Single-center study, prospective, phase II trial.

The study objectives are :

• To assess safety and pharmacokinetics of the combination of PIO and TKI in CML subjects who experience a loss of MMR following a first TKI discontinuation.
• To assess survival without loss of MMR over a 12 months period following a second TKI discontinuation in subjects who achieve or maintain < MR4.5 with the combination PIO and TKI administered for at least 6 months.

Inclusion Criteria:

1. CML in any phase. patient in MR4
2. Loss of MMR following a first or subsequent TKI discontinuation trial.
3. Patient prior treated with imatinib, dasatinib, nilotinib, or bosutinib
4. Age >18 years.
5. Serum bilirubin <1.5 x upper limit of normal values.
6. AST (SGOT)/ALT (SGPT) <2.5x upper limit of normal values.
7. Females of child bearing potential must agree to abstain from sexual activity or to use a medically approved contraceptive measure/regimen during and for 3 months after the treatment period. Women of child bearing potential must have a negative urine pregnancy test at the time of enrollment. Acceptable methods of birth control include oral contraceptive, intrauterine device, transdermal/implanted or injected contraceptives and abstinence.
8. Males must agree to abstain from sexual activity or agree to utilize a medically-approved contraception method during and for 3 months after the treatment period.
9. Signed informed consent.
10. Be able and willing to comply with study visits and procedures

Exclusion Criteria:

1. Known loss of CCyR by marrow cytogenetic or blood FISH for BCR-ABL1.
2. Loss of CHR.
3. Participation in another clinical trial with any investigative drug within 30 days prior to study enrolment.
4. Prior allogeneic hematopoietic stem cell transplantation.
5. Patient requiring anti-diabetic medications to manage hyperglycemia.
6. Cardiovascular disease: history of congestive heart failure, myocardial infarction within the 6 months of study entry, symptomatic cardiac arrhythmia requiring treatment.
7. Hepatic insufficiency
8. History of bladder cancer.
9. Diagnosed hematuria.
10. Known osteoporosis with curative therapy (prophylactic therapy is not an exclusion criteria)
11. Known history of macular edema.
12. Known history of ABL1-domain mutation associated with resistance to the discontinued TKI.
13. Known allergy to PIO.
14. Pregnant or breastfeeding.
15. Use of TZD within 28 days prior to enrollment.
16. Significant gastrointestinal condition that could potentially impair the absorption or disposition of the drug.
17. Uncontrolled peripheral edema (2+ or more) of any etiology