Tyrosine-kinase inhibitor (TKI) discontinuation may be considered among patients with chronic myeloid leukemia (CML) who achieve prolonged deep molecular response (DMR), according to a study published in The Lancet Oncology.1
Targeted therapies among patients with CML have improved over time, leading to patients achieving high rates of DMR — a prerequisite criteria for TKI discontinuation. TKI discontinuation could lead to significant economic savings for patients, as well as a reduction of treatment-related adverse events (AE); however, the conditions for ceasing TKI therapy are not entirely clear.
In the prospective European Stop Tyrosine Kinase Inhibitor (EURO-SKI) study (ClinicalTrials.gov Identifier: NCT01596114), researchers enrolled 758 patients with CML receiving first- or second-line TKI treatment. TKI therapy was discontinued among patients who had a TKI treatment duration of at least 3 years, maintained DMR (detectable BCR-ABL1 ≤ 0.01%; undetectable BCR-ABL1) for at least 1 year, and had at least 3 PCR analyses that showed DMR within a year before study entry. Molecular response was assessed once a month for the first 6 months after discontinuation, then every 6 weeks until 12 months, then every 3 months for at least 3 years. The median follow-up was 27 months.
Results of a prespecified interim analysis — performed after the 6-month molecular relapse-free survival status was known for 200 patients — demonstrated that of the 755 evaluable patients, the molecular relapse-free survival rate was 61% (95% CI, 57%-64%) and 50% (95% CI, 46%-54) at 6 months and 12 months, respectively.
Nearly half (371) patients lost major molecular response (MMR) after discontinuation and 13 restarted TKI therapy while in MMR. Four patients died from non-CML reasons, 6 patients died in chronic phase CML after MMR loss and reinitiating TKI therapy for non-CML reasons, and 2 patients lost MMR despite reinitiating TKI therapy.
Factors that significantly increased the probability of MMR maintenance at 6 months among patients who received first-line imatinib therapy included longer treatment duration (P = .001) and longer DMR duration (P = .0032).
An estimated cost-savings of €22 million was reported with TKI discontinuation, and no serious AEs were observed.
The authors concluded that patients who achieve DMR have good molecular relapse-free survival, and they should be “considered for TKI discontinuation, particularly those who have been in deep molecular response for a long time. Stopping treatment could spare patients from treatment-induced side-effects and reduce health expenditure.”
- Saussele S, Richter J, Guilhot J, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial [published online May 4, 2018]. Lancet Oncol. doi: 10.1016/S1470-2045(18)30192-X