Pioglitazone, Other TZDs May Add Benefit to TKI Therapy in CML

A laboratory study showed that peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists such as pioglitazone could help treat chronic myeloid leukemia (CML) patients who are resistant or otherwise unresponsive to treatment with tyrosine kinase inhibitors (TKIs). The addition of these drugs not only could eradicate leukemic stem cells, but could also help kill other progenitor cells and differentiated cells in various phases of CML.

“Failure to complete eradication of CML cells with the current state-of-the-art treatment results from insensitivity of leukemia stem cells (LSCs) to TKIs,” wrote study authors led by Piotr Mrowka, PhD, of the Medical University of Warsaw in Poland. Because better BCR-ABL1 inhibition with newer generation TKIs will likely not help many of these patients, attention has turned to combination therapies.

In a previous study, other researchers showed that pioglitazone, a thiazolidinedione (TZD) used to treat diabetes, added to imatinib could induce a sustained molecular response. The new study used in vitro analysis of stem cells to test whether TZDs could have benefit when combined with newer TKIs including dasatinib, nilotinib, and ponatinib. The results were published online ahead of print in the Blood Cancer Journal.

The researchers found several promising results. First, the addition of pioglitazone to the newer TKIs resulted in significantly decreased clonogenic potential of K-562 cells, a type of CML cell line. The effect was not only a reduction in number of cells, but also on the size and morphology of the cell colonies.

The combination was also investigated with regard to CD34+ progenitor cells from two chronic-phase and two blast-phase CML patients. Cell colony formation was significantly inhibited by pioglitazone with the TKIs in comparison to the TKIs alone. These effects were similar with other TZDs as well, including ciglitazone, troglitazone, and rosiglitazone.

Other effects also suggest a benefit with TZDs with TKIs. Cell cycle arrest increased when pioglitazone was added to dasatinib, ponatinib, and nilotinib. Further measures confirmed that the TZD increased the apoptotic activity of the TKIs.

“Synergism between pioglitazone and second- and third-generation TKIs presented in our data suggests that the combination treatment can be successfully applied also in patients resistant to the first- or second-line therapy,” the authors wrote.

They acknowledged that from a clinical perspective, the use of these drugs may raise some questions. Rosiglitazone has been withdrawn from market in Europe, and pioglitazone carries a US Food and Drug Administration warning regarding an increased risk of bladder cancer. However, a large population study published in late 2014 found that there was no such increased risk.

“The benefit of such treatment in patients with leukemia can overweight potential risk, and therefore the use of TZDs can be justified,” the authors wrote. “We believe that introduction of PPAR-gamma agonists to the therapy may constitute a real breakthrough, finally leading to the cure of CML.”