Front-line Treatment of BCR-ABL+ Chronic Myeloid Leukemia (CML) With Dasatinib

Study Overview
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Brief Summary
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The GIMEMA CML Working Party promotes a multicentric, observational, non company sponsored, prospective study of Chronic Myeloid Leukemia (CML) patients treated frontline with dasatinib. Patients will be followed for 5 years. This study will help the definition of guidelines for the treatment of CML patients in early phases. The primary objective of the study is to describe, in the clinical practice, the rate of events leading to permanent discontinuation after 2 years of treatment with dasatinib as frontline therapy in newly diagnosed CML patients.

Detailed Description
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The primary objective is to describe, in the clinical practice, the rate of events leading to permanent discontinuation after 2 years of treatment with dasatinib as frontline therapy in newly diagnosed CML patients. Imatinib mesylate, a protein tyrosine kinase inhibitor (TKI) targeting BCR-ABL, has become in the last decade the standard of care for Chronic Myeloid Leukaemia (CML) in chronic phase (CP)1-3. Dasatinib is a second generation TKI, effective in imatinib-resistant and imatinib-intolerant patients, which demonstrated superior efficacy to imatinib in early CP BCR-ABL+ CML patients 4,6,7. Most data on second generation TKIs are from company-sponsored studies, generally implemented in selected referral centres. The long-term outcome is still unknown. The high rate of study discontinuation observed within the phase 3 study may influence the mid-term and the long-term data interpretation6,7. A long-term post-marketing surveillance in large independent trial is extremely important to confirm the feasibility of a frontline treatment with the second generation TKI dasatinib and to evaluate the efficacy in a nationwide experience. Moreover, obtaining a deep molecular response is extremely relevant in order to consider TKIs discontinuation. This condition is known as Complete Molecular Response (CMR) and is further defined according to the sensitivity achieved (for the definition see the Criteria of evaluation section). As far as treatment discontinuation, two experiences have been published so far, aimed at evaluating the persistence of the CMR after imatinib discontinuation. The first was a pilot study32 where 12 patients were included. These 12 patients discontinued imatinib after at least 2 years of CMR (median duration of negativity, 32 months). Six patients displayed a molecular relapse with a detectable BCR-ABL transcript at 1, 2, 3, 4, and 5 months. Imatinib was then reintroduced and led to a novel molecular response. Six other patients (50%) still have an undetectable level of BCR-ABL transcript after a median follow-up of 18 months (range, 9-24 months). The results of this pilot trial have been confirmed and extended in a second trial, the STIM trial33: 100 patients were enrolled, median follow-up 17 months, 69 patients with at least 12 months follow-up: 42 (61%) of these 69 patients relapsed (40 before 6 months, one patient at month 7, and one at month 19). At 12 months, the probability of persistent CMR for these 69 patients was 41% (95% CI 29-52). All patients who relapsed responded to reintroduction of imatinib. An increase of the CMR rate could possibly translate in a higher proportion of patients candidate to stopping anti-CML treatment, with higher probability of remaining disease-free in the long term. Interestingly, dasatinib was able to induce higher 36-month cumulative MR4 and MR4.5 rates than imatinib7. The advantages of this possible future scenario could be: first, the possibility of treatment discontinuation at least in patients with chronic clinical adverse events; second, a potential reduction of the costs of TKI treatment (after the introduction of TKI, the costs of CML treatment is increasing year by year, with the increasing prevalence of CML patients). In summary, 1) Most data on second generation TKIs are from company-sponsored studies; 2) The high rate of study discontinuation observed within the phase III study may influence the data interpretation; 3) A long-term post-marketing surveillance in large independent trial is extremely important to confirm the efficacy in a nationwide experience; 4) The persistence of CMR after TKI discontinuation have been described in selected patients with deep molecular response; 5) A stable CMR is a pre-requisite for treatment discontinuation; 6) A detailed description of the kinetic of the molecular response, potentially related to a subsequent treatment discontinuation, will be done.

