Experience with decitabine in imatinib resistant CML

Ryan Smith, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 12, 2003

Faculty Disclosure: Hagop M. Kantarjian, M.D.
In this presentation Dr. Kantarjian discusses the use of decitabine for the treatment of CML which has not been approved by the FDA.

Presenter: Hagop Kantarjian, MD
Affiliation: M.D. Anderson Cancer Center

Imatinib has revolutionized the treatment of CML. Higher cytogenetic and molecular responses, as well as better outcomes in patients treated with imatinib have been demonstrated when comparing them with patients treated with prior standard therapy of interferon and ara-C. Unfortunately, there has also been resistance seen with imitanib therapy. Mechanisms postulated for resistance include bcr-abl amplification and overexpression, abl mutation, and cytogenetic clonal evolution. DNA methylation could play a role in many of these and has been demonstrated as a mechnism in tumor progression in many cancers including CML. Hence, hypomethylation could decrease resistance, decrease progression, and improve efficacy of treatment.

Decitabine is a cytosine analog (similar to ara-C) that has been demonstrated as a hypomethylator, even at lower doses. In the past, decitabine has been used in high doses for leukemia therapy, with some efficacy but with severe myelotoxicity. As the mechanism for imatinib resistance is thought to often result from methylation and since decitabine, at low doses, is a hypomethylation agent, its use in patients with imatinib resistant CML was explored.

The study group consisted of 27 patients who had progressed on imatinib, and included both patients still in the chronic phase and patients in the accelerated or blastic phase. These patients were given decitabine 15 mg/m2 IV for 10 days with continued imatinib therapy. In these patients, 63% had a hematologic response, with 8/27 having a complete response. In addition, 40% had a cytogenetic response, with 5/27 having a complete cytogenetic response. Toxicity included close to 40% with thrombocytopenia and 70% with neutropenia.

Imatinib should now be considered standard of care in the treatment of CML. Although imatinib has been revolutionary in treating this disease, failures are bound to occur and have been noted. Treatment of these failures are variable, but include stem cell transplant, traditional therapy with interferon and ara-C, and investigational studies. As with many investigational studies, this study of decitabine requires longer follow up, more complete toxicity data and comparison to other therapies. However, decitabine appears to be promising as an efficacious and fairly safe method of treating CML patients who have failed imatinib.