Retro-prospective Observational Study on Risk of Progression in CP-CML Patients Eligible for TKI Discontinuation

Study Overview
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Brief Summary
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The purpose of this study is to investigate the safety profile of TKI discontinuation in clinical practice, with particular regard on the risk of progression after treatment discontinuation.

Detailed Description
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This study will enroll approximately 3000 CP-CML patients that must have a history of at least 4 years of TKI treatment and at least 18 months of DMR. Events developing in patients after the end of discontinuation and TKI resumption will be considered as linked to the discontinuation if they will develop within 36 months from the end of discontinuation. This rule will apply also to subsequent TD attempts. In case of a second or subsequent discontinuation attempt after the failure of a previous one (for molecular relapse), patients must have re-achieved a DMR with TKI therapy resumption and must keep DMR for at least 18 months before another TD. Collection of data will be retrospective and prospective, as each center will collect the data for 24 months. Patients who discontinued before the opening of this study will contribute to the retrospective cohort, while those who will discontinue after it will contribute to the prospective cohort. Patients who discontinued before the opening of this study but will continue their discontinuation after it, will contribute to both cohorts. For patients prospectively recruited, monitoring of disease status will be performed to assess the maintenance of the molecular remission during the study period. Patients with an atypical BCR-ABL1 fusion gene, which does not allow the use of Q-RT-PCR, will be monitored by qualitative PCR and will be analyzed separately. For these patients, negativity of nested qualitative RT-PCR will be considered a surrogate of DMR of patients monitored by Q-RT-PCR, while loss of negativity of first-round qualitative PCR will be considered a surrogate of loss of MMR (i.e. molecular relapse). Accordingly, for patients monitored by qualitative PCR, TKI resumption after TD will be provided in case of a new positivity of first-round PCR. .

Official Title
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Retro-prospective Observational Study on Risk of Progression in Chronic Phase-Chronic Myeloid Leukemia Patients Eligible for Tyrosine Kinase Inhibitor Discontinuation (TFR - PRO)

Conditions
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Chronic Myeloid Leukemia

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated IRB/IEC-approved informed consent for the prospective cohort patients. Age >= 18 years. Male or female patients with CML diagnosed in chronic phase (CP). At least 4 years of TKI treatment. At least 18 months of DMR. Exclusion Criteria: Allogeneic hematopoietic stem cell transplantation. CML diagnosed in AP or BC

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Retrospective cohort<br>Patients who discontinued before the opening of this study will contribute to the retrospective cohort. | |
| Prospective cohort<br>Patients who will discontinue after it will contribute to the prospective cohort. | |
| Retrospective/Prospective cohort<br>Patients who discontinued before the opening of this study but will continue their discontinuation after it, will contribute to both cohorts. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The quantification of the risk of progression | To quantify the risk of progression to accelerated phase (AP) or blast phase (BP), expressed as time adjusted rate (TAR), after TKI discontinuation in CML patients who undergo a first or subsequent TKI discontinuation attempt | 36 Month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the time adjusted rate (TAR) of progression from Chronic phase-Chronic Myeloid Leukemia to Accelerated phase (AP) or Blastic phase (BP) by using the percentage of blasts, promyelocytes, basophils or platelet in blood or bone marrow | To compare the TAR (time adjusted rate) of progression to AP or BP that is obtained in the target population to that obtained in a similar population of patients with the same characteristics who do not discontinue TKI treatment | 36 Month | 
| Progression free survival (PFS) after TKI discontinuation. | PFS will be defined as time between discontinuation and progression to AP or BP. | 36 Month | 
| Rate of molecular relapse (loss of MR3 or MMR) | Rate of molecular relapse (loss of MR3 or MMR) at 12 and 24 months after TKI discontinuation. | 36 Month | 
| Relapse free survival (RFS) after TKI discontinuation. | Relapse free survival (RFS) after TKI discontinuation. RFS will be defined as time between discontinuation and loss of MMR (i.e. molecular relapse). | 36 Month | 
| Percentage of relapsed patients who obtain a new deep molecular response (DMR) within 6-12 months of treatment resumption among all patients who restart TKI treatment because of a molecular relapse after TKI discontinuation. | The following criteria will be used to define DMR (43): MR4 = either (i) detectable disease with <0.01% BCR-ABL1IS or (ii) undetectable disease in cDNA with >10 000 ABL1 transcripts. MR4.5 = either (i) detectable disease with <0.0032% BCR-ABL1IS or (ii) undetectable disease in cDNA with >32 000 ABL1 transcripts in the same volume of cDNA used to test for BCR-ABL1. MR5 = either (i) detectable disease with <0.001% BCR-ABL1IS or (ii) undetectable disease in cDNA with >100 000 ABL1 transcripts in the same volume of cDNA used to test for BCR-ABL1. | 36 Month |