What is included in long-term monitoring of chronic myelogenous leukemia (CML)?

Updated: May 23, 2021
  • Author: Emmanuel C Besa, MD; Chief Editor: Sara J Grethlein, MD, FACP  more...
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Answer

Molecular monitoring in CML is a powerful tool to document treatment responses and predict relapse. Nonetheless, the proliferation of clinical trials and guidelines using the molecular endpoints of CML has outpaced practice norms, commercial laboratory application, and reimbursement practices, leaving some clinicians feeling anxiety (if not confusion and despair) about molecular monitoring in the day-to-day treatment of CML. 

Given the power of molecular monitoring in the transplantation setting, which has now been largely displaced by effective TKIs, molecular monitoring was used in the TKI trials as a measure of disease response. Such monitoring is now advocated for the routine clinical care of CML. The cytogenetic response is monitored every 3-6 months. Methods include karyotyping and fluorescence in situ hybridization (FISH) to count the percentage of bone marrow cells that are Ph1 positive. [64]  

The most sensitive method for detecting CML is quantitative reverse transcriptase PCR (RT-PCR) for BCR/ABL messenger RNA (mRNA), which can detect one CML cell in approximately 100, 000 to 1 million cells. The assay has well-documented pitfalls, mostly revolving around its complexity and the lack of standardization across laboratories. On an extremely positive note, peripheral blood can be used instead of bone marrow for monitoring, because a good correlation exists between BCR/ABL mRNA in bone marrow and peripheral blood.

Molecular responses are defined by the magnitude of reduction in BCR-ABL transcripts from a standardized value (rather than an individual patient's original level). A major molecular response (MMR) is defined as a more than 3-log reduction in BCR-ABL/control gene ratio. The criteria for monitoring patients receiving TKIs are summarized in the European LeukemiaNet and National Comprehensive Cancer Network (NCCN) guidelines. [65]

The goal is 100% normal cells after 1-2 years of therapy. Patients who remain BCR/ABL positive (ie, those with minimal residual disease [MRD]) should be kept on maintenance therapy as long as they continue to have MRD.

Early monitoring after starting TKI therapy may also be useful in predicting response. The rate of BCR-ABL decline in the initial 2 to 3 months of imatinib therapy is a strong predictor of subsequent response, as patients with less than 1-log reduction after 3 months had a 13% probability of ever achieving an MMR after 2.5 years of follow-up, compared with more than 70% in patients with more than 1-log response. [66]  

Cortes et al found that patients with chronic phase CML who have a less than 1-log reduction after 3 months of imatinib therapy had a 55% chance of ever achieving a MMR at 2 years, compared with those with a more than 1-log or 2-log reduction, in whom an MMR was achieved in 84% and 95%, respectively. [67]  

More than 80% of newly diagnosed patients with CML in the chronic phase will achieve a complete cytogenetic response with the standard dose of 400 mg/day of imatinib. The probability of progression-free survival is strongly correlated with the level of response, approaching 100% in those patients who achieve molecular remission (a reduction of BCR/ABL mRNA by at least 3-log at 12 mo).

High Sokal risk predicts poorer outcome, but responses during treatment generally override pretherapeutic prognostic variables. When less-sensitive tests become negative, more-sensitive tests are done; thus, monitoring should be tailored to the level of response attained by a given patient.


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