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Sustained MR4 and molecular monitoring in CML
respectively.10 Our results confirm the excellent outcome of patients who achieve sMR4 or better, but this was not the focus of our study; instead, we used our database of prolonged molecular monitoring to try to provide an evi- dence base for the frequency of molecular monitoring and a practical guide for clinical management.
One criticism of the use of our findings is that we are recommending reduced frequency of monitoring and hos- pital interactions in a group of patients who are candidates for trials of dose-reduction and/or discontinuation for treatment-free remission (TFR). We deliberately defined sMR4 as MR4 sustained for 12 months as this is identical to the criterion used to confirm eligibility for a trial of treatment discontinuation in the EURO-SKI study.28 However, many patients are reluctant to discontinue ther- apy, and of those who do cease treatment, approximately half will have to recommence TKI because of loss of MR3,29-31 resulting in the majority continuing to require life-long treatment and monitoring. These patients, who have responded well and durably to TKI, may welcome fewer hospital visits.
We acknowledge some limitations in our study. We are aware that it is a retrospective observational study. In addition, we included all patients who achieved sMR3, including those who had at some point received higher or lower than standard doses of TKI and those who were known to be non-compliant. However, we feel that this reflects the ‘real-life’ clinical situation, and it is not surpris- ing that these groups are more likely to lose molecular responses. Our study does confirm the requirement to adhere to more rigorous monitoring in these vulnerable patient groups.
In summary, we have shown that risk of loss of MR3 is negligible in patients who have achieved sMR4, particular- ly in those who remain on standard dose TKI who have
not demonstrated prior resistance and who are known to be compliant. As a consequence, we suggest that sMR4 is regarded as a secure molecular threshold, representing a level of response that may justify less frequent monitoring in patients who are not considering, or who have failed, a trial of treatment discontinuation. For patients and health- care providers, the identification of a secure level of molecular response has a number of direct and indirect benefits. For patients, the knowledge that they have reached a level of residual disease that is associated with a negligible risk of loss of response will not only be reassur- ing, improving morale and quality of life, but also facilitate the acceptance of alternative management styles, includ- ing remote care. The consequent reduction in hospital vis- its will be cost saving to both patients and healthcare providers.
There are, of course, reasons other than molecular mon- itoring, for continuing to provide close interactions between patients and healthcare professionals: continued close supervision may promote compliance, allow recog- nition and management of adverse events and co-morbidi- ties, optimize the use of expensive medication, facilitate advice regarding parenting, and provide valuable reassur- ance of on-going response. Our results simply provide support for patients and healthcare professionals who wish to consider relaxing the need for hospital visits.
Acknowledgments
JFA and DM acknowledge the support of the Imperial College NIHR Biomedical Research Centre. JFA is a NIHR Senior Investigator. SC acknowledges the support of Ariad (Incyte) and Pfizer. GN acknowledges the support of ARIAD (Incyte). The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.
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