DESTINY Study: De-Escalation of TKIs Is Safe for Patients With CML

Author’s Perspective

Lead author Richard E. Clark, MD: “Thanks to modern therapy with tyrosine kinase inhibitors (TKIs), many patients with chronic myeloid leukemia (CML) have deep and enduring molecular responses (MRs) for many years, though some are troubled by side effects that can affect quality of life. Rather than abruptly stopping treatment, the DESTINY study first decreases treatment to half of the standard TKI dose for 12 months. … The data show that 98 percent of patients in stable MR4 and 81 percent of patients in stable MR3 can go on to half the standard dose of their TKI without losing deep response.”

Previous studies demonstrated that patients with chronic myeloid leukemia (CML) who achieve a deep molecular response (MR4; defined as a BCR-ABL1:ABL1 ratio consistently <0.01%) can safely de-escalate tyrosine kinase inhibitor (TKI) therapy. New research published in The Lancet Haematology suggests that the threshold for de-escalation could be extended to include patients who achieve a stable major molecular response (MR3; defined as a BCR-ABL1:ABL1 ratio ≤0.1%).

In the ongoing, non-randomized, phase II DESTINY study, Richard E. Clark, MD, from the Department of Haematology at the Royal Liverpool University Hospital in the United Kingdom, and co-authors enrolled 174 adult patients (median age = 59 years; range = 50-68 years) with an MR3 (n=49) or MR4 (n=125) response from 20 hospitals in the U. K. between December 16, 2013, and April 10, 2015. The median durations of TKI therapy were 7.7 years (range = 5.1-10.7 years) and 6.5 years (range = 4.8-10.2 years) for those in MR3 and MR4, respectively.

Eligible patients had BCR-ABL1–positive CML, received TKI therapy for at least three years, and had a minimum of three polymerase chain reaction tests in the preceding 12 months of ≤0.1 percent (≤0.01 percent for the MR4 group); each with ≥10,000 ABL1 control transcripts. Patients who were resistant to previous TKIs or switched therapies for intolerance more than once were excluded.

Upon enrollment, patients decreased their entry TKI dose to half of the standard dose for 12 months (imatinib 200 mg daily, dasatinib 50 mg daily, or nilotinib 200 mg twice-daily).

During 12 months at half-dose therapy, 12 patients (7%) had molecular recurrence (primary endpoint; defined as loss of MR3) – all of whom were receiving imatinib. All 12 patients regained at least MR3 within four months after resuming the full TKI dose (median time to recovery = 77 days; range not provided).

Molecular recurrence was significantly lower in the MR4 cohort (2% for MR4 vs. 19% for MR3; hazard ratio = 0.12; 90% CI 0.04-0.37; p=0.0007), and patients in MR4 had a longer median time to relapse (8.7 months vs. 4.4 months; ranges and p value not provided).

Molecular recurrence did not appear to be related to age, sex, weight, performance status, BCR-ABL1 transcript type, or duration of TKI therapy. In addition, “too few patients were receiving dasatinib or nilotinib to allow comparison of recurrence rates between imatinib and second-generation TKI recipients,” the authors wrote.

Common adverse events (AEs), such as lethargy, diarrhea, rash, nausea, periorbital edema, and hair thinning, improved during the first three months of de-escalation, but not thereafter. Thirty-six patients (21%) reported 53 new musculoskeletal symptoms.

Sixteen serious AEs were reported, but were deemed unrelated to TKI or the underlying CML. One serious AE resulted in death because of worsening preexisting peripheral arterial occlusive disease in an imatinib-treated patient.

The study is limited by its non-randomized design. In addition, Dr. Clark added, “at present we are not able to predict who will lose their response on half-dose treatment. We may be able to do so once further follow-up data become available.”

Most patients (MR4 cohort: n=36; 73% and MR3 cohort: n=117; 94%) are continuing on study to assess discontinuation of TKI therapy.

Newcastle University and Bloodwise provided funding for the study.

Professor Clark reported grants from Bloodwise, as well as grants and personal fees from Novartis, Bristol-Myers Squibb, and Pfizer, and personal fees from Ariad/Incyte. Jane F. Apperley reported grants and personal fees from Ariad/Incyte and Pfizer, and personal fees from Bristol-Myers Squibb and Novartis.

Source: Clark RE, Polydoros F, Apperley JF, et al. De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial. Lancet Haematol. 2017;4:e310-6.

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