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

Phase 2

Completed

• Conditions: Acute Myeloid Leukemia

• Registration Number: NCT01452646
• Lead Sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2011-10-12
• Study First Submitted QC: 2011-10-14
• Study First Posted: 2011-10-17
• Study Start: 2012-01
• Primary Completion: 2017-07
• Study Completion: 2018-07-10
• Status Verified: 2018-08
• Last Update Submitted: 2018-08-03
• Last Update Posted: 2018-08-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 515

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Primary Outcome Measures

Name	Time	Method
Treatment strategy in terms of Overall Survival (OS) at 24 months.	24 months from study entry.	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.

Secondary Outcome Measures

Name	Time	Method
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)	At 24 months from study entry	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.
Quality of Life evaluation	Before treatment starts, after induction, at one year after baseline evaluation.	QoL should be measured at three different time points: 1. At Baseline (before treatment starts).; 2. 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).; 3. At one year after baseline evaluation.
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
Estimation of Disease Free Survival (DFS) from Complete Response (CR) evaluation.	At 24 months from study entry	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.
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
Estimation of Event Free Survival (EFS) from study entry.	at 24 months 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.
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

Trial Locations

Locations (61)

U.O. di Ematologia - Azienda Ospedaliera - Pia Fondazione di Culto e di Religione Card. G.Panico; 🇮🇹 Tricase, (le), Italy

Complesso Ospedaliero S. Giovanni Addolorata; 🇮🇹 Roma, (rm), Italy

Policlinico di Tor Vergata; 🇮🇹 Rome, (rm), Italy

S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo; 🇮🇹 Alessandria, Italy

Azienda Ospedaliera - Nuovo Ospedale "Torrette"; 🇮🇹 Ancona, Italy

Az. Ospedaliera S. G. Moscati; 🇮🇹 Avellino, Italy

Unità Operativa Ematologia 1 - Università degli Studi di Bari; 🇮🇹 Bari, Italy

UOC Ematologia Ospedale " Monsignor Raffaele Dimiccoli"; 🇮🇹 Barletta, Italy

Ist.Ematologia e Oncologia Medica L.e A. Seragnoli; 🇮🇹 Bologna, Italy

Divisione di Ematologia Ospedale A. Perrino; 🇮🇹 Brindisi, Italy

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