Join Elias Jabbour, MD, and Susan O'Brien, MD, as they present their multidisciplinary expertise on a range of cases pertaining to chronic myelogenous leukemia. 

Chronic myelogenous leukemia (CML) is characterized by the presence of Ph chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t(9;22)]. Tyrosine kinase inhibitor (TKI) therapy (with imatinib, dasatinib or nilotinib) is the standard first‑line treatment for patients with newly diagnosed chronic phase CML.
Early molecular response to first‑line TKI therapy has emerged as an effective prognostic indicator of long‑term durable responses and survival. Quantitative reverse transcriptase polymerase chain reaction (QPCR) is the most sensitive assay available for monitoring molecular response. An International Scale (IS) has been established to standardize molecular monitoring with QPCR across different laboratories. QPCR using IS provides a more precise and less invasive assessment of response to TKI therapy and is now considered the preferred method for monitoring response to TKI therapy. QPCR (IS), however, is still not available in many laboratories. Alternatively, laboratories with no access to QPCR (IS) assays may establish their own standardized baseline, based on a large number of pre‑treatment samples. Molecular response to TKI therapy is measured as the log‑reduction of BCR‑ABL1 mRNA from the standardized baseline (not a reduction from the actual baseline level in an individual patient). Bone marrow cytogenetics can be used if QPCR (IS) is not available.

BCR-ABL kinase domain mutations are a frequent mechanism of resistance to TKI therapy. Dasatinib and nilotinib are active against a majority of mutations that confer resistance to imatinib (except for T315I) and are effective second‑line therapy options for patients resistant or intolerant to imatinib. In addition, other BCR-ABL mutations such as F317L, V299, Y253H, E255, and F359 also confer resistance to dasatinib and nilotinib. Bosutinib and ponatinib are active against a variety of mutations (E255K/V, F317L, F359V, G250E, M351T, and Y253H) that confer resistance to dasatinib and nilotinib. Bosutinib is an effective treatment option for patients with resistance or intolerance to  prior TKI therapy including imatinib, dasatinib or nilotinib.Ponatinib is a treatment option for patients with T315I mutation and for patients who have failed on multiple TKIs.Omacetaxine is an option for patients with resistance and/or intolerance to two or more TKIs and for patients with T315I mutation.

Although the availability of more potent TKIs has significantly improved the outcomes of patients with newly diagnosed CML, the vast majority of patients with a clinically undetectable level of BCR‑ABL1 transcripts by the most sensitive PCR measures remain with residual disease that may eventually lead to relapse. Treatment interruptions and non‑adherence to TKI therapy may lead to undesirable clinical outcomes.  Results from recent studies suggest that discontinuation of TKI therapy (with close molecular monitoring) may be possible in carefully selected patients. Ongoing clinical trials are evaluating the optimal selection criteria for safe discontinuation of TKI therapy. At the present time, the guidelines recommend continuation of TKI therapy indefinitely in responding patients.

The goal of TKI therapy is to achieve a complete cytogenetic response within 12 or 18 months of initiation of therapy and to prevent disease progression to accelerated or blast phase. In general, the selection of appropriate first‑line TKI therapy is dependent on the disease phase, physician’s experience, patient’s age, ability to tolerate therapy, and the presence of comorbid conditions. Monitoring response to TKI therapy enables physicians to identify patient’s treatment options. Mutational analysis at the time of failure or loss of response to first-line benefit from alternate TKI therapy would be helpful in the selection of subsequent TKI therapy. Physicians should integrate molecular monitoring with QPCR (IS) as an essential component in the clinical management of patients with CML. Patient education on adherence to TKI therapy and close monitoring of patient’s adherence is critical to achieve optimal responses. Evaluation of patient compliance to TKI therapy and drug interactions should be done prior to changing therapy for patients with inadequate initial response. Adequate and appropriate management of side effects and scheduling appropriate follow‑ups to review side effects could be helpful to improve patient adherence to therapy.