Report on EHA 2014 – Part 2
European Hematology Association annual meeting, Milan, Italy, June 12-15, 2014
TKIs are used in CML to suppress the abnormal signalling that promotes uncontrolled proliferation of white blood cells. How effective a given medication is can be determined with a blood test that determines the amount of signalling molecules (called BCR-ABL transcripts).
A key goal is to reduce the BCR-ABL transcript level to less than 10% (a 1-log reduction) within the first three months of starting a TKI, and several new studies have looked at what this milestone means in real terms.
A group in Australia compared people who achieved a 1-log reduction at three months with those who did not reach this target (Branford and colleagues. EHA 2014; abstract P278). At four years, overall survival was 97% for those who achieved the milestone compared to 87% who did not – a substantial difference.
The ever-expanding number of treatments available means that more people will be able to achieve an early response. A growing trend is to start with a more potent medication such as Tasigna or Sprycel. For example, a Spanish study found that about 97% of people starting Tasigna achieved the 1-log reduction milestone within the first three months (Steegmann and colleagues. EHA 2014; abstract P281).
This early impact on CML can provide a number of long-term benefits. The ENESTnd study looked at whether there was an advantage to starting therapy with Tasigna rather than Gleevec and 5-year results are now available (Hughes and colleagues. EHA 2014; abstract S677). Overall survival after five years was 94-96% with Tasigna compared to 92% with Gleevec. Substantially more people on Tasigna had undetectable disease (a 4.5-log reduction) compared to those on Gleevec (83% vs. 31%). This means that their CML is highly controlled, and they may be able to stop treatment altogether at some point. (We’ll look at Stop trials in Part 3 of this report.)
The three-month milestone is only one of the sign posts along the way. Current guidelines also recommend that people achieve a 2-log reduction at six months, and a 3-log reduction at 12 months (Baccarani and colleagues. Blood 2013;122:872-884). If these goals aren’t achieved, fortunately a switch to another medication can get you back on track. A study in Spain looked at a group of 52 people who were switched to Sprycel or Tasigna after they didn’t achieve any of the milestones of treatment response (Garcia-Gutierrez and colleagues. EHA 2014; abstract P881). Changing treatments significantly improved their chances of achieving a major molecular response within a year (42% vs. 24%), and tripled their chances of having a deep molecular response (4.5-log reduction) within two years (23% vs. 7%). The researchers concluded that switching to Sprycel or Tasigna may be the preferred option for some people.
Sprycel can be associated with fluid build-up in the lungs (pleural effusion), which may require them to adjust the dose or stop treatment. But an emerging concept is to personalize the Sprycel dose to minimize this effect. The OPTIM dasatinib trial has looked at adjusting the dose to achieve the minimum amount of drug in the blood stream that will be effective (Rousselot and colleagues. EHA 2014; abstract S678). This strategy significantly reduced the cumulative risk of developing pleural effusion over three years of treatment (from 30% to 11%). Less drug also meant fewer people stopped therapy because of side effects (from 27% to 13%). However, a lower dose was just as effective as higher doses with respect to the proportion who achieved a major molecular response (82-88%) or a 4.5-log reduction (32-39%). So it appears that you can have better safety without trading off effectiveness. This approach may be a bit intensive and would need to take into account that foods and other medications can alter blood levels of the drug. But personalized dosing may enable more people to stay on treatment and achieve their goals while minimizing their risk of side effects.
We’ll continue our coverage of EHA 2014 in the next issue.