Alternative approaches to eradicating the malignant clone in chronic myeloid leukemia: tyrosine-kinase inhibitor combinations and beyond

Van Etten
Hematology 2013 2013:189-200; doi:10.1182/asheducation-2013.1.189

Abstract

In patients with chronic myeloid leukemia (CML) in chronic phase who have achieved complete molecular remission on imatinib therapy, clinical trials from France and Australia have demonstrated that the majority experience prompt molecular relapse of their leukemia upon discontinuation of the drug, showing that long-term monotherapy with tyrosine kinase inhibitors is not curative in the majority of patients with CML. This has focused attention on strategies to eradicate residual disease in CML that is presumed to arise from malignant Ph+ stem cells, which should result in permanent cure and long-term leukemia-free survival. Here, we review the evidence that targeting CML stem cells will be of clinical benefit and discuss pharmacological and immunological approaches to accomplish this goal. Where possible, we link preclinical studies of CML stem cell biology to emerging results from clinical trials of agents that may target these cells.
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Conclusions and future directions: getting into the clinic

From the foregoing summary, it is clear that we have no shortage of innovative approaches to eliminating CML stem cells. A major challenge for the field is testing which of these strategies will be safe and effective in our CML patients who are on TKI treatment, recognizing that most of these patients are asymptomatic with an excellent quality of life and, as a corollary, that any proposed intervention must have very low toxicity and morbidity. The time is ripe for clinical trials of these approaches because we now have multiple targeted therapies with dosing and safety profiles as single agents that have been established. Our own preferences for those strategies that have the strongest existing evidence and best chance for success are indicated in Table 1. Because the depth of molecular responses continues to increase with time on TKI treatment, it is clear that such trials will need to be randomized and must compare cohorts of patients on the same TKI at the same point after initiation of treatment. Given that CML is a relatively rare condition, this poses a challenge, but the rising prevalence of the disease and the potential cost savings of discontinuing TKI treatment should motivate all stakeholders (patients, caregivers, payers) to participate in such studies. Outside of a clinical trial, should we advise our CML patients to drink wine, consume fish oil, or take NSAIDs? That these are all reasonable suggestions is a measure of just how far we have come in the treatment of CML.

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http://asheducationbook.hematologylibrary.org/content/2013/1/189.full?si...