The Efficacy of Therapy in Patients With Acute Myeloid Leukemia and Down Syndrome in Russia

This prospective non-randomized multicenter trial created based on protocol ML DS 2006 and aimed at standardization of current therapy approaches and creating a national network for diagnostic, treatment and monitoring of children (0-18 years) with AML and Down syndrome in Russia. Based on the results the investigators expect to increase long-term overall and event-free survival in children with AML and DS and reduce the immediate and remote toxicity of chemotherapy by reducing the dose load of chemotherapeutic drugs.

Patients to be included: Age 0-18 years

* Diagnosis of AML, MDS and presence of Down syndrome (constitutional trisomy 21 and mutation in the GATA1 gene)
* Signed informed consent

Patients not be included:

* Children with Down syndrome and acute lymphoblastic leukemia (ALL)
* Severe comorbidities with contraindications to the treatment according to the protocol
* Pre-treatment >14 days with intensive induction therapy
* Refusal of all therapy or important elements of therapy

NB: Patients with Transient Abnormal Myelopoiesis (TAM) are eligible for enrollment but will be included in the analysis as a separate group.

Patients with M7 AML, trisomy 21 in the tumor clone (without the Down syndrome phenotype) and mutation in the GATA1 gene should be discussed individually with the protocol group to determine the treatment strategy, as patients with M7 AML and trisomy 21 in tumor clone (without the Down syndrome phenotype) are not included in current version of pediatric AML clinical recommendations.

If a patient meets the inclusion criteria, but cannot/should not receive treatment according to the protocol, he/she can be enrolled in the study as a patient under observation. The results of therapy of patients under observation will not be taken into account in the assessment of treatment efficacy.

The study protocol therapy for all patients includes four chemotherapy blocks:

Course 1 AIE (cytarabine/idarubicin/etoposide) Course 2 AI (cytarabine/idarubicin) Course 3 HAD (high-dose cytarabine (1g)/daunorubicin) Course 4 HA (high-dose cytarabine)/ Efficacy parameters include Response rate; event-free survival (EFS); relapse-free survival (RFS); overall survival (OS); treatment-related mortality, myelogram, MRD Safety to be monitored based on CTCAE v5.0 The AML-DS-2025 protocol does not include a maintenance therapy course in order to reduce toxicity and improve quality of life.

• 4 chemotherapy blocks: Course 1 AIE (cytarabine/idarubicin/etoposide), Course 2 AI (cytarabine/idarubicin), Course 3 HAD (high-dose cytarabine (1g)/daunorubicin), Course 4 HA (high-dose cytarabine). (Drug): 4 chemotherapy blocks: Course 1 AIE (cytarabine/idarubicin/etoposide), Course 2 AI (cytarabine/idarubicin), Course 3 HAD (high-dose cytarabine (1g)/daunorubicin), Course 4 HA (high-dose cytarabine).

Primary outcomes

• event-free survival [up to 2 years]: Response rate; event-free survival (EFS)
• relapse-free survival (RFS) [up to 2 years]
• overall survival (OS) [up to 2 years]
• treatment-related mortality [up to 2 years]

Secondary outcomes

• CTCAE [up to 2 years]: Number of adverse events by Common Terminology Criteria for Adverse Events (CTCAE) 5.0

Sex: All, ages: 1 Day to 18 Years

Inclusion Criteria:

* Age 0-18 years
* Diagnosis of AML, MDS and presence of Down syndrome (constitutional trisomy 21 and mutation in the GATA1 gene)
* Signed informed consent

Exclusion Criteria:

* Children with Down syndrome and acute lymphoblastic leukemia (ALL)
* Severe comorbidities with contraindications to the treatment according to the protocol
* Pre-treatment >14 days with intensive induction therapy
* Refusal of all therapy or important elements of therapy