The François-Jacob Biology Institute, in collaboration with the Department of Hematology and Oncology at the Mignot Hospital in Versailles, France, has developed a therapeutic strategy to treat the residual disease of chronic myeloid leukemia (LMC). A phase 2 clinical trial in 24 patients, with a three-year follow-up, now shows the legitimacy of this approach. These results provide a proof of concept of this double treatment as imagined at the François-Jacob Institute in Fontenay-aux-Roses (a town in the region of Paris, France).

"Our idea is based on the fact that in LMC, as in many other types of cancer, the diseased cells are heterogeneous," said CEA researcher Stéphane Prost. "Outside of the tumor mass is a subpopulation of leukemic stem cells that form the original source of cancer cells and are not completely eliminated by conventional therapy." The persistence of these resistant leukemic stem cells could explain the relapse observed in 50 to 60% of the patients when the treatments are stopped. After a series of studies originally focusing on HIV (see here), the team from the François-Jacob Institute has developed a therapy that combines the traditional treatment for LMC that targets differentiated cancer cells (imatibinib) with pioglitazone, which targets leukemic stem cells. No preclinical trials were required to initiate a phase 2 clinical trial in patients, as pioglitazone was already licensed for the treatment for type 2 diabetes.

"A total of 24 patients were treated during one year with this add-on therapy," Prost said. "The combined treatment was well tolerated and 56% of patients yielded major molecular response, compared to 23% in a reference group." This major molecular response that the scientists investigated implies that, within the limits of our technical means, we can no longer detect the biomarkers indicating the presence of the residual nidus of leukemic cells. Three years after the discontinuation of the pioglitazone, the percentage of patients who reached major molecular response (56%) continued to increase up to 88%. "This suggests that the benefits of pioglitazone persist and continue downstream for several years," Prost said. Following the success of this trial, called ACTIM, other trials are underway. The ACTIW trial, conducted by Prof. P. Rousselot in Versailles, France, tests the effects of pioglitazone combined with several LMC treatments. Two other trials conducted by Professor P. Rousselot in Versailles, France and J. Khoury in Atlanta, USA, evaluated this therapeutic strategy for the management of relapsed patients after a first discontinuation of conventional therapy (the risk of relapse expected after discontinuation for the treatment is then high, reaching about 85%). Meanwhile, clinical trials to treat acute myeloblastic leukemia based on this strategy are underway.