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Chronic myeloid leukemia patients with a stable molecular response may safely decrease the dose of their tyrosine kinase inhibitor

A study presented at ASH 2016 suggests that many chronic myeloid leukemia (CML) patients may be able to safely reduce tyrosine kinase inhibitor (TKI) side effects by cutting their dose in half. In contrast to other trials, which focus on patients who are nearly free of leukemia as measured by very sensitive tests, this trial included some patients with a stable molecular remission level demarcated according to international standards as MR3. These results suggest that a wider range of patients may be able to safely reduce TKI therapy than was previously thought feasible.

Several studies have established that some CML patients with enduring deep molecular responses to TKI therapy can discontinue treatment. However, these studies are confined to patients in stable MR4, i.e. patients whose BCR-ABL/ABL ratio is consistently below 0.01%. Although there are anecdotal reports of successful treatment cessation for a few months in patients in stable MR3 (i.e. BCR-ABL <0.1%; major molecular response) but not MR4 (e.g. during pregnancy), such patients have not hitherto been formally studied in a stopping trial. In the British De-Escalation and Stopping Therapy with Imatinib, Nilotinib or sprYcel (DESTINY) study, patients in at least stable MR3 initially decreased their TKI to half the standard dose for 12 months, followed by complete cessation.

In order to be eligible for the study, patients should have received the same TKI since the original diagnosis and should have been on TKI therapy for at least 3 years. All PCR tests in the past 12 months should have indicated a MR3. In total, 174 patients (male 98; female 76) were recruited in the study. At entry, 148 patients were receiving imatinib, 16 were on nilotinib and 10 were treated with dasatinib.

After 12 months of half-dose therapy (imatinib 200mg daily, nilotinib 200mg twice daily or dasatinib 50mg daily), the rate of molecular recurrence was lower in patients with stable MR4 at entry (3 of 125 patients; 2.4%) than in patients with an MR3 but not MR4 (9 of 49 patients; 18.4%) (p< 0.001). Also the median time to relapse was shorter in the sustained MR3 group than in those with a sustained MR4 (4.4 months vs. 8.7 months). However, all 12 patients with molecular recurrence regained MR3 within 4 months of resumption of full dose TKI. Overall, the vast majority of patients in this study (93%) showed no evidence of leukemia rebound one year after cutting their TKI dose in half. Moreover, many patients reported a significant decrease in TKI-associated side effects within the first three months.

In their conclusion, the investigators stated that these findings might indicate that some patients are being unnecessarily over-treated. The other important implication is that patients do not have to have extremely low BCR/ABL1 levels in order to safely try reducing their TKI dose. It was so that participants who started with an MR4 were significantly less likely to experience a leukemia rebound (seen in 2.4% of these patients) compared with those classified as MR3 (18.4%), but the low rates of rebound overall suggest that it is safe for MR3 patients to attempt to reduce their TKI dose if desired.



Clark R, Polydoros F, Apperley J et al. Chronic Myeloid Leukaemia Patients with Stable Molecular Responses (at least MR3) May Safely Decrease the Dose of Their Tyrosine Kinase Inhibitor: Data from the British Destiny Study. Presented at ASH 2016; Abstract 938.

Speaker Mhairi Copland


Mhairi Copland, PhD, Professor of Translational Haematology,
Paul O'Gorman Leukaemia Research Centre, University of Glasgow, Glasgow, United Kingdom


See: Keyslides


Professor of Translational Haematology
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