February 2013 Vol 6, No 1, Special Issue - Leukemia
Wayne Kuznar

An early major molecular re­sponse (MMR) identifies pa­tients with chronic myeloid leukemia (CML) who are more likely to achieve undetectable BCR-ABL1 transcripts while receiving imatinib therapy, and represent candidates for entry into studies of discontinuing therapy, said Susan Branford, PhD, Department of Genetics and Molecular Pathology, University of Adelaide School of Medicine, Australia.

“The opportunity to discontinue kinase inhibitor therapy while maintaining a deep remission is desirable for many CML patients,” she said. Some patients have long-term treatment-related side effects, which is especially problematic for younger patients, whereas others become pregnant. The cost of therapy is also a consideration for many patients who wish to discontinue treatment with imatinib.

“Some carefully selected patients can sustain remission after imatinib discontinuation,” said Dr Branford.

The first requirement for successful discontinuation is likely to be stable deep molecular response based on a sensitive real-time quantitative polymerase chain reaction (PCR) assay. In the French Stop Imatinib (STIM) study, the overall probability of maintaining a response after discontinuation of imat­inib was 39% versus 42.7% in the Australian CML8 (TWISTER) study. The studies had similar enrollment criteria: patients received imatinib for at least 3 years and had stable undetectable BCR-ABL1 for at least 2 years, with a PCR sensitivity of 5 log and 4.5 log, respectively, she said.

It is not known how many patients receiving imatinib will eventually meet these PCR criteria for a discontinuation trial, noted Dr Branford. For this analysis, the CML8 PCR discontinuation criteria are defined as “stable UMR4.5.”

To determine the number of patients who were treated with first-line imat­inib and who achieve the CML8 PCR discontinuation criteria and the factors that predict its achievement, Dr Branford and her colleagues examined the MMR of 415 de novo patients with chronic-phase CML who were enrolled in consecutive clinical trials of imatinib since July 2000.

The assigned daily imatinib doses were 400 mg (n = 90), 600 mg (n = 202), and 800 mg (n = 123).

Of the 415 patients, 117 had confirmed undetectable BCR-ABL1 (MR4.5). Of these patients, 80 had follow-up of at least 24 months: 64% had stable MR4.5 for 24 months, only 1 patient lost MMR, and the remainder had fluctuating positive BCR-ABL1.

At 8 years of imatinib therapy, the cumulative incidence of stable UMR4.5 was 43%. The cumulative incidence of stable UMR4.5 was >60% for all patients who achieved MMR by 12 months and only 16% for patients with MMR between 12 and 18 months, which suggests that the speed of the response is an important factor.

“An estimated 58 of the 415 [14%] patients would maintain response if imatinib was discontinued after stable UMR4.5,” she said.

During imatinib therapy, females had significantly lower median BCR-ABL1 values at every assessment up to 42 months. Dr Branford speculated that women may be more compliant with their therapy, resulting in a better response, or that biological differences may influence the response.

The 3-month BCR-ABL1 value also predicted stable UMR4.5. A stable UMR4.5 was achieved by 59% of patients with a BCR-ABL1 value of <1.0% at 3 months.

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Last modified: March 4, 2013
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