Targeted therapy with tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes for patients with chronic myeloid leukemia (CML), offering the majority of them the chance to live normal lifespans. Yet lifelong daily treatment carries the risk of a range of adverse effects and a staggeringly high cost.
That has led to a number of studies examining the feasibility of stopping TKI therapy after patients achieved a sustained deep molecular response of MR4 or better.
Now, a groundbreaking study published in The Lancet Haematology concluded that a broader range of patients may attain similar outcomes with a significantly reduced dosage.1 In addition, the study’s lead author said, putting patients on half-dose therapy as a precursor to stopping treatment completely appears to eliminate most adverse effects, drastically reduce costs, and yield even better relapse-free survival (RFS) rates.
Those results, presented at the European Hematology Association congress in late June, found that a year of reduced dosage prior to stopping correlated to a 20% improvement in RFS over stopping alone.2
“We never thought for a minute that we would get better results in ultimately stopping just by having an extra year of de-escalation,” said Richard E. Clark, MD, professor of hematology in the department of molecular and clinical cancer medicine at the University of Liverpool in England.
What causes the difference remains unknown.
“There’s something mysterious about our trial that gives better results,” he said.
His theories about the causes include the possibility that the reduced dose somehow triggers a response in the leukemic stem cell that makes it more susceptible to TKI treatment. Or, conversely, he said, “that when you wind down the treatments you in some way wake up the immune system so that the immune system can ‘take out’ those stem cells.”
The DESTINY study (ClinicalTrials.gov Identifier: NCT01804985) was carefully designed to permit an eventual comparison with the results of the multicenter European Leukemia Net study examining “the exact preconditions for stopping CML treatment.”3
That study, known as the EURO-SKI trial, included 821 patients in 11 countries. The results presented in December showed that “molecular recurrence-free survival was 62% (95% CI: 59%-67%) at 6 months, 56% (CI: 52%-59%) at 12 months, and 52% (CI: 48%-56%) at 24 months.”
The authors also noted that treatment duration had a significant impact on relapse rates.
“One additional year of treatment increases the odds to stay in [major molecular response] at 6 months by 16%,” the authors wrote. “Molecular relapse-free survival at 6 months was 65.5% for imatinib treatment [given for longer than] 5.8 years and 42.6% for treatment [given for] 5.8 years [or less].”