Decitabine as Maintenance Therapy After Standard Therapy in Treating Patients With Previously Untreated Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This phase II trial is studying the side effects and how well decitabine works when given as maintenance therapy after standard therapy in treating patients with previously untreated acute myeloid leukemia. Drugs used in chemotherapy, such as cytarabine, daunorubicin, etoposide, busulfan, and decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving decitabine as maintenance therapy after standard therapy may keep cancer cells from coming back.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the efficacy, feasibility, and toxicities when one year of maintenance therapy with decitabine is given to patients < 60 years with untreated acute myeloid leukemia (AML) who achieve and maintain first complete remission (CR) following an established induction and intensification regimen. II. To determine the 1-year disease free survival rate for AML patients in first CR treated with maintenance decitabine. SECONDARY OBJECTIVES: I. To measure biologic response to decitabine in evaluable patients with fusion genes to determine eradication of minimal residual disease. II. To measure surrogates for deoxyribonucleic acid (DNA) demethylation including downregulation of DNA methyltransferase 1 (DNMT1) and induction of fetal hemoglobin. III. To examine the significance of gene re expression following ex vivo decitabine exposure in primary AML cells taken at the time of diagnosis on clinical outcome and on gene expression at the time of relapse after in vivo decitabine exposure. IV. To continue to evaluate the effectiveness of a cytogenetically risk-adapted approach for consolidation therapy for patients with core binding factor (CBF) or non-CBF AML. V. To continue the investigation begun in Cancer and Leukemia Group B (CALGB) 19808 aimed at correlation of the rate of relapse and toxicity with intravenous (IV) busulfan pharmacokinetics when busulfan and etoposide are used as the preparative regimen for autologous stem cell transplantation for AML patients in first CR. VI. To correlate outcome measures such as complete response (CR), disease-free survival (DFS), event-free survival (EFS), and overall survival (OS), with pretreatment characteristics such as age, sex, race, blood counts, morphology, immunophenotype, cytogenetics, and molecular features of AML. OUTLINE: REMISSION INDUCTION THERAPY: Patients receive cytarabine IV over 168 hours on days 1-7 and daunorubicin hydrochloride IV over 5-10 minutes and etoposide IV over 2 hours on days 1-3. Patients undergo bone marrow biopsy on day 14. Patients with residual leukemia proceed to second remission induction therapy. Patients achieving complete remission (CR) proceed to intensification therapy. SECOND REMISSION INDUCTION THERAPY: Patients receive cytarabine IV over 120 hours on days 1-5 and daunorubicin hydrochloride IV and etoposide IV over 2 hours on days 1 and 2. Patients undergo bone marrow biopsy on day 42. Patients with residual leukemia are removed from the study. Patients achieving CR proceed to intensification therapy. INTENSIFICATION THERAPY: Patients are stratified and receive intensification therapy according to cytogenetic findings (favorable cytogenetics [t(8;21)(q22q22), inv(16)(p13;q22), or t(16;16)(p13;q22) by cytogenetic and/or molecular analysis] vs unfavorable cytogenetics [all other cytogenetic findings, including normal cytogenetics]). FAVORABLE CYTOGENETICS: Within 2-4 weeks after achieving CR, patients receive high-dose cytarabine IV over 3 hours twice daily on days 1, 3, and 5. Treatment repeats every 28 days for up to 3 courses. UNFAVORABLE CYTOGENETICS: Peripheral blood stem cell (PBSC) mobilization: Within 2-4 weeks after achieving CR, patients receive etoposide IV over 96 hours and high-dose cytarabine IV over 2 hours twice daily on days 1-4 and filgrastim (G-CSF) subcutaneously (SC) once daily beginning on day 14 and continuing until blood counts recover. Patients then proceed to transplantation. PBSC OR BONE MARROW TRANSPLANTATION: Patients receive busulfan IV over 2 hours 4 times daily on days -7 to -4 and etoposide IV over 4 hours on day -3. Patients undergo autologous PBSC or bone marrow transplantation on day 0 and receive G-CSF SC once daily beginning on day 0 and continuing until blood counts recover. UNFAVORABLE CYTOGENETICS AND UNABLE TO UNDERGO PBSC TRANSPLANTATION: Within 2-4 weeks after achieving CR, patients receive etoposide, high-dose cytarabine, and G-CSF as in unfavorable cytogenetics (PBSC mobilization) followed by 2 courses of high-dose cytarabine as in favorable genetics. MAINTENANCE THERAPY: Within 60-90 days after completion of intensification therapy, patients receive decitabine IV over 1 hour on days 1-5. Treatment repeats every 6 weeks for up to 8 courses. After completion of study treatment, patients are followed up every 2 months for 1 year, every 6 months for 2 years, and then yearly for 2 years.

