Adding Pioglitazone to Imatinib May Improve Response in CML
STAT5 plays a key role in many hematologic malignancies.
In patients with chronic myeloid leukemia in chronic phase (CML-CP), pioglitazone in combination with imatinib was well tolerated and was associated with a favorable response rate, suggesting that adding pioglitazone to a kinase inhibitor may have a synergistic effect.1
The proof-of-concept phase 2 ACTIM study (ClinicalTrials.gov Identifier: NCT02888964), published in the journal Cancer, showed that 56% (95% CI, 37-76) of 24 patients with CML-CP who were treated with imatinib plus pioglitazone achieved a molecular response 4.5, defined BCR-ABL1/ABL1IS RNA levels of 0.0032% or less, by month 12.
In addition, 88% of 17 evaluable patients who were still receiving imatinib reached molecular response 4.5 by month 48. Therapy duration ranged from 1.9 to 15.5 months.
In comparison, investigators estimated in a parallel cohort of patients treated with imatinib alone that 23% would spontaneously convert from major molecular response to molecular response 4.5.
For the study, patients with CML-CP who had been treated with imatinib for at least 2 years at a stable daily dose and achieved a major molecular response but not a molecular response 4.5 were eligible for enrollment. In addition to imatinib, patients received pioglitazone starting at a dose of 30 to 45 mg per day.
Pioglitazone, a hypoglycemic agent used to treat diabetes mellitus type 2, is an agonist of peroxisome proliferator-activated receptor γ (PPAR-γ), which have been shown to decrease transcription of STAT5. STAT5 is a transcription factor that plays a key role in many hematologic malignancies.
Investigators are enrolling patients for the ACTIW randomized trial (ClinicalTrials.gov Identifier: NCT02767063) to evaluate the optimal duration of imatinib with pioglitazone and determine the ideal PPAR-γ agonist to be used in this setting.
1. Rousselot P, Prost S, Guilhot J, et al. Pioglitazone together with imatinib in chronic myeloid leukemia: a proof of concept study. Cancer. 2016 Dec 27. doi: 10.1002/cncr.30490 [Epub ahead of print]