TKI Dose Reduction Improves Treatment-Free Remission Protocols for Chronic Myeloid Leukemia

Final results of the DESTINY study (ClinicalTrials.gov Identifier: NCT01804985) showed that a high percentage of carefully selected patients with chronic myeloid leukemia (CML) remain in treatment-free remission when cessation of tyrosine kinase inhibitor (TKI) therapy is preceded by a dose reduction.  The findings from this study were published in Lancet Haematology.¹

Although long-term therapy targeting the BCR-ABL tyrosine kinase has been shown to be very effective in patients with CML, the occurrence of low-level adverse effects of these TKIs has prompted investigations into whether treatment can be safely terminated in some patient groups. Most previous studies evaluating cessation of TKI therapy in the setting of CML focused on patients in stable MR4, defined as molecular response 4 logs below an internationally agreed standard (BCR-ABL1:control gene ratio always 0.01% or lower during a preliminary observation period). Furthermore, most of these studies did not involve TKI dose reductions prior to treatment cessation. Maintenance of at least a major molecular response (MMR) status (ie, BCR-ABL1:control gene ratio always 0.1% or lower) following treatment cessation was observed in 50% to 60% of patients in these studies.

This randomized phase II study conducted at multiple centers in the United Kingdom included adult patients in the first chronic phase of CML who had received at least 3 years of treatment with a standard dose of imatinib, nilotinib, or dasatinib, and were in stable MMR for at least 12 months prior to study enrollment. All enrolled patients were treated with TKI therapy at half the standard dose for 12 months, followed by TKI treatment cessation for 24 months, for a total study period of 36 months. Separate analyses were performed for those in stable MR4 and MMR in the 12-month period preceding study enrollment.

Of the 174 patients enrolled in the DESTINY study between December 2013 and May 2015, 72% and 28% were assigned to the MR4 and MMR groups, respectively. At study entry, the median duration of TKI therapy was 6.9 years.

A key finding from this study was a significant difference in 3-year recurrence-free survival (RFS; defined as maintenance of at least MMR) when the MR4 group (72%) was compared with the MMR group (36%; P <.0001). On multivariate analysis, only MR4/MMR status and duration of prior TKI therapy were predictive of RFS.

For those patients with disease recurrence, no patient had progressive disease. In addition, 91% returned to MMR status at 5 months following re-initiation of full-dose TKI therapy.

“Our finding that 72% of patients in stable MR4 are recurrence-free at 2 years after stopping is the best reported in this group of patients and implies that the results of stopping treatment might be more successful if preceded by a gradual withdrawal of treatment. The data also suggest that treatment discontinuation might be feasible for some patients whose molecular response is in MMR but not MR4, although we urge further studies in this group of patients,” the study authors noted in conclusion.

Reference

Clark RE, Polydoros F, Apperley JF, et al. De-escalation of tyrosine kinase inhibitor therapy before complete treatment discontinuation in patients with chronic myeloid leukaemia (DESTINY): a non-randomised, phase 2 trial.Lancet Haematol. 2019;6(7):e375-e383.