Official Title
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Front-line Treatment of BCR-ABL+ Chronic Myeloid Leukemia (CML) With Dasatinib. An Observational Multicentric Study.

Conditions
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Chronic Myeloid Leukemia

Intervention / Treatment
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* Behavioral: Dasatinib discontinuation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cytogenetic and/or molecular confirmed diagnosis of Ph+ and/or BCR-ABL+ CML; Age 18 years; Early chronic phase, less than 6 months from diagnosis. Prior treatment with Hydroxyurea or Anagrelide is allowed; Signed written informed consent according to ICH/EU/GCP and national local laws prior to any study procedures. Exclusion Criteria: Prior treatment with any protein tyrosin-kinase inhibitor (TKI) or interferon; Recommendations and precautions before allocating a new CML case to dasatinib are fully described in the prescribing information.

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 |
| --- | --- |
| CML patients<br> | Behavioral: Dasatinib discontinuation<br>* Treatment decision is at the discretion of the investigator and must not be made on the basis of this observational study. Patients should have their treatment initiated in accordance with the summary of product characteristics.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of dasatinib permanent discontinuing patients. | The cumulative rate of dasatinib permanent discontinuation by 2 years. | After 2 years from study entry. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of dasatinib permanent discontinuing patients. | The cumulative rate of dasatinib permanent discontinuation by 5 years. | After 5 years from study entry. | 
| Number of confirmed MR4 and MR4.5. | The rate of confirmed MR4 and MR4.5 by 24 months. | After 2 years from study entry. | 
| Number of confirmed MR4 and MR4.5. | The rate of confirmed MR4 and MR4.5 by 60 months. | After 60 months from study entry. | 
| Number of stable MR4 and MR4.5 and characteristics. | The stability of MR4 and MR4.5. | After 60 months from study entry. | 
| Number of Complete Cytogenetic Responses (CCgR) | The rate of Complete Cytogenetic Response (CCgR) at 1 year. | After one year from study entry. | 
| Number of Major Molecular Response (MMR). | The rate of Major Molecular Response (MMR) at 1 year. | After one year from study entry. | 
| Number of days to response (CCgR, MMR, MR4, MR4.5). | The median time to response and the overall estimated probability of response (CCgR, MMR, MR4, MR4.5). | After 4 years from study entry. | 
| Number of overal surviving patients |  | After five years from study entry. | 
| Number of progression-free survival patients. |  | After five years from study entry. | 
| Number of failure-free survival patients. |  | After five years from study entry. | 
| Number of event-free survival patients. |  | After five years from study entry. | 
| Number of responses | Overall responses and long-term outcome according to baseline prognostic factors (including: Sokal score34, Euro score35 and EUTOS score36; presence of additional chromosomal abnormalities in Ph+ cells; BCR-ABL transcript type; comorbidity score index). | After 7 years from study entry. | 
| Number of responses according to BCR-ABL transcript levels. | Overall responses and long-term outcome according to BCR-ABL transcript levels and CgR at 3 months and at 6 months. | After 3 and 6 months from study entry. | 
| Number of patients with fasting glucose modifications. | Fasting glucose modifications (diabetic and normo-glycemic patients) and HbA1C modifications (diabetic patients only) during the first 24 months. | After 24 months from study entry. | 
| Number of patients with modifications of body mass index during treatment compared to baseline. | Modifications of body mass index during treatment compared to baseline. | After 7 years from study entry. | 
| Number of patients with modifications of serum lipids during treatment compared to baseline. | Modifications of serum lipids during treatment compared to baseline. | After 7 years from study entry. | 
| Patient reported quality of life. |  | At 3, 6, 9, 12, 18, 24 months from study entry. | 
| Number of adverse events. |  | At 3, 6, 9, 12, 18, 24 months from study entry. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Myeloid Leukemia, Early phase, CML, Dasatinib