Treatment of Newly Diagnosed Standard Risk Acute Lymphoblastic Leukemia in Children

Study Overview
=================
Brief Summary
-----------------
Aim of this study is to investigate the outcome of NGS MRD based risk stratified treatment for standard risk acute lymphoblastic leukemia in children and adolescents.

Official Title
-----------------
Treatment of Newly Diagnosed Standard Risk Acute Lymphoblastic Leukemia in

Conditions
-----------------
Lymphoblastic Leukemia in Children

Intervention / Treatment
-----------------
* Drug: induction: vincristine, L-asparaginase, dexamethasone, intrathecal Ara-C, intrathecal Methotrexate
* Drug: Consolidation: Vincristine, Mecaptopurine, Intrathecal Methotrexate
* Drug: Consolidation: Vincristine, Mecaptopurine, Cyclophosphamide, Cytarabine, L-asparaginase, Intrathecal Methotrexate
* Drug: Interim Maintenance(IM): Vincristine, Methotrexate, Intrathecal Methotrexate
* Drug: Interim Maintenance(IM): Vincristine, Methotrexate, Mercaptopurine, Intrathecal Methotrexate
* Drug: Delayed Intesification(DI): Vincristine, Mercaptopurine, L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Dexamethasone, Intrathecal Methotrexate
* Drug: Delayed Intesification(DI): Vincristine, L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Dexamethasone, Intrathecal Methotrexate
* Drug: Maintenance: Vincristine, Mercaptopurine, Methotrexate, Dexamethasone, Intrathecal Methotrexate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Newly diagnosed pediatric/adolescent acute lymphomblastic leukemia patient with NCL standard risk that stratifies all 1-5 of following 1 year old ≤ Age < 10 years old white blood cell at initial diagnosis < 5x10^10/L (50,000uL) CNS 1 or 2 No testis involvement Satisfaction of following organ functions A. Kidney function (satisfies i or ii) i. Creatinine clearance (or radioisotope-measured GFR) ≥ 70mL/min/1.73m2 ii. Creatinine value according to age/sec satisfies the following: 1 to < 2 years: Male: 0.6 / Female: 0.6, 2 to < 6 years: Male: 0.8 / Female: 0.8, 6 to < 10 years: Male: 1 / Female: 1, 10 to < 13 years: Male: 1.2 / Female: 1.2, 13 to < 16 years: Male: 1.5 / Female: 1.4, ≥ 16 years: Male: 1.7 / Female: 1.4 B. Liver function i. Direct bilirubin < 3.0mg/dL C. Cardiac function i. Shortening fraction ≥ 27% confirmed by cardiac echography ii. Ejection fraction ≥ 50% confirmed by cardiac echography Exclusion Criteria: Steroid administration within 2 weeks before the diagnosis t(9;22) or t(4;11)(q11;q23) or chromosome < 44 or iAMP21 or t(17;19)/TCF3-HLF One of the following syndromes: Down syndrome, Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachman-Diamond syndrome, or other bone marrow failure syndrome Burkitt leukemia/lymphoma When the clinical trial subject(or legal representative) does not consent or is unable to give written consent

