Treatment of Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplasia

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier:
NCT00136084
First received: August 24, 2005
Last updated: November 2, 2012
Last verified: November 2012
Results First Received: March 5, 2010  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Leukemia, Myelocytic, Acute
Interventions: Drug: Cladribine, Cyclophosphamide, Cytarabine, Daunorubicin, Dexamethasone
Drug: Etoposide, Cytarabine, Gemtuzumab, L-asparaginase, Mercaptopurine, methotrexate, Mitoxantrone, Prednisone, Vincristine

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
238 patients were recruited between October, 2002 and June, 2008.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
238 patients were enrolled on the study. This report is based on results for 223 patients. 15 patients were excluded for the following reasons: 7 were switched to lymphoid-directed therapy shortly after enrollment, 6 were determined to be ineligible shortly after enrollment (wrong diagnosis), and 2 were not randomized.

Reporting Groups
  Description
Arm 1: (HDAC) High-dose Cytarabine (HDAC)
Arm 2:(LDAC) Low-dose Cytarabine (LDAC)

Participant Flow:   Overall Study
    Arm 1: (HDAC)     Arm 2:(LDAC)  
STARTED     109     114  
COMPLETED     61     72  
NOT COMPLETED     48     42  
Death                 12                 5  
Unacceptable toxicity                 8                 11  
Relapse                 20                 23  
Lost to Follow-up                 2                 0  
No Response                 1                 2  
Withdrawal by Subject                 5                 1  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Arm 1: (HDAC) High-dose Cytarabine (HDAC)
Arm 2:(LDAC) Low-dose Cytarabine (LDAC)
Total Total of all reporting groups

Baseline Measures
    Arm 1: (HDAC)     Arm 2:(LDAC)     Total  
Number of Participants  
[units: participants]
  109     114     223  
Age  
[units: years]
Mean ± Standard Deviation
  8.57  ± 6.08     8.48  ± 6.32     8.49  ± 6.19  
Gender  
[units: participants]
     
Female     50     48     98  
Male     59     66     125  



  Outcome Measures
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1.  Primary:   Minimal Residual Disease (MRD).   [ Time Frame: Day 22 MRD measurement ]

Measure Type Primary
Measure Title Minimal Residual Disease (MRD).
Measure Description Detection of Minimal Residual Disease following one course of chemotherapy where positive MRD was defined as one or more leukemic cell per 1000 mononuclear bone-marrow cells (>=0.1%).
Time Frame Day 22 MRD measurement  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Of the 223 randomized patients, 205 patients were included in the day 22 MRD analysis. 18 patients were not included in the day 22 MRD analysis. 5 patients had inadequate sample for MRD, 11 patients had no suitable phenotype to determine MRD, 1 patient was not done on MRD, and 1 patient was lost for follow-up.

Reporting Groups
  Description
Arm 1: (HDAC) High-dose Cytarabine (HDAC)
Arm 2:(LDAC) Low-dose Cytarabine (LDAC)

Measured Values
    Arm 1: (HDAC)     Arm 2:(LDAC)  
Number of Participants Analyzed  
[units: participants]
  99     106  
Minimal Residual Disease (MRD).  
[units: participants]
   
MRD Positive     31     43  
MRD Negative     68     63  


Statistical Analysis 1 for Minimal Residual Disease (MRD).
Groups [1] All groups
Method [2] Cochran-Mantel-Haenszel
P Value [3] .1559
Odds Ratio (OR) [4] 1.624
95% Confidence Interval ( .832 to 3.205 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The study was designed to test the null hypothesis that HDAC and LDAC result in the same proportion of patients with positive MRD after 22 days. Power calculations indicate that enrollment of a total of 186 MRD-evaluable patients in a 5-stage O’Brien-Fleming group sequential design gives 80% power at the 5% level to detect a change in the MRD-positive proportion from 0.50 to 0.30. The design was developed using East statistical software.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The p-value was computed using a Monte Carlo approximation (10000 permutations) to an exact, risk-group stratified, test.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  The p-value is not adjusted for multiple comparisons. The a priori threshold for statistical significance is 0.041 so that the overall level of the study is maintained at 0.05 across the 4 interim analyses and the final analysis.
[4] Other relevant estimation information:
  The odds ratio is defined as the ratio of the odds that a LDAC patient is MRD positive to the odds that a HDAC patient is MRD positive.



