Can early response to treatment with tyrosine kinase inhibitors predict long-term outcomes?

This study examined the effect of early treatment response to different tyrosine kinase inhibitors on long-term outcomes in patients with chronic myeloid leukemia (CML). Researchers reported that early treatment response is predictive of long-term outcomes across all tyrosine kinase inhibitors studied.

CML is a disease in which the bone marrow makes too many mature and immature white blood cells. It is typically a slowly progressing disease that occurs mainly during or after middle age. Targeted therapy has become the standard first-line treatment for CML. Targeted therapy is a type of treatment that uses drugs or small molecules that block the growth and spread of cancer.

Tyrosine kinase inhibitors (TKIs) are a type of targeted therapy that block enzymes called tyrosine kinases. Imatinib (Gleevac), nilotinib (Tasigna), and dasatinib (Sprycel) are TKIs commonly used to treat CML. Early treatment response to TKIs is often associated with good long-term treatment outcomes. Treatment response is often measured based on patients showing decreased abnormal chromosomes (cytogenetic) or genetic abnormalities (molecular) in the blood or bone marrow. 

The aim of this study was to examine the effect of early treatment response to 3 different TKIs on long-term outcomes.

483 CML patients treated with TKIs were included in this study. In these patients, CML was newly diagnosed and in the chronic (early) phase. Patients were treated with either imatinib at a high or a low dose, nilotinib, or dasatinib. Early treatment response (cytogenetic and molecular) was measured at 3 and at 6 months. Treatment outcomes were followed for an average of 72 months.

Overall, 88% of patients achieved complete cytogenetic response. 82% of patients achieved major molecular response. 69% of patients achieved complete molecular response. Major cytogenetic response at 3 months was higher for patients treated with high-dose imatinib (91%), nilotinib (97%), or dasatinib (95%) when compared with those treated with low-dose imatinib (73%).

Patients with a worse cytogenetic response at 3 months had a lower probability (81%) of being disease progression or treatment failure free at 3 years. Patients with a better response at 3 months had a higher probability (97%) of being disease progression or treatment failure free at 3 years.  At 6 months, the cytogenetic response was also a significant predictor of later events such as disease progression or treatment failure. A similar trend was observed for molecular responses at 3 and at 6 months. The likelihood to experience a negative event over 3 years was not significantly different among the different TKI treatment groups.

3-year overall survival rate (proportion who have not died from any cause since treatment) was 92% for patients showing only a minor cytogenetic response at 3 months. This was significantly lower compared to patients showing a major cytogenetic response at 3 months (96 to 98%). At 5 years, overall survival was 58% for patients showing only a minor cytogenetic response at 3 months. Overall survival at 5 years remained high among patients showing a major cytogenetic response at 3 months (84 to 89%). Similar outcomes were observed for treatment responses measured at 6 months. OS was similar between cytogenetic response categories regardless of TKI dose.

Younger age, high-risk disease, and low-dose imatinib were found to be predictors of poor cytogenetic response at 3 months.

Researchers concluded that early treatment response to TKIs is predictive of long-term treatment outcomes. No significant differences were found between different TKIs with the exception of low-dose imatinib, which was associated with poorer treatment responses.