Cytarabine and Daunorubicin With or Without Gemtuzumab Ozogamicin in Treating Older Patients With Acute Myeloid Leukemia or Myelodysplastic Syndromes

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy, such as cytarabine and daunorubicin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as gemtuzumab ozogamicin, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. It is not yet known whether cytarabine and daunorubicin followed by gemtuzumab ozogamicin is more effective than cytarabine and daunorubicin in treating acute myeloid leukemia or myelodysplastic syndromes. PURPOSE: This randomized phase III trial is studying cytarabine and two different doses of daunorubicin to see how well they work compared to cytarabine and daunorubicin followed by gemtuzumab ozogamicin in treating older patients with acute myeloid leukemia or myelodysplastic syndromes.

Detailed Description
-----------------
OBJECTIVES: Primary Compare the event-free and disease-free survival of older patients with acute myeloid leukemia, refractory anemia with excess blasts (RAEB), or RAEB in transformation treated with induction therapy comprising cytarabine in combination with two different doses of daunorubicin followed by cytarabine alone with or without post-induction therapy comprising gemtuzumab ozogamicin. Secondary Compare the complete remission rate in patients treated with these regimens. Compare the overall survival of patients treated with these regimens. Compare the toxicity of these regimens in these patients. Determine the probability of relapse and death during first complete remission in patients treated with post-induction gemtuzumab ozogamicin. Correlate prognostic factors (e.g., CD33 positivity, multidrug resistance phenotype, or cytogenetics) with probability of complete remission and overall, event-free, and disease-free survival of patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center and diagnosis (acute myeloid leukemia [AML] vs myelodysplastic syndromes [MDS]) for induction therapy. Patients are stratified according to participating center, diagnosis (AML vs MDS), induction treatment arm (I vs II), and response to induction therapy (complete remission [CR] vs no CR) for post-induction therapy. Induction therapy (course 1): Patients are randomized to 1 of 2 induction treatment arms. Arm I: Patients receive cytarabine IV continuously on days 1-7 and daunorubicin IV over 3 hours on days 1-3. Arm II: Patients receive cytarabine as in arm I and daunorubicin as in arm I but at a higher dose. Approximately 28-35 days after the start of course 1 (or sooner if the bone marrow shows evidence of resistant disease), patients in both arms proceed to course 2 of induction therapy. Induction therapy (course 2): All patients receive cytarabine IV over 6 hours twice daily on days 1-6. After completion of course 2, patients undergo assessment of remission status. Patients who do not achieve CR are removed from the study. Patients achieving CR proceed to post-induction therapy and undergo a second randomization. Post-induction therapy: Patients are randomized to 1 of 2 post-induction treatment arms. Arm I: Patients receive no further chemotherapy. Arm II: Patients receive gemtuzumab ozogamicin IV over 2 hours on days 1, 29, and 57 in the absence of disease relapse or unacceptable toxicity. After completion of study treatment, patients are followed monthly for 1 year, every 3 months for 2 years, every 4-6 months for 2 years, and then periodically thereafter. PROJECTED ACCRUAL: A total of 600 patients will be accrued for this study within 4-5 years.

Official Title
-----------------
Randomised Induction and Post Induction Therapy in Older Patients (≥61 Years of Age) With Acute Myeloid Leukemia (AML) and Refractory Anemia With Excess Blasts (RAEB, RAEB-t)

Conditions
-----------------
Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
-----------------
* Drug: cytarabine
* Drug: daunorubicin hydrochloride
* Drug: gemtuzumab ozogamicin


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically or cytologically confirmed diagnosis of 1 of the following: Acute myeloid leukemia (AML) M0-M2 or M4-M7 FAB subtype No AML with cytogenetic abnormality t(15;17) (M3) Patients with secondary AML progressing from prior myelodysplasia* or biphenotypic leukemia are eligible Refractory anemia with excess blasts (RAEB) or RAEB in transformation International Prognostic Scoring System score ≥ 1.5 NOTE: *Any prior hematological disease of ≥ 4 months duration No chronic myelogenous leukemia in blastic crisis No prior polycythemia rubra vera No primary myelofibrosis PATIENT CHARACTERISTICS: Age 61 and over Performance status WHO 0-2 Life expectancy Not specified Hematopoietic Not specified Hepatic ALT and/or AST ≤ 2.5 times upper limit of normal (ULN)* Bilirubin ≤ 2 times ULN* NOTE: *Unless elevation is caused by organ infiltration by AML Renal Creatinine ≤ 2 times ULN* NOTE: *Unless elevation is caused by organ infiltration by AML Cardiovascular No myocardial infarction within the past 6 months LVEF > 50% by MUGA, echocardiogram, or other methods No unstable angina No unstable cardiac arrhythmia No severe and/or uncontrolled hypertension Other No uncontrolled diabetes No severe and/or uncontrolled infection No other severe and/or uncontrolled medical condition PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy More than 6 months since prior chemotherapy Endocrine therapy Not specified Radiotherapy Not specified Surgery Not specified Other No prior induction therapy for AML or myelodysplastic syndromes

Ages Eligible for Study
-----------------
Minimum Age: 61 Years
Maximum Age: 120 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 |
| --- | --- |
| Active Comparator: Arm A low dose Dauno<br>Induction 45 mg Dauno | Drug: cytarabine<br> <br> Drug: daunorubicin hydrochloride<br> <br> |
| Experimental: ARM B high dose Dauno<br>Induction 90 mg Dauno | Drug: cytarabine<br> <br> Drug: daunorubicin hydrochloride<br> <br> |
| No Intervention: Arm 1 no further treatment<br> | |
| Experimental: Arm 2 Mylotarg<br>Post induction treatment with Mylotarg | Drug: gemtuzumab ozogamicin<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival after induction therapy |  |  | 
| Disease-free survival after maintenance therapy |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete remission (CR) rate after induction therapy |  |  | 
| Overall survival after induction therapy |  |  | 
| Toxicity after induction therapy |  |  | 
| Toxicity after maintenance therapy |  |  | 
| Probability of relapse and death in first CR after maintenance therapy |  |  | 
| Overall survival after maintenance therapy |  |  | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
adult acute monocytic leukemia (M5b), adult erythroleukemia (M6a), adult pure erythroid leukemia (M6b), adult acute megakaryoblastic leukemia (M7), adult acute myeloblastic leukemia with maturation (M2), adult acute myeloblastic leukemia without maturation (M1), adult acute myelomonocytic leukemia (M4), adult acute monoblastic leukemia (M5a), refractory anemia with excess blasts in transformation, refractory anemia with excess blasts, secondary acute myeloid leukemia, untreated adult acute myeloid leukemia, de novo myelodysplastic syndromes, adult acute minimally differentiated myeloid leukemia (M0), adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), secondary myelodysplastic syndromes