2.  Secondary:   Proportion of Minimal Residual Disease (MRD)+ Patients Who Become MRD- After One Course of Gemtuzumab Ozogamicin (GO)   [ Time Frame: Consolidation I ]

Measure Type Secondary
Measure Title Proportion of Minimal Residual Disease (MRD)+ Patients Who Become MRD- After One Course of Gemtuzumab Ozogamicin (GO)
Measure Description To estimate the proportion of minimal residual disease (MRD)+ patients who become MRD- after one course of gemtuzumab ozogamicin (GO)
Time Frame Consolidation I  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Sixteen patients received GO treatment during consolidation I. One patient with negative MRD received GO treatment, which was not consistent with the protocol definition. 15 patients were analyzed. Out of the 15 patients, 7 patients were treated on HDAC arm and 8 patients were treated on LDAC arm.

Reporting Groups
  Description
Overall Post-GO Treatment MRD

Measured Values
    Overall  
Number of Participants Analyzed  
[units: participants]
  15  
Proportion of Minimal Residual Disease (MRD)+ Patients Who Become MRD- After One Course of Gemtuzumab Ozogamicin (GO)  
[units: Participants]
 
Negative     11  
Positive     4  


Statistical Analysis 1 for Proportion of Minimal Residual Disease (MRD)+ Patients Who Become MRD- After One Course of Gemtuzumab Ozogamicin (GO)
Groups [1] Overall
Method [2] Binomial proportion
Binomial proportion [3] .733
95% Confidence Interval ( .449 to .922 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Estimate of the proportion of negative minimal residual disease.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.



3.  Secondary:   Proportion of MRD Reduction After One Course of Cytarabine + Daunomycin + Etoposide (ADE) + GO   [ Time Frame: Induction II ]

Measure Type Secondary
Measure Title Proportion of MRD Reduction After One Course of Cytarabine + Daunomycin + Etoposide (ADE) + GO
Measure Description To estimate proportion of patients with MRD reduction after one course of Induction II (cytarabine + daunomycin + etoposide (ADE) + GO), who had no response to first course of induction therapy.
Time Frame Induction II  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Out of the 30 patients received ADE + GO treatment, one patient had inevaluable MRD prior to and after the treatment. 29 patients were analyzed. Out of the 29 patients, 10 patients were treated on HDAC arm and 19 patients were treated on LDAC arm.

Reporting Groups
  Description
Overall Patients who have no response to one course of induction therapy

Measured Values
    Overall  
Number of Participants Analyzed  
[units: participants]
  29  
Proportion of MRD Reduction After One Course of Cytarabine + Daunomycin + Etoposide (ADE) + GO  
[units: Participants]
 
Decrease     27  
Increase or no change     2  


Statistical Analysis 1 for Proportion of MRD Reduction After One Course of Cytarabine + Daunomycin + Etoposide (ADE) + GO
Groups [1] Overall
Method [2] Binomial proportion
Binomial proportion [3] .931
95% Confidence Interval ( .772 to .992 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.



4.  Secondary:   Proportion of Patients Experienced Toxicity of Cytarabine + Daunomycin + Etoposide (ADE) + GO.   [ Time Frame: Induction II ]

Measure Type Secondary
Measure Title Proportion of Patients Experienced Toxicity of Cytarabine + Daunomycin + Etoposide (ADE) + GO.
Measure Description To estimate proportion of patients experiencing CTC Grade 3 or 4 toxicity during Induction II (Cytarabine + Daunomycin + Etoposide (ADE) + GO), who had no response to first course of induction therapy
Time Frame Induction II  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
30 patients received ADE + GO during induction II and were analyzed. Out of the 30 patients, 11 patients were treated on HDAC arm, and 19 patients were treated on LDAC arm.

Reporting Groups
  Description
Overall Post-GO Treatment MRD

Measured Values
    Overall  
Number of Participants Analyzed  
[units: participants]
  30  
Proportion of Patients Experienced Toxicity of Cytarabine + Daunomycin + Etoposide (ADE) + GO.  
[units: Participants]
 
Experienced Grade 3 or 4 toxicities     27  
Did not experience Grade 3 or 4 toxicities     3  


Statistical Analysis 1 for Proportion of Patients Experienced Toxicity of Cytarabine + Daunomycin + Etoposide (ADE) + GO.
Groups [1] Overall
Method [2] Binomial proportion
Binomial proportion [3] .9
95% Confidence Interval ( .735 to .979 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.



