Several studies have established that some chronic myeloid leukaemia (CML) patients with enduring deep molecular responses to tyrosine kinase inhibitor (TKI) therapy can discontinue treatment. However, these studies are confined to patients in stable MR4, i.e. whose BCR-ABL/ABL ratio is consistently below 0.01% (molecular response 4 logs below an arbitrary baseline). 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 addition, we questioned whether some patients who experience molecular recurrence on stopping TKI might nevertheless be able to safely decrease TKI treatment without molecular recurrence.
In the British De-Escalation and Stopping Therapy with Imatinib, Nilotinib or sprYcel (DESTINY) study, patients in at least stable MR3 (on the International Standard) initially decreased their TKI to half the standard dose for 12 months, followed by complete cessation. Key entry requirements included first chronic phase of CML; receiving the same TKI since original diagnosis (except that one switch was permissible if for intolerance to the initial drug); on TKI for at least 3 years; all PCR tests in the past 12 months were in at least MR3 (minimum of 3 tests, each with >10,000 ABL control transcripts). Central monitoring was carried out monthly. Molecular recurrence was defined as loss of MR3 (>0.1%) on two consecutive samples; this prompted resumption of full dose of their entry TKI.
Between December 2013 and April 2015, 174 patients (male 98; female 76) were recruited after giving informed consent from 20 UK centres. At entry, 148 patients were receiving imatinib, 16 nilotinib and 10 dasatinib. After 12 months of half-dose therapy (imatinib 200mg daily, nilotinib 200mg twice daily or dasatinib 50mg daily), molecular recurrence was lower in patients with stable MR4 at entry (3 of 125 patients; 2.4%) than in those in MR3 but not MR4 (9 of 49 patients; 18.4%) (p < 0.001). The median time to relapse was shorter in the sustained MR3 group than in those in sustained MR4 at entry (4.4 months vs 8.7 months). The probability of molecular recurrence on de-escalation was not related to age, gender, performance status, prior TKI (imatinib vs second generation) or the duration of TKI therapy (median 7.0 years overall). No progression to advanced phase or loss of cytogenetic response was seen; one death and 15 serious adverse events occurred which were all unrelated to CML or TKI treatment. All 12 patients with molecular recurrence regained MR3 within 4 months of resumption of full dose TKI. During the first 3 months of de-escalation but not thereafter, the number of patient-reported common TKI side effects decreased, though interestingly 53 new musculoskeletal symptoms were reported by 36 patients (21%) which were typically mild and transient.
In CML patients with stable MR3 or better, decreasing TKI treatment to half the standard dose appears safe, and is associated with improvement in TKI related side effects, implying that many patients with stable responses are being overtreated. Studies of more ambitious de-escalation are warranted.
Clark:Ariad: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau. Apperley:Novartis: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Ariad: Honoraria, Speakers Bureau. Pocock:Gilead Sciences: Other: Sponsorship to attend the EHA 2016 Meeting; Janssen: Speakers Bureau; Takeda: Honoraria. Smith:Bristol Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Byrne:Bristol Myers Squibb: Consultancy, Speakers Bureau. O'Brien:Ariad: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Copland:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ARIAD: Honoraria, Membership on an entity's Board of Directors or advisory committees.
Asterisk with author names denotes non-ASH members.
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