A Prospective Randomized Comparison of HDAC vs AD in the Induction Chemothrapy for AML.

Study Overview
=================
Brief Summary
-----------------
This trial is a single-center, non-blind, two-arm randomized prospective controlled trial to compare the effectiveness of two induction chemotherapy regimens (high-dose cytarabine plus daunorubicin [HDAC] vs. cytarabine plus high-dose daunorubicin [AD]) in acute myeloid leukemia (AML). The primary hypothesis of the study is that AD is superior to HDAC in terms of event-free survival (EFS, time from registration to induction failure, relapse, or death).

Detailed Description
-----------------
Induction chemotherapy Arm I [HDAC]: cytarabine 3.0 g/m2 q12hr 3-hour iv infusion on days 1, 3, 5 plus daunorubicin 45 mg/m2/day continuous iv infusion for 3 days (D1-3). Arm II [AD]: cytarabine 200 mg/m2/day continuous iv infusion for 7 days (D1-7) plus daunorubicin 90 mg/m2/day continuous iv infusion for 3 days (D1-3). Interim bone marrow examination Interim bone marrow aspiration and biopsy will be done between 14 and 21 days after start of induction chemotherapy. If bone marrow has blasts < 10%, no additional chemotherapy will be given until the recovery of blood counts (absolute neutrophil counts rise over 1,000/μL and platelet counts over 100,000/μL) or post-induction day 35, when bone marrow examination will be repeated to evaluate CR. After the marrow examination, re-induction course will be given. If interim bone marrow examination shows persistent leukemia (blasts ≥ 10%), re-induction course could be given. Patients who did not attain CR after the re-induction chemotherapy will be eliminated from the study. Re-induction chemotherapy Cytarabine 200 mg/m2/day iv infusion for 5 days (D1-5) plus daunorubicin 45 mg/m2/day iv infusion for 2 days (D1-2) Post-remission consolidation chemotherapy Adverse risk group: up to 3 courses of intermediate-dose cytarabine (1.0 g/m2/day iv for 5 days [D1-5]) plus etoposide (150 mg/m2/day iv for 3 days [D1-3]) Favorable/intermediate risk group: up to 3 courses of high-dose cytarabine (3.0 g/m2/day q12 hr iv for 3 days [D1, 3, 5]) Autologous or allogeneic hematopoietic cell transplantation (HCT) can be performed based on the risk of relapse. The bone marrow examination will be done after the completion of consolidation chemotherapy or before HCT.

Official Title
-----------------
A Prospective Randomized Comparison of High-dose Cytarabine an High-dose Daunorubicin in the Induction Chemothrapy for Acute Myeloid Leukemia

Conditions
-----------------
Acute Myeloid Leukemia

Intervention / Treatment
-----------------
* Drug: High dose Cytarabine
* Drug: Cytarabine
* Drug: Hign dose Daunorubicin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Previously-untreated AML (≥ 20% blasts in bone marrow and/or peripheral blood) Age of 15 years or older, 60 years or younger Adequate performance status (Karnofsky score of 50 or more) Adequate hepatic and renal function (AST, ALT, and bilirubin < 2.5 x upper normal limit and creatinine < 2.0 mg/dL & creatinine clearance ≥ 50 mL/min). Elevation of AST or ALT due to hepatic infiltration of leukemic cells will be permitted. Adequate cardiac function (left ventricular ejection fraction ≥45% on heart scan or echocardiogram) Signed informed consent Exclusion Criteria: Patients with history of chemotherapy for leukemia or cytarabine and anthracycline treatment for any malignancy. Hydroxyurea for reduction of leukemic cell burden before induction chemotherapy will be permitted. Patients with acute promyelocytic leukemia Patients with blast crisis of chronic myeloid leukemia Patients with central nervous system (CNS) leukemia or granulocytic sarcoma without bone marrow involvement Presence of uncontrolled and/or severe medical condition (infection, bleeding, cardiovascular disease including myocardial infarction within previous 6 months.) Nursing women, pregnant women, women of childbearing potential who do not want adequate contraception Patients with a diagnosis of prior malignancy unless disease-free for at least 5 years following therapy with curative intent (except curatively treated nonmelanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia)

Ages Eligible for Study
-----------------
Minimum Age: 15 Years
Maximum Age: 60 Years

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High-dose cytarabine<br>High-dose cytarabine 3.0 g/m2 q12hr 3-hour iv infusion on days 1, 3, 5 plus daunorubicin 45 mg/m2/day continuous iv infusion for 3 days (D1-3). | Drug: High dose Cytarabine<br>* High dose Cytarabine 3.0 g/m2 q12hr 3-hour iv infusion on days 1, 3, 5 plus daunorubicin 45 mg/m2/day continuous iv infusion for 3 days (D1-3).<br>* Other names: HDAC;|
| Experimental: high-dose daunorubicin<br>cytarabine 200 mg/m2/day continuous iv infusion for 7 days (D1-7) plus high-dose daunorubicin 90 mg/m2/day continuous iv infusion for 3 days (D1-3). | Drug: Cytarabine<br>* cytarabine 200 mg/m2/day continuous iv infusion for 7 days (D1-7)<br>* Other names: AD;Drug: Hign dose Daunorubicin<br>* Hign dose Daunorubicin 90 mg/m2/day continuous iv infusion for 3 days (D1-3).<br>* Other names: AD;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of relapse | defined for all patients achieving CR; measured from the date of CR achievement until the date of relapse; patients not known to have relapsed are censored on the date they were last examined; patients who died without relapse are counted as a competing cause of failure | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival | Defined for all patients; measured from the starting date of registration to the date of induction treatment failure, or relapse from CR, or death from any cause; patients not known to have any of these events are censored on the date they were examined | 3years | 
| Overall survival | Defined for all patients; measured from the starting date of registration to the date of death from any cause-patients not known to have died at last follow-up are censored on the date they were last known to be alive | 3years |