that Bcl-2 mRNA levels were down-regulated in 75% of evaluable patients.

The current study included 29 patients who were 60 years of age or older with newly diagnosed AML. All received treatment with cytarabine, daunomycin and Genase e? Complete remi io occurred in 14 patients (48%). Seven of these 14 patients have rela ed. They suggested that the degree of down regulation of Bcl-2 correlated with re o e. These authors stated that CALGB would be performing a randomized trial in older patients with newly diagnosed AML to determine the contribution of Genase e?

Comments: It抯 impo ible to tell from this study whether or not Genase e?contributed to outcome and the randomized trial will be of great interest.

References:

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<1> Marcucci G, Stock W, Dai G, et al. Phase I study of oblimersen sodium, an antise e to Bcl-2, in untreated older patients with acute myeloid leukemia: pharmacokinetics, pharmacodynamics, and clinical activity. Journal of Clinical Oncology. 2005;23: published ahead of print on April 22, 2005 as 10.1200/JCO.2005.09.118.

<2> Marcucci G, Byrd J, Dai G, et al. Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antise e oligonucleotide, in combination with chemotherapy in refractory or rela ed acute leukemia