Study of Imatinib Discontinuation in Chronic Myeloid Leukemia With Deep Molecular Response (EDI-PIO)

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

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.

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%.

Treatment-free remission time after imatinib discontinuation in patients with CML treated with pioglitazone for 3 months before imatinib discontinuation

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

Proportion of patients with MMR, MR4.0 and MR4.5 at 3, 6 and 12 months after imatinib discontinuation

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

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