While patients with chronic myeloid leukemia (CML) can continue indefinitely on tyrosine kinase inhibitors (TKIs), researchers increasingly question the need for life-long treatment in a significant number of patients. New guidelines from the National Comprehensive Cancer Network (NCCN) published in the Journal of the National Cancer Institute this summer can help clinicians identify which patients should stay on therapy and which ones can safely discontinue.
TKI treatment can cost more than $100,000 per person per year and may be associated with significant adverse events, according to a study published in Nature Reviews Clinical Oncology, so discontinuation has clear benefits—but at what cost in terms of survival?
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Chronic myeloid leukemia. (Source: Paulo Henrique Orlandi Mourao)
TKIs revolutionized CML therapy and transformed the disease from a death sentence to a chronic condition. TKIs attack the Philadelphia chromosome, a fusion of the BCR and ABL genes, and eliminate mature CML cells and stunt the development of other cells with the aberrant fused genes. Success on TKIs is measured by the change in the amount of BCR-ABL protein present following treatment compared to initial rates, with rates that are 1/1000 of baseline referred to as molecular response 3.0 (MR3.0) and 1/10000 as MR4.0.
Studies of treatment discontinuation have been restricted to patients achieving at least MR4.0. The European Stop Tyrosine Kinase Inhibitor Study (EURO-SKI) found that 38% of patients who discontinued therapy after taking TKIs for at least 3 years and achieving an MR4.0 or better in the last year did not relapse for at least 3 years, according to the JCNI article. Most of those who experienced a relapse did so within the initial 6 months after treatment cessation. A recent French study found 44% of patients who discontinued therapy remained relapse-free at 77 months, said the authors.
According to the new NCCN guidelines, patients who have had at least 3 years of TKI therapy and who achieved an MR4.0 or better in the last 2 years could be considered for discontinuation. Patients with any history of accelerated or blast-phase CML should not stop therapy. Resistance to imatinib also contraindicates treatment cessation, regardless of response to other TKIs.
Some patients may be eager to discontinue therapy, particularly those who experience significant side effects. For those who express more wariness, the DESTINY study may provide a reassuring bridge. The UK study halved 125 patients’ standard dose of TKIs prior to stopping treatment altogether. Less than 7% of patients relapsed during the lower dose period. Patients who do relapse generally will respond to treatment once it begins again, the researchers said.
