2014 American Society of Clinical Oncology (ASCO) meeting
It’s now well established that TKIs (tyrosine kinase inhibitors [Gleevec, Sprycel, Tasigna, Bosulif]), the medications most commonly used to treat CML, are highly effective in controlling disease.
But how well do they work over the longer term?
Three studies presented at ASCO 2014 examined this issue. The first was a five-year follow-up of the ENESTnd study, which compared the relative effectiveness of Gleevec (imatinib) and Tasigna (nilotinib) (Larson and colleagues. ASCO 2014; abstract 7073). The present study updated the two-year results published in 2011 (Kantarjian and colleagues. Lancet Oncol 2011;12:841-851). People in ENESTnd took either Gleevec (400 mg once daily), or one of two doses of Tasigna (300 or 400 mg twice daily). Overall, people taking Tasigna did better than those on Gleevec. With the higher dose of Tasigna, 77% achieved a major molecular response (MMR; a 3-log reduction or better) compared to 60% on Gleevec. Moreover, 52% in the Tasigna group achieved a deep molecular response (4.5-log reduction or better) compared to 31% in the Gleevec group.
So Tasigna was more likely to induce more complete suppression of CML. This difference was reflected in the overall survival rate. In the Tasigna group, 96% were alive after 5 years of treatment compared to 92% in the Gleevec group. This rate includes those who died from other causes. The actual mortality rate due to CML was 1.4% with Tasigna and 5.7% with Gleevec over 5 years. A caveat with this analysis is that many of the people who enrolled in the ENESTnd study dropped out for various reasons during the 5-year follow-up period (38% in the Tasigna group, 50% in the Gleevec group), so this should be factored in when interpreting the results.
In a similar vein, a recently published study looked at outcomes in people starting treatment with Sprycel (dasatinib) instead of Gleevec (Jabbour and colleagues. Blood 2014;123:494-500). This trial, called DASISION, reported results similar to those from ENESTnd. In the 3-year follow-up, a higher proportion of people starting treatment with Sprycel achieved a faster, deeper molecular response, which translated to a lower risk of disease progression and better overall survival with this second-generation drug.
A second study presented at ASCO looked at whether people taking high-dose Gleevec (800 mg once daily) for 10 years did better than those taking the usual dose of Gleevec (400 mg once daily) (Sasaki and colleagues. ASCO 2014; abstract 7024). The benchmark was an early complete cytogenetic response (CCyR) (i.e. no detectable cells with the Philadelphia chromosome); “early” was defined as 3 or 6 months. Overall, 56% of people taking high-dose Gleevec achieved CCyR at 3 months compared to 30% with the usual Gleevec dose. At 6 months, the CCyR rates were 77% and 39%, respectively. This early response was associated with a higher likelihood of achieving a major molecular response (MMR) within the first year (72% with the higher dose, 36% with the usual dose).
An early response is important because it has been shown to have the greatest impact on survival over the longer term (Jabbour and colleagues. Blood 2011;118:4541-4546). In this regard, an early response appears to be even more significant than a deeper response, although both of these measures are important to how well a person does.
Overall survival at 10 years was 84% with high-dose Gleevec compared to 80% with the usual dose (results include non-CML deaths). Even though twice as many people achieved MMR at one year with the high-dose regimen, the survival difference was quite similar.
But what about people who have been faithfully taking the usual dose of Gleevec 400 mg for the past 10 years instead of another regimen? A large German study, called the CML-Study IV, was launched in 2002 to examine this question (Hochhaus and colleagues. Internist [Berl] 2002;43:1228). According to the most recent results, overall survival at 10 years was 84% – or the same as was reported in the study discussed above with high-dose Gleevec (Hehlmann and colleagues. ASCO 2014; abstract 7021). Over the course of the study, a remarkable 60% have achieved MR5 (a 5-log reduction for their molecular response, so CML is essentially undetectable by the most sensitive laboratory tests). About 1 in 7 people experienced serious adverse effects, but no one died because of drug side effects. The most common side effects with Gleevec were swelling (edema), stomach problems, muscle/joint pain, and rash.
The researchers concluded that Gleevec is a very safe drug even when it’s taken for over 10 years and remains an excellent treatment choice for people with CML.
So taken together, these long-term results tell us that there are many roads to achieving an early response – Gleevec, high-dose Gleevec or the second-generation medications Tasigna and Sprycel – but all provide a path to better long-term outcomes.