COMMENTARY

New CML Data Post Signs on Route to Treatment-Free Remission

Theodore Bosworth

Disclosures

February 10, 2017

Increasing the proportion of patients with chronic myeloid leukemia (CML) who achieve a rapid decline in BCR-ABL1 transcript levels within the first year on therapy appears likely to boost the proportion who eventually achieve treatment-free remission, according to a critical review of available data. The evidence from CML stop-treatment trials, including new data presented at the 2016 annual meeting of the American Society of Hematology (ASH), indicate that indefinite disease control is dependent on not only suppressing BCR-ABL1 transcript levels below the threshold of detection, but also the speed at which that suppression is achieved.

"In CML, the focus has shifted from measuring cytogenetic response to monitoring transcript levels of BCR-ABL1, with particular attention to milestones of response over the first 12 months," said Susan Branford, PhD, head of the leukemia unit at the Center for Cancer Biology in Adelaide, Australia, speaking on the state of molecular monitoring of CML at the 2016 ASH meeting.

Defining Response

The key critical goal for measuring and monitoring response to tyrosine kinase inhibitor (TKI) therapy in patients with CML is deep molecular response (DMR), according to Dr Branford. Owing to evidence that DMR is a vital prognostic measure, there has been a rigorous effort to standardize definitions and improve the quality and reproducibility of laboratory measures of DMR.

According to Dr Branford, the most widely accepted definition of DMR is a BCR-ABL1 transcript level ≤ 0.01% on the standardized International Scale. However, with improving sensitivity of polymerase chain reaction (PCR) assays, more rigorous cut-off values have been introduced to create subcategories of DMR that may offer further prognostic value. The ≤ 0.01% cut-off value, now labeled "MR4" and considered to be a minimal measure of disease suppression, has been joined by values for MR4.5 (≤ 0.0032%) and MR5 (< 0.001%).

The Trajectory of Response

Since 2013, guidelines from the National Comprehensive Cancer Network and others have recommended molecular monitoring as a strategy to judge treatment response and consider alternative TKIs when thresholds of suppression are not achieved in a timely manner. Specifically, BCR-ABL1 transcript levels > 10% 6 months after initiating a TKI have been a criterion of treatment failure, but Dr Branford reported that there is increasing appreciation for understanding the slope of the decline over time. She emphasized that single values at 3 or 6 months provide insufficient information, because they do not establish whether patients are on a trajectory of BCL-ABL1 suppression that will eventually take them to the goal of major molecular response (MMR), which is defined as BCR-ABL1 transcript levels < 0.1% by 12 months. MMR by 12 months is now considered an important predictor of indefinite disease control.

"At our institution, we monitor the molecular response at 1, 2, 3, 6, and 12 months," said Dr Branford, emphasizing that the kinetics of TKI response provide valuable information in determining whether a change in TKI is needed. Although the definitions of treatment failure, which include both BCR-ABL1 transcript levels > 10% at 6 months and > 1% at 12 months, are accepted as absolute thresholds where a change in TKI is considered warranted, Dr Branford indicated that failure to see a steady decline in BCL-ABL1 transcript levels during the initial months of treatment should also be used as a warning of an inadequate response.

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