Monday, July 24, 2006

Gleevec: Tough on Leukemia, Rough On the Heart?

Imatinib mesylate (or Gleevec), a small-molecule inhibitor of the ABL kinase, is, as we all know, the flagship of the molecularly-targeted cancer therapeutics. According to the Novartis literature (and lots of other people I'm sure) it cures a lot of patients with chronic myeloid leukemias (CMLs) expressing the BCR-ABL gene fusion (ie the famous Philadelphia chromosome). That same literature claims that the drug has no important toxicity, so they apparently didn't notice when patients' hearts started conking out, despite their lack of prior cardiac problems. Some clinicians were paying attention, and they now report on congestive heart failure in 10 patients and cardiotoxicity observed upon adminsitration of gleevec to healthy mice in Nature Medicine. This study highlights the important need to study the potential side effects of new drugs, something that a lot of drug companies financing their development would rather we forget. Not that gleevec should be pulled from the market - CML is obviously a serious and hard-to-treat disease and the benefits might be worth risking the cardiotoxiticy. Then again, heart failure is pretty serious too and the risk might not be worth it. Obviously then what's needed is more detailed and quantitative study of the cardiotoxic risk associated with Gleevec so that clinicians and patients can make the most informed decisions. It's interesting to note that the cardiotoxicity now reported can apparently be observed simply by giving the drug to mice and examining their hearts. It's hard to believe Novartis couldn't have done that during more than a decade of preclinical investigation, but probably typical of the way drug research is currently being carried out. As a result patients are less informed and ultimately the companies themselves risk knee-jerk public reaction and their products getting pulled off the market when bad things start happening. Another important point made here is that even the most well-targeted drugs can have side effects - all the more reason to investigate toxicities as thoroughly as possible and be more open to examining not just the more profitable small molecule drugs, but all other possible types of novel therapeutics.


Anonymous said...

For someone that has CML and Gleevec is their only possible effective treatment, I will take my chances with it. Living with CML without Gleevec is not living, but dying. I will take my chances with it. Two years and counting. If you don't have CML butt out of the discussion.