When to Stop Tyrosine Kinase Inhibitors for the Treatment of Chronic Myeloid Leukemia

The outcome of chronic myelogenous leukemia (CML) patients presenting in the chronic phase has changed dramatically since the introduction of tyrosine kinase inhibitor (TKI) therapy with imatinib in 2001 and second-generation TKIs in 2007. With the availability of TKI therapy, standardized molecular monitoring, and the adoption of response-adapted intervention for patients who “fail” to respond adequately, as defined in evidence-based international guidelines[ 1 , 2 ], patients with this historically fatal disease now have survival approaching that of the normal population [ 3 ]. While it was initially believed that TKI therapy would need to be continued indefinitely, it is now well accepted that a subgroup of patients who achieve a deep and sustained molecular response (DMR) can successfully discontinue TKI therapy and maintain a treatment-free remission (TFR). This was first demonstrated in the STIM1 trial [ 4 ] following demonstrated feasibility in a smaller study (STIM-Pilot) [ 5 ]. Discontinuation of first-line imatinib in patients who maintained a state of undetectable molecular residual disease (UMRD) for at least 2 years, measured by quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) with a sensitivity of 0.0032% (− 4.5 logs) on the International Scale (IS), UMRD4.5, the molecular relapse-free survival after 60 months was 36% [ 4 ]. This sets a precedent for a growing list of TKI discontinuation trials with minimal criteria for the necessary DMR to achieve varying from major molecular response (MMR) to UMRD5.0, sustained for a minimum of 1 to 2 years, and different criteria for the reinstatement of treatment ranging from molecular relapse to the loss of MMR. Variable rates of TFR have been reported with the majority falling in the range of 40 to 60% with success or failure occurring in the first 6 months in the majority of patients. The rate of TFR is strongly influenced by how it is defined as first shown in the A-STIM trial where the estimated rate of TFR increased from 46 to 64% at 2 years using STIM1 versus the loss of MMR as criteria [ 6 ]. Results from “real-world” studies are in general agreement with those from prospective clinical trials and have confirmed the importance of maintaining MR4.0 for at least 2 years to ensure a reasonable chance of success. Discontinuation of TKI therapy in the clinical trial setting appears to be safe with the majority of patients who fail to maintain a TFR regaining a DMR after a few months of restarting TKI therapy. Only a single patient has died to date after transforming to advanced phase disease in more than 2500 patients reported. The heterogeneity of trial criteria and results raises several challenges to define criteria for when it is appropriate and safe to stop TKI therapy in general clinical practice. This review highlights some of these challenges.

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