Alvocidib, Cytarabine, and Mitoxantrone Hydrochloride or Cytarabine and Daunorubicin Hydrochloride in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

• Complete response rate [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  The final analysis will be by Fisher's exact test.
  
  

• Incidence of toxicities, characterized as percentages by treatment and grade [ Time Frame: Up to 14 days after completion of study treatment ] [ Designated as safety issue: Yes ]
  
• Disease-free survival [ Time Frame: Time from randomization until death from any cause or relapse or recurrence, assessed up to 5 years ] [ Designated as safety issue: No ]
  Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated.
  
  
• Overall survival [ Time Frame: From time of enrollment until time of death, assessed up to 5 years ] [ Designated as safety issue: No ]
  Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated.
  
  
• Progression-free survival [ Time Frame: Time from study entry to the first date that recurrent or progressive disease is objectively documented, or death from any cause occurs, assessed up to 5 years ] [ Designated as safety issue: No ]
  Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated.
  
  
• Proportion of patients with minimal residual disease [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  Comparisons of the treatments with respect to MRD will be based on the proportion of patients with MRD at each time point (e.g., day 14, recovery from induction but before beginning course 2, etc.).
  
  

PRIMARY OBJECTIVES:

I. To compare the rate of complete remission (CR) after 1 course of induction therapy with the timed-sequential combination of alvocidib (flavopiridol), cytarabine (cytosine arabinoside [ara-C]), and mitoxantrone hydrochloride (FLAM) vs traditional "7+3" cytarabine and daunorubicin hydrochloride (ara-C + Daunorubicin) for adults (age 18 to 70) with newly diagnosed, previously untreated, intermediate-risk or poor-risk acute myelogenous leukemia (AML).

SECONDARY OBJECTIVES:

I. To evaluate and compare the toxicities of FLAM vs 7+3.To compare the 2-year disease-free survival (DFS) and overall survival (OS) in response to FLAM vs 7+3.

II. To detect and compare the presence of minimal-residual disease (MRD) remaining after FLAM vs 7+3.

III. To determine the expression of ABC transport proteins multidrug resistance 1 (MDR1, ABCB1) and breast cancer resistance protein (BCRP, ABCG2) on AML blasts pretreatment and correlate the expressions of one or both proteins with CR and DFS in response to FLAM vs 7+3.

OUTLINE: This is a multicenter study. Patients are stratified according to risk features: age (< 50 vs ≥ 50), secondary AML (pre-existing MDS, MPD, t-AML, or severe multi-lineage dysplasia) and/or known adverse cytogenetics, and hyperleukocytosis (WBC ≥ 50,000/mm³). Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive alvocidib IV over 1 hour on days 1-3, cytarabine IV over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9. Patients who achieve complete or partial response to the first course (completion of all doses) may receive a second course of treatment or high-dose cytarabine after 21-63 days following blood count recovery, and/or undergo allogeneic bone marrow transplant.

ARM II: Patients receive cytarabine IV continuously on days 1-7 and daunorubicin hydrochloride IV on days 1-3. Patients who have residual disease on day 14 may receive additional cytarabine for 5 days and daunorubicin hydrochloride for 2 days. Patients may undergo blood and bone marrow collection for correlative studies.

After completion of study therapy, patients are followed up every 3 months for 2 years, every 6 months for 5 years, and then annually thereafter.