A number of studies have shown that people taking a second-generation medication, such as Sprycel or Tasigna, can reach key treatment milestones earlier than if they start treatment with Gleevec. This idea has received additional support with the results of a new phase II study (Hjorth-Hansen and colleagues. Eur J Haematol 2015;94:243-250).
In the NordCML006 study, people received either the standard dose of Sprycel or a standard dose of Gleevec and were followed for three years. Those in the Sprycel group were four times more likely to achieve a major molecular response (MMR, i.e. a 3-log reduction in BCR-ABL transcripts) within the first three months of treatment compared to those starting on Gleevec (36% vs. 8%), and twice as likely to achieve that same degree of disease control after one year (81% vs. 46%).
However, by 18 months, those in the Gleevec group had caught up, and the proportion of people achieving MMR with Sprycel and Gleevec was very similar (73% vs. 65%). Where the Gleevec group did not catch up was in the proportion who achieved a deep molecular response, defined as a 4-log reduction or better. After three years of treatment with Sprycel, about 60% of people had reached a 4-log reduction or a 4.5-log reduction. This was substantially higher than the proportion of people treated with Gleevec who had a 4-log reduction (40%) or a 4.5-log reduction (21%).
These results are very similar to those seen in the DASISION trial of Sprycel, and the ENESTnd trial of Tasigna, both of which investigated the benefits of starting with second-generation therapies. In DASISION, the faster, deeper molecular response with Sprycel was associated with a lower risk of disease progression and better overall survival (Jabbour and colleagues. Blood 2014;123:494-500). In ENESTnd, twice as many people achieved MMR after 12 months of treatment with Tasigna compared to Gleevec (Saglio and colleagues. N Engl J Med 2010;362:2251-2259).
Another observation from the NordCML006 study was that Sprycel was more effective in reducing the burden of leukemic stem cells – the “seeds” from which CML emerges (Mustjoki and colleagues. Leukemia 2013;27:1520-1526). The thinking to date has been that TKIs are not able to target stem cells, but they do appear to have some effect. However, additional therapies are probably needed to fully eradicate CML in most cases.