Part 3 of 3
In part 1 we looked at how a person’s response to TKI treatment is assessed and the importance of reaching key milestones. In Part 2 we looked at how a faster, deeper molecular response can translate to better outcomes, such as improved survival and a reduced risk of having leukemia progress to a more aggressive phase. In fact, many recent studies have found that if people can achieve and sustain a deep response (e.g. a 4-log reduction or better), many will be able to stop treatment altogether without experiencing a relapse. While some may backslide and start to lose their molecular response once treatment is withdrawn, they can usually regain their molecular response once they start their medication. This is another advantage of a deep response: there’s a bit of wiggle room to lose some response without losing control of leukemia altogether.
Treatment milestones are well and good, but they’re only useful if a sizeable proportion of people starting a TKI have a reasonable chance of reaching them. So how do the different treatments compare with respect to the likelihood of achieving a deep molecular response (MR4)?
In the SPIRIT study, 14% of people taking the standard 400 mg dose of Gleevec had reached MR4 after one year and 21% had reached that mark by two years (Preudhomme and colleagues. N Engl J Med 2010;363:2511–2521). The results were better in the CML-Study IV: 8% reached MR4 by 1 year, 31% by 2 years, and 46% by three years (Hehlmann and colleagues. J Clin Oncol 2011;29:1634-1642.). Doubling the dose of Gleevec (400 mg twice daily) produced even better results: 20% reached MR4 by 1 year, 43% by 2 years, and 57% by three years. After 6-7 years of standard Gleevec, 70% of people in the IRIS trial had reached MR4 (Hughes and colleagues. N Engl J Med 2003;349:1423-1432; Branford and colleagues. Clin Cancer Res 2007;13:7080-7085).
The second-generation TKIs are more potent then Gleevec, which means that more people can reach MR4 earlier. In the ENESTnd trial of Tasigna, 20% reached MR4 by 1 year (compared to 6% on Gleevec), and 50% had reached it by 2 years (compared to 26% on Gleevec) (Larson and colleagues. Leukemia 2012;26:2197-2203). In the ENEST1st study, 20% reached MR4 within the first six months of treatment (Hochhaus and colleagues. Haematologica 2012;97:74 [abstract 0188]).
Similarly, in the SO325 study, 27% of people taking Sprycel 100 mg reached MR4 within the first year (compared to 21% on Gleevec) (Radich and colleagues. Blood 2012;120:3898-3905). In the DASISION trial, these differences were even greater. Twice as many people achieved MR4.5 at one year with Sprycel compared to Gleevec (17% vs. 8%) (Kantarjian and colleagues. Blood 2012;119:1123-1129). At three years, 35% had reached MR4 with Sprycel compared to 22% with Gleevec (Jabbour and colleagues. Blood 2014;123:494-500).
MR4 was not studied in the BELA trial of Bosulif (Cortes and colleagues. J Clin Oncol 2012;30:3486-3492). Interestingly, a similar proportion of people reached CCyR with Bosulif and Gleevec at one year; but Bosulif was much more effective in getting people to MMR and was associated with fewer CML-related deaths.
In looking at the different TKIs, it’s important to note that the goal is not the journey. The goal is to achieve a rapid suppression of leukemia activity, but how you get there doesn’t matter. Any of the TKIs can take you there – but what is critical is arriving at that point. If a person has a robust response to Gleevec, then Gleevec may be the best option for the moment. With one of the second-generation agents (Tasigna or Sprycel), there’s a greater likelihood of reaching the target quickly, which may translate to a better long-term outcome.
Molecular testing is not Pass or Fail. Many people who don’t have a rapid response will ultimately achieve MMR or better. And if one TKI doesn’t do the job, there are many other treatment options available: switching from Gleevec to Tasigna or Sprycel; switching from one of the second-generation drugs to another one, or to Bosulif; or trying a newer treatment such as Iclusig or Synribo.
Achieving a deep molecular response has great appeal as a treatment goal. It offers the possibility of living with undetectable disease, with the added incentive that leukemia may be so well controlled that you may be able to stop treatment altogether in a few years from now.