Study of Imatinib Discontinuation in Chronic Myeloid Leukemia With Deep Molecular Response

Study Overview
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Brief Summary
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The purpose of this study is to evaluate treatment-free remission after imatinib discontinuation in patients with chronic myeloid leukemia with deep molecular response. Before discontinuation, patients will receive pioglitazone associated with imatinib during 3 months.

Detailed Description
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Treatment of chronic myeloid leucemia (CML) with tyrosine kinase inhibitors (TKIs) changed dramatically the prognosis of CML, with high rates of cytogenetic and molecular remission and increase of overall and progression-free survival. However, the long-term treatment of CML has a high cost to the health system, due to the price of these drugs and the need for continued use. In addition, chronic adverse effects may compromise the quality of life of patients. Discontinuation trials of TKIs have been developed in order to identify groups of patients who may benefit from treatment discontinuation if they have obtained deeper molecular responses.The primary objective of this study is to evaluate treatment free remission (TFR) after imatinib discontinuation in patients treated for more than 3 years with imatinib and with deep molecular response stable for two years (defined in the present study as a molecular response of 4.5 log reduction in breakpoint cluster region (BCR)-Abelson murine leukemia viral oncogene homolog 1(ABL) transcripts levels according to the international scale (MR 4.5; BCR-ABL/ABL ratio < or = 0.0032%). Patients with these criteria will receive pioglitazone for 3 months concomitant with imatinib, prior to discontinuation. After imatinib discontinuation, patients will be evaluated by molecular assessment of BCR-ABL transcripts levels by quantitative real time polymerase chain reaction (RQ-PCR) monthly during the first year, every 2 months in the second year and then every 3 months. The criteria for restarting treatment will be the loss of major molecular response (MMR), documented by a single RQ-PCR test > 0.1%, or confirmed loss of 4 log reduction molecular response (MR4.0), by 2 consecutive RQ-PCR tests > 0.01%.

Official Title
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Pilot Study of Imatinib Discontinuation in Patients With Chronic Myeloid Leukemia With Deep Molecular Response - Evaluation of Pioglitazone in Treatment-free Remission (EDI-PIO)

Conditions
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Leukemia, Chronic Myeloid

Intervention / Treatment
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* Drug: Pioglitazone 30 Mg Oral Tablet
* Other: imatinib discontinuation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: CML in chronic phase treatment with imatinib for 3 or more years MR4.5 (RQ-PCR< ou =0.0032%) confirmed by 4 RQ-PCR tests for BCR-ABL in the last 2 years (2 tests within the last 6 months) Eastern Cooperative Oncology Group Performance Status (ECOG) 0-2 Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 reference level Bilirubins ≤ 1.5 reference level Contraceptive precautions for women Exclusion Criteria: Patients less than 18 years Severe organ disfunction (liver or kidney) Severe cardiovascular disease: grade I-IV from New York Heart Association (NYHA) or acute myocardial infarction in the last six months, symptomatic arrhythmias Fluid retention grade 3 or 4 Osteoporosis in treatment Patients with previous CML in accelerated or blast phase or blast or Philadelphia positive (Ph+) acute lymphoid leukemia (ALL) BCR-ABL mutations related to resistance Previous allogeneic bone marrow transplantation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pioglitazone<br>Pioglitazone will be given 30 mg/day, orally, for 3 months, before imatinib discontinuation | Drug: Pioglitazone 30 Mg Oral Tablet<br>* 30 mg/day, orally, for 3 months, before imatinib discontinuation<br>* Other names: cloridrato de pioglitazona 30mg EMS S/A, Brasil;Other: imatinib discontinuation<br>* imatinib discontinuation after 3 months of pioglitazone<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-free remission after imatinib discontinuation | Treatment-free remission time after imatinib discontinuation in patients with CML treated with pioglitazone for 3 months before imatinib discontinuation. Calculated from the date of imatinib discontinuation until imatinib reintroduction | Through study completion (five years) | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | assessment of number of participants with treatment-related adverse events as assessed by CTCAE v4.0 during the 3 months of treatment with imatinib and pioglitazone | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| proportion of patients with MMR, MR4.0, MR4.5 | Proportion of patients with MMR, MR4.0 and MR4.5 at 3, 6 and 12 months after imatinib discontinuation | 3, 6 and 12 months | 
| Time from imatinib discontinuation until loss of MMR | Time measured from the date of imatinib discontinuation until the date of loss of MMR, in days | Through study completion (five years) | 
| Rate of loss of complete cytogenetic response | % of patients who lost complete cytogenetic response | Through study completion (five years) | 
| Time to reach MMR after restarting imatinib | Time measured from the date of the reestart of imatinib until the achievement of MMR, days | Through study completion (five years) | 
| Overall survival after imatinib discontinuation | Overall survival is calculated from the date of imatinib discontinuation until the date of death by any cause | Through study completion (five years) | 
| Progression-free survival after imatinib discontinuation | PFS is calculated from the date of imatinib discontinuatio until the date of progression of the disease | Through study completion (five years) | 
| Event-free survival after imatinib discontinuation | Event-free is calculated from the date of imatinib discontinuation until the date of loss of complete hematologic response, disease progression or death | Through study completion (five years) | 
| Molecular relapse free survival | Calculated from the date of imatinib discontinuation until de loss of major molecular response | Through study completion (five years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BCR-ABL Positive, Leukemia, Chronic Myeloid, Imatinib, Pioglitazone