Ages Eligible for Study
-----------------
Minimum Age: 1 Year
Maximum Age: 9 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Standard-low (SL)<br>Induction-> SL Consolidation(4weeks)-> Interim Maintenance 1st-> Delayed Intesificaion-> Interim Maintenance 2nd-> Maintenance | Drug: induction: vincristine, L-asparaginase, dexamethasone, intrathecal Ara-C, intrathecal Methotrexate<br>* vincristine 1.5mg/m2 L-asparaginase 6,000U/m2 Dexamethasone 6mg/m2 Intrathecal Cytarabine Intrathecal Methotreate<br>Drug: Consolidation: Vincristine, Mecaptopurine, Intrathecal Methotrexate<br>* Vincristine 1.5mg/m2 Mecaptopurine 50mg/m2 Cyclophosphamide 1,000mg/m2 Cytarabine 75mg/m2 L-asparaginase 6,000U/m2 Intrathecal Methotrexate<br>Drug: Interim Maintenance(IM): Vincristine, Methotrexate, Intrathecal Methotrexate<br>* Vincristine 1.5mg/m2 Methotrexate 5,000mg/m2 Intrathecal Methotrexate<br>Drug: Delayed Intesification(DI): Vincristine, Mercaptopurine, L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Dexamethasone, Intrathecal Methotrexate<br>* Vincristine 1.5mg/m2 Mercaptopurine 50mg/m2 L-asparaginase 6,000IU/m2 Doxorubicin 25mg/m2 Cyclophosphamide 1,000mg/m2 Cytarabine 75mg/m2 Dexamethasone 10mg/m2 Intrathecal Methotrexate<br>Drug: Maintenance: Vincristine, Mercaptopurine, Methotrexate, Dexamethasone, Intrathecal Methotrexate<br>* Vincristine 1.5mg/m2 Mercaptopurine 50mg/m2 Methotrexate 20mg/m2 Dexamethasone 6mg/m2 Intrathecal Methotrexate<br>|
| Experimental: Standard-average (SA)<br>Induction-> SH Consolidation(8weeks)-> Interim Maintenance 1st-> Delayed Intesificaion-> Interim Maintenance 2nd-> Maintenance | Drug: induction: vincristine, L-asparaginase, dexamethasone, intrathecal Ara-C, intrathecal Methotrexate<br>* vincristine 1.5mg/m2 L-asparaginase 6,000U/m2 Dexamethasone 6mg/m2 Intrathecal Cytarabine Intrathecal Methotreate<br>Drug: Consolidation: Vincristine, Mecaptopurine, Cyclophosphamide, Cytarabine, L-asparaginase, Intrathecal Methotrexate<br>* Vincristine 1.5mg/m2 Mecaptopurine 50mg/m2 Cyclophosphamide 1,000mg/m2 Cytarabine 75mg/m2 L-asparaginase 6,000IU/m2 Intrathecal Methotrexate<br>Drug: Interim Maintenance(IM): Vincristine, Methotrexate, Intrathecal Methotrexate<br>* Vincristine 1.5mg/m2 Methotrexate 5,000mg/m2 Intrathecal Methotrexate<br>Drug: Delayed Intesification(DI): Vincristine, Mercaptopurine, L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Dexamethasone, Intrathecal Methotrexate<br>* Vincristine 1.5mg/m2 Mercaptopurine 50mg/m2 L-asparaginase 6,000IU/m2 Doxorubicin 25mg/m2 Cyclophosphamide 1,000mg/m2 Cytarabine 75mg/m2 Dexamethasone 10mg/m2 Intrathecal Methotrexate<br>Drug: Maintenance: Vincristine, Mercaptopurine, Methotrexate, Dexamethasone, Intrathecal Methotrexate<br>* Vincristine 1.5mg/m2 Mercaptopurine 50mg/m2 Methotrexate 20mg/m2 Dexamethasone 6mg/m2 Intrathecal Methotrexate<br>|
