This phase II trial studies how well pioglitazone hydrochloride and tyrosine kinase inhibitor (TKI) therapy works in treating patients with chronic myeloid leukemia (CML) that has come back after a period of improvement (relapsed) after a first TKI discontinuation. TKI may stop the growth of cancer cells by blocking certain enzymes need for cell growth. Although TKI therapies are effective against CML, there are residual cancer cells called leukemia stem cells that are able to hide from TKIs. Pioglitazone is a drug approved by the Food and Drug Administration to treat diabetes and has been shown in laboratory studies to increase CML stem cell death when given together with TKI therapy. Giving pioglitazone with TKI therapy may be effective in treating patients with CML.

PRIMARY OBJECTIVES:

I. To assess safety of the combination of pioglitazone (PIO) and TKI in CML subjects who experience a loss of major molecular response (MMR) following a first TKI discontinuation.

II. To assess survival without loss of MMR following a second TKI discontinuation in subjects who achieve or maintain < molecular response (MR)^4.5 with the combination PIO and TKI administered for at least 6 months.

OUTLINE:

Patients receive pioglitazone orally (PO) once daily (QD) on days 1-28. Patients also start or continue the same TKI therapy at the pre-discontinuation doses. Courses repeat every 28 days for 6 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every month for 3 months, every 3 months for 1 year, and then every 6 months for 4 years.

Inclusion Criteria:

• Chronic myeloid leukemia (CML) in any phase
• Philadelphia chromosome positive acute lymphoblastic leukemia
• Loss of major molecular response (MMR) following a first TKI discontinuation trial
• Serum bilirubin < 1.5 x upper limit of normal values
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x upper limit of normal values
• 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
• 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
• Patient requiring anti-diabetic medications to manage hyperglycemia are eligible. Adjustments of other anti-diabetic agents will be made with close monitoring of blood glucose
• Informed consent
• Be able and willing to comply with study visits and procedures

Exclusion Criteria:

• Known loss of complete cytogenetic response (CCyR) by marrow cytogenetic or blood fluorescence in situ hybridization (FISH) for breakpoint cluster region (BCR)- v-abl Abelson murine leukemia viral oncogene homolog 1 (ABL1)
• Loss of complete hematologic response (CHR)
• Participation in another clinical trial with any investigative drug within 30 days prior to study enrollment
• Chronic graft-versus-host disease requiring systemic immunosuppression post-allogeneic hematopoietic stem cell transplantation
• Cardiovascular disease: history of congestive heart failure, myocardial infarction in the 6 months preceding study entry, symptomatic cardiac arrhythmia requiring treatment
• History of bladder cancer
• Gross (visible) hematuria
• Known history of osteoporosis
• Known history of macular edema
• Known history of ABL1-domain mutation that predicts resistance to the discontinued TKI
• Significant medical or psychiatric disorder that would interfere with consent, study participation, or follow-up
• Known allergy to pioglitazone
• Pregnant or breastfeeding
• Use of thiazolidinedione (TZD) within 28 days prior to enrollment
• Significant gastrointestinal condition that could potentially impair the absorption or disposition of the drug
• Uncontrolled peripheral edema (2+ or more) of any etiology
• Active cancer that requires therapy in the form of chemotherapy or radiation