Tyrosine kinase inhibitors (TKIs, e.g. Gleevec, Tasigna, Sprycel, Bosulif, Iclusig) transformed the treatment of CML when they were introduced at the beginning of the 21st century. These medications target the leukemia gene that induces white blood cells to proliferate, effectively suppressing the CML disease process.
Blocking the activity of the leukemia over the longer term may result in a cure for a minority of people with CML. But in most cases, CML will return if the person stops taking their TKI. This was shown in the “stop trials”, in which people with profound suppression of their CML tried discontinuing their medication. Some could achieve what has been termed “treatment-free remission”. (See Treatment-free remission – how well do people do?, CML-IQ, November 26, 2015.) But remission – a reduction in disease activity – is not the same as cure.
A limitation of TKIs is that they don’t effectively target the underlying cause of CML – the leukemia stem cells. TKIs may suppress the fire, but leukemia stem cells residing in the bone marrow are the hot embers that can reignite the flame. TKIs are highly effective in treating CML. But for there to be a cure, the leukemia stem cells must be destroyed so the body won’t have the potential to start the CML process all over again.
A great deal of research has investigated ways of specifically targeting leukemia stem cells. The most recent candidate is a class of drugs that stimulates PPAR (for peroxisome proliferator-activated receptor). PPARs function as a switch to regulate the expression of genes – turning them on or off – thereby altering the body’s metabolism. For example, the group of drugs called TZD (for thiazolidinediones) affect how fat cells function, how the body processes glucose and the amount of good (HDL) and bad (LDL) cholesterol in the blood stream. So these medications, such as Actos (pioglitazone) and Avandia (rosiglitazone), have been used to treat people with Type 2 diabetes.
TZD drugs have many effects on the body in addition to those that are beneficial for people with diabetes. Around the time that Gleevec was being developed, some researchers reported that PPAR was present in considerable amounts in the bone marrow, and that PPAR drugs could suppress the proliferation of leukemia stem cells (Hirase and colleagues. Oncology 1999;57 Suppl 2:17-26). A laboratory study subsequently found that combining a TZD drug with Gleevec could suppress leukemia activity even in cells obtained from people with blast-crisis CML (Zang and colleagues. Cell Cycle 2006;5:2237-2243).
Two recent studies have provided important new information. The first study found that Actos (pioglitazone) could gradually drain the pool of leukemia stem cells (Prost and colleagues. Nature 2015;525:380-383). In fact, three people with chronic-phase CML taking Gleevec were temporarily given Actos, and all three were then able to achieve a complete molecular response (CMR). The preferred term is now “molecularly undetectable leukemia”, and what it means is that PCR testing was unable to find any evidence of leukemia activity. CMR was maintained in these people for 4-5 years.
The second study followed on this work by looking at combining TZD drugs with the more potent TKIs (Tasigna, Sprycel and Iclusig) (Glodkowska-Mrowka and colleagues. Blood Cancer Journal 2016;6:e377). In what the authors called a “breakthrough”, TZD drugs such as Actos sensitized CML cells to the effects of the TKIs, stopped most leukemia cells from dividing, and helped the TKIs to destroy these cells.
More research will be needed to investigate these very promising effects. What it could mean is that adding a diabetes drug to the treatment regimen for a short time may make the TKI more effective, which may enable more people to achieve a deep molecular response and, perhaps in some cases, achieve an actual cure. The combination may also enable people with progressive CML (accelerated-phase or blast crisis) to respond better to TKI therapy.
An advantage of this approach is that the add-on therapy being tested is already available for diabetes, so that might speed up the approval process if further studies show that the combination is effective. It may also be a disadvantage. Red flags have been raised about the toxicity of TZD drugs. Avandia has been withdrawn from use in some countries due to concerns about an increased risk of heart attacks. Actos has been linked to an increased risk of bladder cancer, but this may be less of an issue if the drug is taken with a TKI for only a short time.