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A therapy to defeat chronic myeloid leukemia (CML) once and for all

​Development of a novel therapy that targets stem cells responsible for chronic myeloid leukemia (CML). The first treated patients no longer present a detectable disease more than 5 years after stopping this new treatment, which represents a solid hope for a lasting recovery.

Published on 2 September 2015

Chronic myeloid leukemia (CML) is a cancer of the blood that affects about 600 new people per year in France. This cancer represents 15 to 20% of all leukemia cases. It affects the stem cells of the bone marrow blood, which give rise to multiple cells that make up our blood.

For the first time, researchers from the Institute of Emerging Diseases and Innovative Therapies at the CEA-IMETI, in collaboration with the department of Hematology and Oncology at the Mignot hospital of Versailles, have developed a new therapy against CML. The current standard treatment uses the molecule "imatinib", which is effective for removing the tumor mass but has little effect on leukemic stem cells (LSC). And yet, the latter are responsible for the disease and its relapses. In addition, CML never really resolves itself, forcing the patient to follow this treatment for life. Biologists from the CEA-IMETI have discovered a novel way to specifically target LSC. They subsequently went further into the molecular bases of this discovery while developing a clinical trial in CML patients, in collaboration with the Mignot hospital of Versailles.

How did the researchers proceed?

The researchers from IMETI were inspired by one of their studies on HIV published in 2008. At the time, scientists searched for why seropositive people present an elevated frequency of anemias, reaching 75-90% at the AIDS stage. Does HIV, which destroys lymphocytes, also affect the production of red blood cells? Perhaps it acts upstream, targeting the hematopoietic stem cells (HSC) that continually generate all new mature blood cells (red cells, lymphocytes, etc.) by differentiation. The CEA researchers in fact discovered that a specific HIV protein activates the PPARϒ receptor within HSC, causing the decrease in expression of the STAT5 protein, which is essential to HSC viability. Moreover, they found that this action could be mimicked by a single new drug used to treat type II diabetes: pioglitazone.

During this study, it became clear that certain leukemic cell lines, and in particular those derived from CML patients, were particularly sensitive to doses, even very low, of pioglitazone.

"Armed with this knowledge, we asked whether pioglitazone and related molecules could eliminate LSC from CML in doses that would have little toxicity on normal HSC", explains Stéphane Prost, researcher at the CEA and first author of the article. After preclinical cellular studies confirming this hypothesis, pioglitazone's market authorization in the context of treating type II diabetes then allowed researchers to test the therapy directly on diabetic patients with stable residual CML, despite their conventional treatment with "imatinib". This approach was essential since animal models of LSC in CML do not exist.

After the first encouraging results, a phase 2 clinical trial was launched, and 24 patients with residual CML took a combined treatment (imatinib + pioglitazone) for 12 months. At the end of the trial, 57% of patients are in complete remission under the combined treatment, as compared to only 27% for the group treated with "imatinib" alone. In addition, the first 3 treated patients showing an important decrease all remain without detectable residual CML, nearly 5 years after stopping pioglitazone. "The ability to target the stem cells responsible for the relapse should give hope for the recovery of patients that will result in a conclusive end to all treatments", says Professor Rousselot, head of the department of Hematology and Oncology at the Mignot hospital in Versailles. This proven effectiveness represents a solid, lasting hope of recovery for patients. Currently, this strategy is being evaluated by the team of scientists on other recurring cancer types.

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