A review of tyrosine kinase inhibitors for CML

This study reviewed evidence of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia (CML).

CML is a disease in which the bone marrow makes too many mature and immature white blood cells. Most patients are diagnosed in the chronic (early) phase. Over recent years, targeted therapy with tyrosine kinase inhibitors (TKIs) has become the standard first-line treatment for CML. TKIs work by blocking enzymes called tyrosine kinases involved in cancer cell growth. Imatinib (Gleevac), dasatinib (Sprycel), and nilotinib (Tasigna) are approved for the first-line treatment of CML in he chronic phase. More recently developed TKIs include ponatinib (Iclusig) and bosutinib (Bosulif). 

A number of studies have shown good long-term disease control with imatinib for chronic-phase CML. A 10-year overall survival rate (proportion who have not died from any cause since treatment) of 83% has been reported. 93% of patients showed major molecular response (MMR; a reduction in genetic abnormalities in the blood or bone marrow). Overall survival rates are higher with imatinib compared to the chemotherapy cytarabine (Cytosar), the previous standard-of-care.

Dasatinib has been shown to be safe and effective as a first-line therapy and as salvage therapy after imatinib. One study reported an MMR rate of 76% at 5 years with dasatinib compared to 64% with imatinib. Treatment response also occurred sooner in the dasatinib group. However, the most important predictor of long-term outcomes was the level of the genetic mutation known as BCR-ABL1 transcript at 3 months. Overall survival and progression rates at 5 years were similar between dasatinib (91%) and imatinib (85%).

In a study involving 73 newly diagnosed chronic-phase CML, nilotinib was administered as first-line therapy at 400 mg twice daily. MMR rate at 7 years was 93%. The MMR was maintained in 70 out of the 73 patients. Overall survival rates are generally similar between nilotinib, dasatinib, and imatinib.

Bosutinib was not found to be superior to imatinib as a first-line therapy after an average treatment period of 28 months. Complete cytogenetic response rates (CCR; few or no abnormal chromosomes in the blood or bone marrow) at 24 months were very similar (79 to 80%). In an ongoing study, bosutinib is showing higher MMR rates compared to imatinib. High MMR rates have also been associated with ponatinib in the first 12 months of treatment. However, more studies are needed.

Side effects during TKI therapy depend on patient characteristics (such as age and other medical conditions) and the type of TKI used. Dasatinib is associated with an increased risk of fluid build-up in the lungs (known as pleural effusion). One study found that pleural effusion occurred in 28% of patients. Severe pleural effusion occurred in only 3%. Patients at high risk of heart problems should avoid nilotinib. Cardiovascular events (such as a stroke or heart attack) were more common with nilotinib (9%) than with imatinib (3%).

This study concluded that selection of an appropriate first-line therapy for CML needs to take into account the unique characteristics of each TKI for each patient individually. More studies are needed that examine the long-term safety of TKIs and whether TKIs should be combined with other treatments.