In a nutshell
This study reviewed evidence of novel agents 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. It is typically a slowly progressing disease that occurs mainly during or after middle age. Most patients are diagnosed in the chronic (early) phase.
Over recent years, 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. One of the first TKIs used to treat CML is imatinib (Gleevac). More recently developed TKIs include nilotinib (Tasigna), dasatinib (Sprycel), ponatinib (Iclusig), and bosutinib (Bosulif).
Methods & findings
A number of long-term studies have shown good long-term disease control with imatinib for chronic-phase CML. An 8-year overall survival rate (proportion who have not died from any cause since treatment) of 93% has been reported. 92% of patients were progression-free at 8 years. 400 mg of imatinib has consistently been found to be as effective as 800 mg in terms of treatment response with a lower rate of side effects. However, there is evidence to suggest that a higher dose of imatinib may shorten the time until response.
In a study of 670 patients no longer responding to imatinib, dasatinib provided effective long-term disease control regardless of dose given. The 6-year overall survival rate ranged from 70 to 77% (depending on dose). As a first-line therapy, 94% of patients who received dasatinib at 100 mg once daily achieved complete cytogenetic response (CCR; few or no abnormal chromosomes in the blood or bone marrow). Major molecular response (MMR; a reduction in genetic abnormalities in the blood or bone marrow) was reached in 82% of patients. Of those who achieved CCR, 94% maintained it over a 30-month follow-up.
In another study, 519 patients with newly diagnosed chronic-phase CML were randomly assigned to treatment groups. CCR was significantly higher with dasatinib (77%) than with imatinib (66%) at 12 months. The rate of MMR was 46% with dasatinib and 28% 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.
In a study involving 73 newly diagnosed chronic-phase CML, nilotinib was administered as first-line therapy at 400 mg twice daily. CCR at 12 months was 96%. MMR at 12 months was 85%. Of these, most were reached within 3 months of treatment. Another study reported the MMR rate at 12 months to be nearly twice as high with nilotinib (44%) when compared to imatinib (22%) as first-line therapy. Side effects were comparable in the two treatment groups.
A recent analysis of 8 studies found that the chances of CCR for dasatinib and nilotinib were about 3 times higher than those for imatinib. No significant differences were observed between dasatinib and nilotinib.
Bosutinib was not found to be superior to imatinib as a first-line therapy in a study of 502 patients. CCR rates were comparable (70% with bosutinib and 68% with imatinib). Bosutinib was also associated with a higher rate of treatment discontinuation due to side effects. However, there is some evidence to suggest higher rates of MMR with bosutinib.
Ponatinib is a treatment option for CML patients considered difficult to treat. This includes patients no longer responding to several lines of TKIs and those with genetic abnormalities (making CML more difficult to treat). 44% of chronic-phase CML patients no longer responding to TKIs achieved CCR with ponatinib. 46% of patients with the T315I mutation achieved CCR with ponatinib. However, there are reports associating ponatinib with an increased risk of blood clots.
A non-TKI treatment option for chronic-phase CML patients is the targeted therapy omacetaxine (Synribo). It works by inhibiting protein growth in tumors. A study administered injections of omacetaxine twice daily in 81 CML patients no longer responding to at least 2 TKIs. Major cytogenetic response was observed in 20% of patients that lasted for an average of 17.7 months. Overall survival was 34 months. A high rate of side effects was noted, mostly low white and red blood cell counts.
The bottom line
This study concluded that TKIs are recommended as first-line treatment for chronic-phase CML include imatinib, dasatinib, and nilotinib. Bosutinib and ponatinib are approved second- or third-line treatments. More studies are needed that examine the long-term safety of TKIs and whether TKIs should be combined with other treatments.
Published By :
Mar 21, 2017