Risk-adapted, MRD-directed Therapy for Young Adults With Newly Diagnosed Acute Myeloid Leukemia

Study Overview
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Brief Summary
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The purpose of this study is to determine whether a risk-adapted, minimal-residual-disease directed therapy for young adults with newly diagnosed acute myeloid leukemia has positive results in terms of overall survival at 24 months.

Detailed Description
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The general objective of this study is that of setting up a multicentre, risk-adapted study that relies on pre-treatment cytogenetic/genetic features and post-consolidation assessment of Minimal Residual Disease (MRD) to establish the final risk assignment and treatment of younger (≤ 60 years) patients with Acute Myeloid Leukemia (AML). Aim of this clinical trial is to verify whether the delivery of a post remission therapy whose intensity is risk-driven will improve the outcome in terms of both increased anti-leukemic efficacy and reduced therapy-related toxicity. All patients will receive induction and consolidation chemotherapy according to the Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) LAM99P protocol. After the first consolidation, patients belonging to the low-risk category (core binding factor positive AML without c-Kit mutations, NPM1 positive FLT3 negative AML) will receive autologous stem cell transplantation, patients with high-risk features (adverse-risk karyotype, FLT3-ITD mutations), will be assigned to allogeneic stem cell transplantation. Patients with FLT3-TKD mutations or c-Kit mutated core binding factor positive AML and those belonging to the intermediate-risk karyotype category will be stratified according to MRD by flow cytometry and will receive risk-adapted treatment (autologous vs. allogeneic stem cell transplantation). All patients who meet the criteria for high-risk definition will be offered the allogeneic transplantation option regardless of the availability of a Human Leukocyte Antigen (HLA) identical sibling. In fact, for those lacking a HLA identical sibling all the other sources of hematopoietic stem cells (matched unrelated donor from international registry, unrelated cord blood, family haploidentical donor) will be considered. Autologous or allogeneic stem cell transplantation will be performed within 3 months from the end of consolidation therapy.

Official Title
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Risk-adapted, MRD-directed Therapy for Young Adults With Newly Diagnosed Acute Myeloid Leukemia. GIMEMA Protocol AML1310. EudraCT Number 2010-023809-36

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Other: Risk-adapted, MRD-directed therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent according to ICH/EU/GCP and national/local laws Patients aged between 18 and 60 years Patients previously untreated for their AML by other chemotherapeutic agents (with the exception of no more than 7 days hydroxyurea (HU)), radiotherapy or more than 7 days corticosteroids Unequivocal diagnosis of untreated de novo AML according to WHO diagnostic criteria (at least 20% blasts in the bone marrow), with FAB classification other than M3 (acute promyelocytic leukemia), documented by bone marrow aspiration (or biopsy in case of dry tap) (not supervening after other myeloproliferative disease or myelodysplastic syndromes of more than 6 months duration) WHO performance status 0-3 Adequate renal (serum creatinine < 2 x the institutional Upper Limit of Normal (ULN)) and liver (total serum bilirubin < 2 x ULN; serum ALT and AST ≤ 3 x ULN) function, unless considered due to organ leukemic involvement Left Ventricular Ejection Fraction (LVEF) >50%, as determined by echocardiogram Absence of severe concomitant neurological or psychiatric diseases and congestive heart failure or active uncontrolled infection Absence of any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and the follow-up schedule. Exclusion Criteria: Patients aged less than 18 or more than 60 years Patients already treated for their AML by other chemotherapeutic agents (with the exception of no more than 7 days HU), radiotherapy or more than 7 days corticosteroids Acute promyelocytic leukaemia Blast crisis of chronic myeloid leukaemia AML supervening after other myeloproliferative disease AML supervening after antecedent myelodysplastic syndromes of more than 6 months duration Other progressive malignant diseases. However, secondary AML following previously cured malignancies may be included as well as secondary AML following previous exposure to alkylating agents or radiation for other reason Inadequate renal or liver function (metabolic abnormalities > 3 times the normal upper limit) Severe heart failure requiring diuretics Ejection fraction < 50% Uncontrolled infections WHO performance status = 4 Severe concomitant neurological or psychiatric diseases Patients who are pregnant or adults of reproductive potential not employing an effective method of birth control. Women of childbearing potential must have a negative serum pregnancy test within 48 hrs prior to administration of chemotherapy. Post-menopausal women must be amenorrhoeic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MRD-directed therapy<br> | Other: Risk-adapted, MRD-directed therapy<br>* The general objective of this study is that of setting up a multicentre, risk-adapted study that relies on pre-treatment cytogenetic/genetic features and post-consolidation assessment of MRD to establish the final risk assignment and treatment of younger (≤ 60 years) patients with AML. Aim of this clinical trial is to verify whether the delivery of a post remission therapy whose intensity is risk-driven will improve the outcome in terms of both increased anti-leukemic efficacy and reduced therapy-related toxicity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment strategy in terms of Overall Survival (OS) at 24 months. | OS is defined as the time interval between the date of study entry and death for any cause; patients still alive will be censored at the time of the last follow-up. | 24 months from study entry. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimation of Disease Free Survival (DFS) from Complete Response (CR) evaluation. | DFS is defined as the time interval between the evaluation of CR -after induction phase- and relapse or death in CR; patients still alive, in first CR, will be censored at the time of the last follow-up. | At 24 months from study entry | 
| Estimation of Event Free Survival (EFS) from study entry. | EFS is defined as the time interval between the date of study entry dose and failure during induction phase, relapse or death whichever comes first; patients still alive, in first CR, will be censored at the time of the last follow-up. | at 24 months from study entry | 
| Rate of patients in CR after induction therapy |  | At 31 days from study entry if pts are in CR or at 69 days from study entry if pts are in PR after 1 induction cycle | 
| Toxicity according to Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0 |  | From study entry to study completion (6 months therapy + 18 months follow-up) | 
| Estimation of OS, EFS, DFS and Cumulative Incidence of Relapse (CIR) according to risk groups (Low, Intermediate, High) | CIR is calculated from the date of achievement of the CR -after induction phase-, using the cumulative incidence method, considering death in CR as a competing risk. Patients still alive, without relapse, will be censored at the time of the last follow-up. | At 24 months from study entry | 
| Estimation of OS, EFS, DFS and CIR according to the Minimal Residual Disease (MRD) level at each evaluation step |  | At 24 months from study entry | 
| Rate of CR patients and estimation OS, EFS, DFS and CIR according to baseline characteristics such as age, performance status, white blood cell (WBC), morphology, cytogenetic and molecular features. |  | At 24 months from study entry | 
| Quality of Life evaluation | QoL should be measured at three different time points: At Baseline (before treatment starts). At the end of Induction phase (after evaluation of response and before start of consolidation therapy for patients in CR or salvage therapy for patients not achieving a CR). At one year after baseline evaluation. | Before treatment starts, after induction, at one year after baseline evaluation. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MRD-directed therapy, acute myeloid leukemia, risk-adapted therapy, young adults