AIvsAD: Idarubicin Versus High Dose Daunorubicin in Acute Myelogenous Leukemia (AML)
Study Details
Study Description
Brief Summary
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.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 3 |
Detailed Description
- INDUCTION CHEMOTHERAPY
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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).
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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).
- INTERIM BONE MARROW EXAMINATION
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Bone marrow aspiration and biopsy will be done between 14 to 21 days after start of induction chemotherapy.
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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.
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If more than 5% blast cells persist at interim or later repeated bone marrow examination, a course of re-induction chemotherapy will be given.
- RE-INDUCTION CHEMOTHERAPY
-Reinduction chemotherapy
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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)
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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.
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Patients who do not have a complete remission after a second course of induction chemotherapy will be removed from the study
- 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.
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A confluent maculopapular eruption or drug-induced desquamation
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Photophobia or conjunctivitis unrelieved within 24 hours by ophthalmic steroid drops
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More than 4 episodes of watery diarrhea per day
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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.
- 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.
- 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)
- TREATMENT EVALUATION *FFICACY EVALUATION
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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).
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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.
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CR with incomplete recovery (CRi): All CR criteria except for residual neutropenia (< 1,000/mcL) or thrombocytopenia (< 100,000/mcL).
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Cause of treatment failure
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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.
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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.
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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.
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Relapse: Bone marrow blasts ≥ 5%; or reappearance of blasts in the blood; or development of extramedullary disease.
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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 Design
Arms and Interventions
Arm | Intervention/Treatment |
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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:
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Outcome Measures
Primary Outcome Measures
- Complete remission rate [five years]
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
Secondary Outcome Measures
- Duration of CR, relapse-free survival(RFS),event-free survival(EFS),Overall survival(OS) [Five years]
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.
Eligibility Criteria
Criteria
Inclusion Criteria:
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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.
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15 years old or older, but 65 years or younger
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Adequate performance status (Karnofsky score of 50 or more)
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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.
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Adequate cardiac function (left ventricular ejection fraction of 45% or more on heart scan or echocardiogram)
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Signed and dated informed consent must be obtained
Exclusion Criteria:
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Patients with acute promyelocytic leukemia or bcr-abl gene rearrangement
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Patients with CNS leukemia
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Patients with primary granulocytic sarcoma without bone marrow involvement
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Prior chemotherapy for leukemia or anthracycline treatment for any malignancy. Hydroxyurea for reduction of leukemic cell burden before induction chemotherapy will be permitted.
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Presence of significant active infection
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Presence of uncontrolled bleeding
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Significant cardiovascular disease including myocardial infarction within previous 6 months
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Any coexisting major illness or organ failure
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Patients with psychiatric disorder or mental deficiency severe as to make compliance with the treatment unlike, and making informed consent impossible
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Nursing women, pregnant women, women of childbearing potential who do not want adequate contraception
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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)
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Asan Medical Center | Seoul | Songpa-gu | Korea, Republic of | 138-736 |
Sponsors and Collaborators
- Cooperative Study Group A for Hematology
Investigators
- Principal Investigator: Je Hwan Lee, Professor, Asan Medical Center
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- C-022