5.  Secondary:   To Estimate the Overall Event-free Survival (EFS) of AML Patients Who Undergo Risk-adapted and Genotype-directed Therapy   [ Time Frame: Five Year ]

Measure Type Secondary
Measure Title To Estimate the Overall Event-free Survival (EFS) of AML Patients Who Undergo Risk-adapted and Genotype-directed Therapy
Measure Description Overall event-free survival (EFS) was defined as the time from study enrollment to induction failure, relapse, secondary malignancy, death, or study withdrawal for any reason, with event-free patients censored on the date of the last follow-up
Time Frame Five Year  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
238 patients were enrolled on the study. Out of 238, 6 were determined to be ineligible and 2 were not randomized. Of the 230 patients, 14 bi-phenotypic leukemia patients were excluded. 216 AML patients were included to estimate EFS.

Reporting Groups
  Description
Overall Evaluation of all study participants

Measured Values
    Overall  
Number of Participants Analyzed  
[units: participants]
  216  
To Estimate the Overall Event-free Survival (EFS) of AML Patients Who Undergo Risk-adapted and Genotype-directed Therapy  
[units: Percentage of Participants]
  62.4  

No statistical analysis provided for To Estimate the Overall Event-free Survival (EFS) of AML Patients Who Undergo Risk-adapted and Genotype-directed Therapy



6.  Secondary:   To Assess Whether Inhibition of DNA Synthesis is Greater After High-dose Ara-C (HDAC) Than After Low-dose Ara-C (LDAC) Therapy   [ Time Frame: Measurements were assessed in Induction I chemotherapy ]

Measure Type Secondary
Measure Title To Assess Whether Inhibition of DNA Synthesis is Greater After High-dose Ara-C (HDAC) Than After Low-dose Ara-C (LDAC) Therapy
Measure Description Inhibition of DNA synthesis is defined as the percentage of DNA synthesis rate at 24-hour post-araC treatment over DNA synthesis rate pre-araC treatment.
Time Frame Measurements were assessed in Induction I chemotherapy  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Of 232 eligible patients, 49 had DNA synthesis rate performed prior to araC treatment. Of the 49 patients, 23 had no 24-hr samples and 3 did not have enough cells in 24-hr samples. 21 patients with both pre and post araC samples were included in the DNA inhibition study. Of the 21 patients, 9 were treated on HDAC and 12 were treated on LDAC.

Reporting Groups
  Description
Arm 1: (HDAC) High-dose Cytarabine (Ara-C) (HDAC)
Arm 2:(LDAC) Low-dose Cytarabine (Ara-C) (LDAC)

Measured Values
    Arm 1: (HDAC)     Arm 2:(LDAC)  
Number of Participants Analyzed  
[units: participants]
  9     12  
To Assess Whether Inhibition of DNA Synthesis is Greater After High-dose Ara-C (HDAC) Than After Low-dose Ara-C (LDAC) Therapy  
[units: Percent Inhibition of DNA Synthesis]
Mean ± Standard Error
  60.6  ± 16.0     72.8  ± 15.6  


Statistical Analysis 1 for To Assess Whether Inhibition of DNA Synthesis is Greater After High-dose Ara-C (HDAC) Than After Low-dose Ara-C (LDAC) Therapy
Groups [1] All groups
Method [2] t-test, 2 sided
P Value [3] 0.60
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.



7.  Secondary:   Relationship of Inhibition of DNA Synthesis and Clinical Response   [ Time Frame: Measurements were assessed in Induction I chemotherapy ]

Measure Type Secondary
Measure Title Relationship of Inhibition of DNA Synthesis and Clinical Response
Measure Description Clinical response is defined as MRD (minimal residual disease) measured by flow cytometry at day 22. The MRD at day 22 is classified as positive (with MRD) or negative (no detectable MRD). The relation between inhibition of DNA synthesis and MRD was performed by logistic regression. In the model, logit of probability of MRD positive was regressed on inhibition of DNA synthesis.
Time Frame Measurements were assessed in Induction I chemotherapy  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Of 232 eligible patients, 49 had DNA synthesis rate performed prior to araC treatment. Of the 49 patients, 23 had no 24-hr samples and 3 did not have enough cells in 24-hr samples. 21 patients with both pre and post araC samples were included in the DNA inhibition study. 17 of the 21 patients had evaluable day 22 MRD.

Reporting Groups
  Description
Overall 17 of the 232 eligible patients

Measured Values
    Overall  
Number of Participants Analyzed  
[units: participants]
  17  
Relationship of Inhibition of DNA Synthesis and Clinical Response  
[units: Percent inhibition of DNA Synthesis]
Mean ± Standard Error
  66.7  ± 12.6  


Statistical Analysis 1 for Relationship of Inhibition of DNA Synthesis and Clinical Response
Groups [1] Overall
Method [2] Regression, Logistic
P Value [3] 0.2287
Odds Ratio, log [4] -0.0139
95% Confidence Interval ( -0.0365 to 0.00873 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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