Idarubicin, Cytarabine, and Gemtuzumab Ozogamicin in Treating Patients With Previously Untreated High-Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia Secondary to Myelodysplastic Syndrome

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as idarubicin and cytarabine, work in different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies, such as gemtuzumab ozogamicin, can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Giving monoclonal antibody therapy together with chemotherapy may kill more cancer cells. Giving healthy stem cells from a donor whose blood closely resembles the patient's blood will help the patient's bone marrow make new stem cells that become red blood cells, white blood cells, and platelets. PURPOSE: This phase II trial is studying how well giving idarubicin and cytarabine together with gemtuzumab ozogamicin works in treating patients with previously untreated high-risk myelodysplastic syndrome or acute myeloid leukemia secondary to myelodysplastic syndrome.

Detailed Description
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OBJECTIVES: Primary Determine the feasibility of combining gemtuzumab ozogamicin with idarubicin and cytarabine with or without cyclophosphamide with total body irradiation vs busulfan followed by allogeneic stem cell transplantation in patients with previously untreated high-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia secondary to MDS. Determine the toxicity profile of this regimen in these patients. Determine the antileukemic/anti-MDS activity of this regimen in these patients. Secondary Determine the hepatotoxicity of this regimen, in terms of veno-occlusive disease, in these patients. Determine the severity of pancytopenia and duration of recovery in patients treated with this regimen. OUTLINE: This is a multicenter study. Patients are assigned to 1 of 2 treatment groups. Group 1 (for patients with no HLA-matched sibling donor): Patients receive remission-induction chemotherapy comprising idarubicin IV over 5 minutes on days 1, 3, and 5; cytarabine IV continuously over 24 hours on days 1-10; and gemtuzumab ozogamicin IV over 2 hours on day 7. Treatment continues for a second course in the absence of unacceptable toxicity. Group 2 (for patients with an HLA-matched sibling donor): Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive myeloablative consolidation chemotherapy comprising cyclophosphamide on days -6 and -5 and total body irradiation twice daily on days -4 to -2. Arm II: Patients receive myeloablative consolidation chemotherapy comprising busulfan on days -8 to -5 and cyclophosphamide on days -4 and -3. Patients in both arms may alternatively undergo T-cell depletion and/or a reduced-intensity conditioning regimen. Approximately 4-8 weeks after completion of consolidation chemotherapy, all patients in group 2 undergo allogeneic bone marrow transplantation or allogeneic peripheral blood stem cell transplantation. Patients in group 2 then proceed to remission-induction chemotherapy as in group 1. Patients achieving complete remission are recommended for consolidation therapy off study. Patients are followed monthly for 6 months, every 2 months for 6 months, and then every 3 months thereafter. PROJECTED ACCRUAL: A total of 28 patients will be accrued for this study within 10 months.

Official Title
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Idarubicin and Ara-C in Combination With Gemtuzumab-Ozogamicin (IAGO) for Young Untreated Patients, Without an HLA Identical Sibling, With High Risk MDS or AML Developing After a Preceding Period With MDS During 6 Months Duration: A Phase II Study

Conditions
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Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: busulfan
* Drug: cyclophosphamide
* Drug: cytarabine
* Drug: gemtuzumab ozogamicin
* Drug: idarubicin
* Procedure: allogeneic bone marrow transplantation
* Procedure: peripheral blood stem cell transplantation
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed diagnosis of 1 of the following: High-risk myelodysplastic syndromes (MDS), including any of the following: Refractory anemia with excess blasts (RAEB) with > 10% blast cells in the bone marrow RAEB in transformation Other forms of MDS with multiple (3 or more) chromosomal abnormalities or chromosome 7 abnormalities AND/OR profound cytopenias, defined as neutrophil count < 500/mm^3 and/or platelet count < 20,000/mm^3 Chronic myelomonocytic leukemia with > 5% blast cells in the bone marrow Chronic myelomonocytic leukemia with neutrophil count > 16,000/mm^3 OR monocyte count > 2,600/mm^3 Secondary acute myeloid leukemia supervening after overt MDS of more than 6 months in duration Patients with or without an HLA-identical sibling No active CNS leukemia PATIENT CHARACTERISTICS: Age 16 to 70 Performance status WHO 0-2 Life expectancy Not specified Hematopoietic See Disease Characteristics Hepatic Bilirubin ≤ 1.5 times upper limit of normal (ULN) Renal Creatinine ≤ 1.5 times ULN Cardiovascular No severe cardiovascular disease No arrhythmias requiring chronic treatment No congestive heart failure No symptomatic ischemic heart disease Pulmonary No severe lung disease Other Not pregnant or nursing Fertile patients must use effective contraception No HIV positivity No other concurrent malignant disease No active uncontrolled infection No history of alcohol abuse (i.e., averaged less than 5 alcoholic consumptions daily for the past year) No concurrent severe neurological or psychiatric disease No other psychological, familial, sociological, or geographical condition that would preclude study compliance PRIOR CONCURRENT THERAPY: Biologic therapy More than 6 weeks since prior growth factors Chemotherapy No prior intensive chemotherapy More than 6 weeks since prior low-dose chemotherapy or hydroxyurea Endocrine therapy Not specified Radiotherapy Not specified Surgery Not specified Other More than 6 weeks since prior immunosuppressants No prior participation in this clinical study

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: busulfan|nan|
|Drug: cyclophosphamide|nan|
|Drug: cytarabine|nan|
|Drug: gemtuzumab ozogamicin|nan|
|Drug: idarubicin|nan|
|Procedure: allogeneic bone marrow transplantation|nan|
|Procedure: peripheral blood stem cell transplantation|nan|
|Radiation: radiation therapy|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of complete remission (CR) or complete remission with incomplete recovery of platelets (CRp) as measured by Cheson response criteria after the start of treatment |  |  | 
| Severe toxicity after the start of treatment |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival from CR/CRp |  |  | 
| Duration of overall survival |  |  | 
| Severity of pancytopenia and duration of recovery in patients who reached CR/CRp after the start of treatment |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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untreated adult acute myeloid leukemia, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, chronic myelomonocytic leukemia, de novo myelodysplastic syndromes, secondary myelodysplastic syndromes, adult acute myeloid leukemia with t(8;21)(q22;q22), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with t(15;17)(q22;q12), childhood myelodysplastic syndromes