Idarubicin Versus High Dose Daunorubicin in Acute Myelogenous Leukemia (AML) (AIvsAD)

A Prospective Randomized Comparison of Idarubicin and High-dose Daunorubicin in Combination With Cytarabine in the Induction Chemotherapy for Acute Myeloid Leukemia

The purpose of this non-inferiority study is to compare the effectiveness of two induction chemotherapy regimens (cytarabine plus idarubicin [AI] versus cytarabine plus high-dose daunorubicin [AD]) in AML. The effectiveness will be evaluated in terms of complete remission (CR) rate.

Study Overview

• Status: Unknown
• Conditions: Acute Myelogenous Leukemia
• Intervention / Treatment: Drug: Cytarabine plus Daunorubicin [Arm II (AD regimen)]

Detailed Description

1. INDUCTION CHEMOTHERAPY

   • For patients randomized to receive Idarubicin (Arm I, AI regimen) will be given Cytarabine 200 mg/m2/day by continuous iv infusion over 24 hours daily for 7 days (D 1-7) along with Idarubicin 12 mg/m2/day iv daily for 3 days (D 1-3).
   • For patients randomized to receive Daunorubicin (Arm II, AD regimen) will be given Cytarabine 200 mg/m2/day by continuous iv infusion over 24 hours daily for 7 days (D 1-7) along with Daunorubicin 90 mg/m2/day iv daily for 3 days (D 1-3).

2. INTERIM BONE MARROW EXAMINATION

   • Bone marrow aspiration and biopsy will be done between 14 to 21 days after start of induction chemotherapy.
   • If the bone marrow is hypoplastic and contains no more than 5% blast cells, further chemotherapy will be deferred and the marrow examination will be repeated at the time of neutrophils over 1,000/mcL and platelets over 100,000/mcL in the peripheral blood for the evaluation of complete remission.
   • If more than 5% blast cells persist at interim or later repeated bone marrow examination, a course of re-induction chemotherapy will be given.

3. RE-INDUCTION CHEMOTHERAPY

   -Reinduction chemotherapy

   • Arm I (AI regimen) : Cytarabine 200 mg/m2/day by continuous iv infusion over 24 hours daily for 5 days (D 1-5) plus idarubicin 8 mg/m2/day iv daily for 2 days (D 1-2)
   • Arm II (AD regimen) : Cytarabine 200 mg/m2/day by continuous iv infusion over 24 hours daily for 5 days (D 1-5) plus Daunorubicin 45 mg/m2/day iv daily for 2 days (D 1-2) .Reinduction chemotherapy should be delayed if there is a significant infection or other co-morbid medical condition.
   • Patients who do not have a complete remission after a second course of induction chemotherapy will be removed from the study

4. POSTREMISSION CHEMOTHERAPY .The same postremission therapy will be given to the patients in both arms. .For patients with good- or intermediate-risk cytogenetic features or unknown cytogenetics (see appendix II), 4 courses of high-dose cytarabine will be given as post-remission therapy. Cytarabine 3 g/m2 will be administered in a 3-hour iv infusion every 12 hours on days 1, 3, and 5 (a total of six doses per course).

   .For patients with high-risk cytogenetic features (see appendix II), 4 courses of intermediate-dose Cytarabine plus Etoposide will be given as post-remission therapy. Cytarabine 1 g/m2 will be given in a 1-hour iv infusion on days 1 to 6 (a total of six doses per course) and Etoposide 150 mg/m2/day will be administered in a 5-hour iv infusion on days 1 to 3 (a total of three doses per course).

   .Sequential courses of postremission therapy will be given no sooner than every 28 days or 1 week after adequate marrow recovery.

   .Postremission chemotherapy should be delayed if there is a significant infection or other co-morbid medical condition.

   .One or two doses of Cytarabine can be omitted according to the attending physician's decision for the followings: .Marrow recovery requires more than 28 days.

   • A confluent maculopapular eruption or drug-induced desquamation
   • Photophobia or conjunctivitis unrelieved within 24 hours by ophthalmic steroid drops
   • More than 4 episodes of watery diarrhea per day
   • A fourfold increase in a previously normal serum aminotransferase or alkaline phosphatase level or a total bilirubin level exceeding 3.0 mg/dL .Treatment with high-dose cytarabine will be discontinued in patients with severe cerebellar ataxia, confusion, or other central nervous system signs thought to be unrelated to antiemetic medication.

5. EVALUATION DURING TREATMENT .During induction and consolidation chemotherapy: CBC with differentials (daily), chemical battery with electrolyte (twice a week), coagulation battery (once a week), chest x-ray (once a week).

   .Bone marrow examination will be repeated on day 15 of induction chemotherapy (for the evaluation of hypocellular marrow) and at the time of ANC ≥ 1,000/μl and platelets ≥ 100,000/μl in the peripheral blood (for the evaluation of complete remission). Chromosomal analysis will be repeated at the time of the evaluation of complete remission.