| Experimental: Standard-high 1 (SH1)<br>Induction-> SL Consolidation(4weeks)-> SH Consolidattion(4weeks)-> Interim Maintenance 1st-> Delayed Intesificaion 1st-> Interim Maintenance 2nd-> Delayed Intestificaion 2nd-> Maintenance | Drug: induction: vincristine, L-asparaginase, dexamethasone, intrathecal Ara-C, intrathecal Methotrexate<br>* vincristine 1.5mg/m2 L-asparaginase 6,000U/m2 Dexamethasone 6mg/m2 Intrathecal Cytarabine Intrathecal Methotreate<br>Drug: Consolidation: Vincristine, Mecaptopurine, Cyclophosphamide, Cytarabine, L-asparaginase, Intrathecal Methotrexate<br>* Vincristine 1.5mg/m2 Mecaptopurine 50mg/m2 Cyclophosphamide 1,000mg/m2 Cytarabine 75mg/m2 L-asparaginase 6,000IU/m2 Intrathecal Methotrexate<br>Drug: Interim Maintenance(IM): Vincristine, Methotrexate, Mercaptopurine, Intrathecal Methotrexate<br>* Vincristine 1.5mg/m2 Methotrexate 5,000mg/m2 Mecaptopurine: 25mg/m2 Intrathecal Methotrexate<br>Drug: Delayed Intesification(DI): Vincristine, L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Dexamethasone, Intrathecal Methotrexate<br>* Vincristine 1.5mg/m2 L-asparaginase 6,000IU/m2 Doxorubicin 25mg/m2 Cyclophosphamide 1,000mg/m2 Cytarabine 100mg/m2 Dexamethasone 6mg/m2 Intrathecal Methotrexate<br>Drug: Maintenance: Vincristine, Mercaptopurine, Methotrexate, Dexamethasone, Intrathecal Methotrexate<br>* Vincristine 1.5mg/m2 Mercaptopurine 50mg/m2 Methotrexate 20mg/m2 Dexamethasone 6mg/m2 Intrathecal Methotrexate<br>|
| Experimental: Standard-high 2 (SH2)<br>Induction-> SH Consolidattion(8weeks)-> Interim Maintenance 1st-> Delayed Intesificaion 1st-> Interim Maintenance 2nd-> Delayed Intestificaion 2nd-> Maintenance | Drug: induction: vincristine, L-asparaginase, dexamethasone, intrathecal Ara-C, intrathecal Methotrexate<br>* vincristine 1.5mg/m2 L-asparaginase 6,000U/m2 Dexamethasone 6mg/m2 Intrathecal Cytarabine Intrathecal Methotreate<br>Drug: Consolidation: Vincristine, Mecaptopurine, Cyclophosphamide, Cytarabine, L-asparaginase, Intrathecal Methotrexate<br>* Vincristine 1.5mg/m2 Mecaptopurine 50mg/m2 Cyclophosphamide 1,000mg/m2 Cytarabine 75mg/m2 L-asparaginase 6,000IU/m2 Intrathecal Methotrexate<br>Drug: Interim Maintenance(IM): Vincristine, Methotrexate, Mercaptopurine, Intrathecal Methotrexate<br>* Vincristine 1.5mg/m2 Methotrexate 5,000mg/m2 Mecaptopurine: 25mg/m2 Intrathecal Methotrexate<br>Drug: Delayed Intesification(DI): Vincristine, L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Dexamethasone, Intrathecal Methotrexate<br>* Vincristine 1.5mg/m2 L-asparaginase 6,000IU/m2 Doxorubicin 25mg/m2 Cyclophosphamide 1,000mg/m2 Cytarabine 100mg/m2 Dexamethasone 6mg/m2 Intrathecal Methotrexate<br>Drug: Maintenance: Vincristine, Mercaptopurine, Methotrexate, Dexamethasone, Intrathecal Methotrexate<br>* Vincristine 1.5mg/m2 Mercaptopurine 50mg/m2 Methotrexate 20mg/m2 Dexamethasone 6mg/m2 Intrathecal Methotrexate<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-year event free survival rate |  | Up to 5-years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmation of the therapeutic effect of the initial treatment response | Relapse-free survival between two groups(NGS-MRD positive vs. NGS MRD negative after induction) offsets by NGS MRD based stratified treatment | Up to 5-years | 
| Disease prognosis-related factor | Relapse-free survival according to presence or absence of known good prognosis factors(high hyperdilpoidy, ETV6/RUNX1, Trisomy 4/10/17) have no clinical significance when NGS MRD based stratified treatment is performed. | Up to 5-years |