Report on ASH 2014 – Part 4
American Society of Hematology annual meeting, San Francisco, USA, December 6-9, 2014
Second-generation medications: an update
Gleevec has long been the gold standard of CML treatment. But more potent second-generation medications (Tasigna and Sprycel) can now be used as first-choice treatments instead of Gleevec. So how well do these two drugs perform in controlling CML?
Tasigna (nilotinib): The initial study that compared Tasigna and Gleevec was called ENESTnd (for Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients), and long-term results are now available (Larson and colleagues. ASH 2014; abstract 4541). Among those still on the study medication after five years, 77% of people in the Tasigna group have a major molecular response (MMR) compared to 60% of those who started on Gleevec. Fewer people taking Tasigna have progressed to accelerated phase or blast crisis CML, and the number of people who have died (from any cause) is lower in the Tasigna group. A limitation, however, is that 40% of people initially in the Tasigna group and 50% in the Gleevec group have dropped out of the study.
Similar results were seen in the ENESTxtnd study, which found that 72.5% of people newly-diagnosed with CML could achieve MMR in the first year of treatment with Tasigna (Hughes and colleagues. ASH 2014; abstract 4542). A separate phase II study in the U.S. reported even better results: 90% of people starting Tasigna early achieved MMR after a median of three months (Daver and colleagues. ASH 2014; abstract 3156). In addition, 45% had a complete molecular response (CMR; a 5-log reduction or better), meaning that leukemia was undetectable. A long-term study of first-choice Tasigna estimated that overall survival after six years was 91% (Gugliotta and colleagues. ASH 2014; abstract 3141).
Sprycel (dasatinib): The first studies to look at Sprycel as the starting therapy were called DASISION (for Dasatinib Versus Imatinib Study in Treatment-Naïve CML Patients), and the long-term results have now been reported (Cortes and colleagues. ASH 2014; abstract 152). At five years, 76% of people taking Sprycel had MMR compared to 64% of those who started on Gleevec. In addition, control of leukemia was achieved more quickly with Sprycel compared to Gleevec, with 84% of people attaining a two-log reduction in the first three months of Sprycel (compared to 64% with Gleevec). Overall survival at five years was similar in the two treatment groups (91% and 90%).
The largest study comparing Sprycel with Gleevec is called SPIRIT-2 (for STI571 Prospective International RandomIsed Trial), which enrolled over 800 people (O’Brien and colleagues. ASH 2014; abstract 517). At one year, 58% of people starting Sprycel had achieved a 3-log reduction compared to 43% in the Gleevec group. The rate of MMR was also slightly higher with Sprycel compared to Gleevec (54% vs. 49%). The risk of progressing to accelerated-phase or blast-crisis CML in the first three years of treatment was low with both medications (1.5% and 2.4%, respectively). People taking Gleevec had a much higher rate of withdrawing from treatment due to poor disease control compared to those taking Sprycel (9% vs. less than 1%). Another difference was side effects. Gastrointestinal symptoms were more likely with Gleevec, whereas fatigue, rash and headache were more common with Sprycel. A longer follow-up is needed to determine if this improved response with Sprycel translates to better long-term outcomes.
The many studies of CML medications produce a confusion of numbers, so one group has pooled the results of five studies to see how the second-generation drugs (Tasigna, Sprycel, Bosulif and Iclusig) stack up against Gleevec (Gurion and colleagues. ASH 2014; abstract 4563).
Overall, people were significantly more likely to achieve MMR at any time point with a second-generation agent compared to Gleevec. After a year of treatment, that likelihood was about twice as great (1.68). The key difference, however, was seen with complete molecular response (i.e. no detectable leukemia). Here the likelihood of reaching CMR after one years was more than twice as great (2.68). There was also a two-thirds reduction in the risk of CML progressing with the newer medications. However, this greater potency is associated with a higher risk of some side effects, such as blood clots, fluid around the lungs, and low platelet counts.
So the main benefits of the newer medications are that they can achieve faster control of leukemia, and a deeper response. Thus far, a faster response has not been shown to be associated with better long-term survival. However, a deeper response means that more people will reach CMR, which is necessary for those who would like to stop treatment in the future.