6. POST-TREATMENT FOLLOW-UP

   .After the completion of postremission treatment (i.e. following consolidation chemotherapy or HCT): CBC with differentials (monthly for the first 12 months, then every 2-3 months for the next 4 years), other studies such as MRD monitoring (as indicated)

7. TREATMENT EVALUATION *FFICACY EVALUATION

   • Complete remission (CR): Bone marrow blasts < 5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count > 1,000/mcL; platelet count > 100,000/mcL; independence of red cell transfusion (Döhner H et al, 2010).
   • All criteria need to be fulfilled; marrow evaluation should be based on a count of 200 nucleated cells in an aspirate with spicules; if ambiguous, consider repeat exam after 5 to 7 days; flow cytometric evaluation may help to distinguish between persistent leukemia and regenerating normal marrow; a marrow biopsy should be performed in cases of dry tap, or if no spicules are obtained; no minimum duration of response required.
   • CR with incomplete recovery (CRi): All CR criteria except for residual neutropenia (< 1,000/mcL) or thrombocytopenia (< 100,000/mcL).
   • Cause of treatment failure
   • Resistant disease (RD): Failure to achieve CR or CRi; only includes patients surviving ≥ 7 days following completion of initial treatment, with evidence of persistent leukemia by blood and/or bone marrow examination.
   • Death in aplasia: Deaths occurring ≥ 7 days following completion of initial treatment while cytopenic; with an aplastic or hypoplastic bone marrow obtained within 7 days of death, without evidence of persistent leukemia.
   • Death from indeterminate cause: Deaths occurring before completion of therapy, or < 7 days following its completion; or deaths occurring ≥ 7 days following completion of initial therapy with no blasts in the blood, but no bone marrow examination available.
   • Relapse: Bone marrow blasts ≥ 5%; or reappearance of blasts in the blood; or development of extramedullary disease.
   • In cases with low blast percentages (5-10%), a repeat marrow should be performed to confirm relapse. Appearance of new dysplastic changes should be closely monitored for emerging relapse. In a patient who has been recently treated, dysplasia or a transient increase in blasts may reflect a chemotherapy effect and recovery of hematopoiesis. Cytogenetics should be tested to distinguish true relapse from therapy-related MDS/AML.

• Study Type: Interventional
• Enrollment (Anticipated): 316
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Je-Hwan Lee, professor; Phone Number: 82-2-3010-3218; Email: jhlee3@amc.seoul.kr

Study Locations

• Korea, Republic of
  • Songpa-gu
    • Seoul, Songpa-gu, Korea, Republic of, 138-736
      • Recruiting
      • Asan Medical Center
      • Contact: Ye Eun Jang, nurse; Phone Number: 82-2-3010-6378; Email: redpin75@paran.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with previously-untreated acute myeloid leukemia (20% or more of blasts in bone marrow and/or blood; M6 subtype may have less than 20% of blasts.). Therapy-related leukemia or leukemia after myelodysplastic syndrome will be included.
• 15 years old or older, but 65 years or younger
• Adequate performance status (Karnofsky score of 50 or more)
• Adequate hepatic and renal function (AST, ALT, bilirubin and creatinine < 2.5 x upper normal limit). Elevation of AST or ALT due to hepatic infiltration of leukemic cells will be permitted.
• Adequate cardiac function (left ventricular ejection fraction of 45% or more on heart scan or echocardiogram)
• Signed and dated informed consent must be obtained

Exclusion Criteria:

• Patients with acute promyelocytic leukemia or bcr-abl gene rearrangement
• Patients with CNS leukemia
• Patients with primary granulocytic sarcoma without bone marrow involvement
• Prior chemotherapy for leukemia or anthracycline treatment for any malignancy. Hydroxyurea for reduction of leukemic cell burden before induction chemotherapy will be permitted.
• Presence of significant active infection
• Presence of uncontrolled bleeding
• Significant cardiovascular disease including myocardial infarction within previous 6 months
• Any coexisting major illness or organ failure
• Patients with psychiatric disorder or mental deficiency severe as to make compliance with the treatment unlike, and making informed consent impossible
• 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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (AI regimen); Cytarabine 200 mg/m2/day by continuous iv infusion over 24 hours daily for 7 days (D 1-7) plus Idarubicin 12 mg/m2/day iv daily for 3 days (D 1-3)	Drug: Cytarabine plus Daunorubicin [Arm II (AD regimen)]; Cytarabine 200 mg/m2/day by continuous iv infusion over 24 hours daily for 7 days (D 1-7) plus Daunorubicin 90 mg/m2/day iv daily for 3 days (D 1-3); Other Names: Cytarabine /Idarubicin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete remission rate	A complete remission will be defined as blasts of 5% or less in a normocellular bone marrow with neutrophils of 1,000/mcL or more and platelets of 100,000/mcL or more in the peripheral blood, the disappearance of all blasts in the peripheral blood, and no evidence of extramedullary leukemic cell infiltration	five years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of CR, relapse-free survival(RFS),event-free survival(EFS),Overall survival(OS)	This study will evaluate the impacts of induction chemotherapy regimen on duration of CR, relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS).; This study will also evaluate the clinical significance of genetic polymorphisms of drug-metabolizing enzymes and mutations of leukemia-related genes.	Five years

Collaborators and Investigators

• Sponsor: Cooperative Study Group A for Hematology
• Investigators: Principal Investigator: Je Hwan Lee, Professor, Asan Medical Center

Publications and helpful links

Helpful Links

• A prospective randomized comparison of idarubicin and high-dose daunorubicin in combination with cytarabine in the induction chemotherapy for acute myeloid leukemia

Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (Anticipated): April 1, 2012
• Study Completion (Anticipated): April 1, 2014

Study Registration Dates

• First Submitted: May 19, 2010
• First Submitted That Met QC Criteria: June 16, 2010
• First Posted (Estimate): June 17, 2010

Study Record Updates

• Last Update Posted (Estimate): June 17, 2010
• Last Update Submitted That Met QC Criteria: June 16, 2010
• Last Verified: June 1, 2010

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Cytarabine; Daunorubicin; Idarubicin
• Other Study ID Numbers: C-022