Diabetes Drug Appears to Eliminate Residual CML

Veronica Hackethal, MD

September 10, 2015

Glitazones, a class of drug commonly used to treat diabetes, may help eradicate residual cancer cells in chronic myelogenous leukemia (CML), according to a study published online September 2 in Nature.

"We found that there's a small subset of quiescent stem cells that are not targeted by the tyrosine kinase inhibitors," commented lead author Philippe Leboulch, MD, professor of medicine and cell biology at the University of Paris. But the addition of a peroxisome proliferator–activated receptor-ʎ (PPAR-ʎ) agonist, such as pioglitazone (Actos, Takeda/Eli Lilly), to standard therapy may eliminate these lingering leukemia stem cells, he said.

"In the few patients we tried the combination therapy on, we could no longer detect any trace of the clone. In some cases where the patients actually stopped taking pioglitazone ― there was one case for over 4.5 years ― we could not detect the clone even after those years of medication interruption," Dr Leboulch continued.

Most cases of CML can be now controlled using a tyrosine kinase inhibitor, the most commonly used of which is imatinib (Gleevec, Novartis Pharmaceuticals Corporation), according to Dr Leboulch.

However, fewer than 10% of patients achieve complete molecular response (CMR), in which malignant cells are fully gone. In most patients, low levels of CML cells persist, which puts patients at risk for relapse and means that they have to take imatinib or similar drugs for life.

The new study found that CML cells are very dependent on high levels of the protein STAT5, Dr Leboulch explained. Tyrosine kinase inhibitors cannot decrease levels of STAT5 in quiescent stem cells, but pioglitazone can. That is because pioglitazone activates the PPAR-ʎ, and STAT5 lies downstream in the PPARʎ pathway. Activating the PPARʎ receptor with pioglitazone reduces STAT5 levels to the point where CML stem cells can no longer live, he explained.

The study grew out of in vitro experiments suggesting that adding pioglitazone to imatinib decreases STAT5 levels as well as levels of quiescent and proliferating CML cells. Researchers also tested other PPARʎ agonists in biological assays, but not in patients, and found that they had the same effect as pioglitazone.

Next, the researchers tested the combination of pioglitazone and imatinib in three patients with CML who had never achieved CMR.

Five years after starting continuous imatinib, patient one received pioglitazone for 10 months, stopped it for 28 months, then took it again for 8 months. The patient reached CMR 10 months after first adding pioglitazone, and CMR was maintained for 4.5 years after the patient first stopped pioglitazone.

Patient two receiving pioglitazone 6 years after starting continuous imatinib therapy and reached CMR 1 year after adding pioglitazone. The patient remained in CMR for 32 months and then withdrew from the study.

Patient three began receiving pioglitazone 4 years after starting continuous imatinib therapy and reached CMR 6 months after adding pioglitazone. The patient remained in CMR for 28 months after stopping pioglitazone. For the last 6 months, the patient also stopped taking imatinib and remained in CMR without any treatment.

One of the next steps in research, Dr Leboulch pointed out, will be to look at whether patients remain disease free after stopping all medication, both pioglitazone and imatinib or other tyrosine inhibitors.

The results from this study need confirmation in a larger group of patients. That has already been done in a phase 2 clinical trial, called ACTIM, with results soon to be published, according to Dr Leboulch. That trial included 24 patients who had both type 2 diabetes and CML with residual disease despite years of taking imatinib.

Because of reports of an increased risk for bladder cancer with pioglitazone, use of the drug was suspended in France during the ACTIM trial. Even with special regulatory authorization to continue the trial, some participants did not receive the full dose for the minimum duration because some clinicians stopped giving pioglitazone to them.

Since then, a recently published study found no statistical link between pioglitazone use and bladder cancer, according to Dr Leboulch. So now a third phase 2 trial, called ACTIW, is being planned. ACTIW will have a larger number of patients who will receive pioglitazone at the required dose and duration.

The study was supported by the Association Laurette Fugain. The authors have disclosed no relevant financial relationships.

Nature. Published online September 2, 2015. Abstract

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