A Prospective Multicenter Clinical Trial of MRD-based Treatment Strategy in Children and Young Adults With AML

Study Overview
=================
Brief Summary
-----------------
Minimal-residual disease (MRD) will be measured either by flow cytometry, or polymerase chain reaction (PCR) methods, in 3 check-points and it will be one of the decision-making control parameter for the optimal therapy tactics. Patients with initially high-risk group and those with high MRD after 2 initial courses of chemotherapy will be assigned to the allogenic transplantation of the hematopoietic stem cells from Human Leucocyte Antigen (HLA) matched or haploidentical family donors.

Detailed Description
-----------------
Genetic alterations in acute myeloid leukemia (AML) clone are well known prognostic risk factors of AML relapse. Standard risk group includes favorable t (15;17) (q22; q21) and inv (16)/t (16;16). High-risk patients have a complex karyotype rearrangement (3 and more), inversion of the long arm in 3rd chromosome and EVI1 gene rearrangement, monosomy 5 and 7, translocations involving KMT2A gene and several rare translocations. All other genotype alterations attributed to the moderate risk group. Besides genetic factors, detection of the minimal residual disease (MRD) after initial chemotherapy and its decrease rate after 1st postremission chemotherapy with high dose Cytarabine and anthracyclines, plays a crucial role in the development of the morphologic relapse. Patients with PCR-MRD<0,1% after 2 courses of chemotherapy have a 30% or less risk of relapse, while PCR-MRD>0,1% - over 70%. In the clinical trial investigators are planning to measure MRD either by immune-phenotype, or PCR methods, in 3 check-points and it will be one of decision-making control parameter for the optimal therapy tactics. Patients with initially high-risk group and those with high MRD after 2 initial courses of chemotherapy will be assigned to the allogenic transplantation of the hematopoietic stem cells from HLA- matched or haploidentical family donors.

Official Title
-----------------
A Prospective Multicenter Clinical Trial of Treatment Strategy Based on MRD Level After 2 Initial Courses of Chemotherapy in Children and Young Adults With Acute Myeloid Leukemia

Conditions
-----------------
Acute Myeloid Leukemia, Childhood

Intervention / Treatment
-----------------
* Other: HSCT


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: de novo acute myeloid leukemia signed informed consent Exclusion Criteria: diagnosis of: Fanconi anemia, acute promyelocytic leukemia, MDS, JMML, AML as secondary malignancy, Dawn syndrome.

Ages Eligible for Study
-----------------
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: intermediate risk MRD2>0,1%<br>MRD2>0,1% - FLA - MRD3 - HSCT | Other: HSCT<br>* allogenic HSCT from 5-8 HLA-MM family donor as a first choice for patients with initial high risk of relapse and for patients with MRD2>0,1% and initial intermediate risk<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| relapse-free survival (RFS) | relapse-free survival from date of diagnosis till date of relapse, or date of death (whichever comes first) or date of last follow up | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall survival (OS) |  | 1 year | 
| event-free survival (EFS) | Event=relapse/nonresponse, death or second malignancy | 2 years | 
| The proportion of of patients with severe adverse effects | The proportion of of patients with severe adverse effects of therapy according to CTCAE (ver 4.3) | 6 months | 
| The proportion of of patients with severe infections | The proportion of of patients with severe infections: number of episodes, grade, after each course of chemotherapy | 1 month | 
| The proportion of of patients with severe cardiotoxicity | The proportion of of patients with severe cardiotoxicity: number of episodes and %EF by echocardiogam | 1 year | 
| MRD dynamic | MRD (IFT and/or PCR) dynamic between check-points | 1 months | 
| MRD specificity and sensitivity | MRD specificity and sensitivity in relapse prognosis | 1, 2, 3 months | 
| Cumulative incidence of relapse | competing event - death in CR | 6 months, 1 year | 
| Cumulative incidence of transplant-related mortality | for transplanted patients | 6 months after HSCT | 
| Cumulative incidence of aGvHD II-IV grade | for transplanted patients | 100 days after HSCT | 
| Cumulative incidence of cGvHD | for transplanted patients | 1 year after HSCT | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
AML, MRD, stem cell transplantation, pediatric, leukemia, haploidentical, TcRab-depletion, young adult