Adding pioglitazone to imatinib may help fight leukemia

Gleevec (imatinib) is a breakthrough therapy that turns deadly chronic myeloid leukemia (CML) into a manageable disease. However, only 5% of patients achieved complete molecular response (CMR)[1] that no Bcr-Abl mRNA is detectable in the marrow.

A group of French researchers added Actos (pioglitazone) to imatinib on two patients diagnosed with both diabetes and CML[2]. Both two patients had never reached CMR in spite of long-term imatinib treatment. Amazingly, they achieved CMR after 1 year of pioglitazone addition.

pioglitazone plus imatinib

Before filing a formal clinical trial application, the researchers prescribed pioglitazone off-label to a third CML patient, this time non-diabetic, who never reached CMR either under long-term imatinib therapy. Finally, CMR was achieved after 6 months of pioglitazone addition.

All patients achieved sustained CMR up to 4.7 years after withdrawal of pioglitazone.

The authors note that activation of PPARĪ³ by pioglitazone reduces expression of STAT5, while imatinib inhibits STAT5 activation by Bcr-Abl pathway. Imatinib alone is sufficient to kill the bulk of cancer cells, but fails to bring STAT5 activity below a threshold for killing cancer stem cells. Pioglitazone is effective at doing so in synergy with imatinib.

The trial is too small. It is difficult to know if the results would reproduce in a lager trial. It is also unknown whether CMR offers significant survival benefit. Imatinib already enable 90% of patients to survive for 5 years. A long-term, larger trial directly comparing the combination therapy versus imatinib alone is warranted.

[1] J Clin Oncol. 2008, 26(20), 3358-3363.
[2] Nature. 2015, doi:10.1038/nature15248.