Risk-adapted, MRD-directed Therapy for Young Adults With Newly Diagnosed Acute Myeloid Leukemia (AML1310)

Gruppo Italiano Malattie EMatologiche dell'Adulto

Status and phase

Completed

Phase 2

Conditions

Acute Myeloid Leukemia

Treatments

Other: Risk-adapted, MRD-directed therapy

Study type

Interventional

Funder types

Other

Identifiers

NCT01452646

AML1310

Details and patient eligibility

About

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.

Full 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.

Enrollment

515 estimated patients

Sex

All

Ages

18 to 60 years old

Volunteers

No Healthy Volunteers

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.