Official Title
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Phase II Study of Maintenance Therapy With Decitabine (NSC #127716) Following Standard Induction and Cytogenetic Risk-Adapted Intensification in Previously Untreated Patients With AML &lt; 60 Years

Conditions
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Acute Myeloid Leukemia, Acute Myeloid Leukemia With Myelodysplasia-Related Changes, Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11, Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11, Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1, Adult Acute Myeloid Leukemia With t(9;11)(p22.3;q23.3); MLLT3-KMT2A, Untreated Adult Acute Myeloid Leukemia

Intervention / Treatment
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* Procedure: Autologous Bone Marrow Transplantation
* Procedure: Autologous Hematopoietic Stem Cell Transplantation
* Drug: Busulfan
* Drug: Cytarabine
* Drug: Daunorubicin Hydrochloride
* Drug: Decitabine
* Drug: Etoposide
* Biological: Filgrastim
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Unequivocal histologic diagnosis of AML (> 20% blasts in the bone marrow based on the World Health Organization [WHO] and/or French American British [FAB] classifications), excluding M3 (acute promyelocytic leukemia); patients with antecedent myelodysplasia are eligible for treatment on this trial only if there were no bone marrow biopsy showing myelodysplastic syndrome (MDS) > 3 months prior to enrollment; patients with therapy-related AML are eligible if they have been free of their primary disease and have not received any chemotherapy for at least 2 years No prior 5-azacitidine or decitabine therapy No prior treatment for leukemia or myelodysplastic syndrome with four permissible exceptions: Emergency leukapheresis Emergency treatment for hyperleukocytosis with hydroxyurea Cranial radiation therapy (RT) for central nervous system (CNS) leukostasis (one dose only) Growth factor/cytokine support

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 59 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (chemotherapy, PBSC or bone marrow transplantation)<br>See Detailed Description. | Procedure: Autologous Bone Marrow Transplantation<br>* Undergo autologous bone marrow transplantation<br>* Other names: Autologous Marrow Transplantation;Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo autologous PBSC transplantation<br>* Other names: autologous stem cell transplantation;Drug: Busulfan<br>* Given IV<br>* Other names: WR-19508;Drug: Cytarabine<br>* Given IV<br>* Other names: WR-28453;Drug: Daunorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubilem;Drug: Decitabine<br>* Given IV<br>* Other names: Dezocitidine;Drug: Etoposide<br>* Given IV<br>* Other names: VP-16-213;Biological: Filgrastim<br>* Given SC<br>* Other names: Tevagrastim;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Completed Maintenance Decitabine. | To determine feasibility of decitabine maintenance, this outcome measures the number of participants who completed all 8 planned cycles of decitabine maintenance as per protocol. | Up to 5 years | 
| Disease-free Survival (DFS) Rate at 1 Year | For participants who achieved a complete remission (CR), this is the percentage of participants who were alive and relapse free at 1 year. The 1 year rate, with 95% confidence interval, was estimated using the Kaplan-Meier method A CR is defined as those with > 20% cellularity of bone marrow biopsy, no presence of extramedullary leukemia for AML, <5 % myeloblast cells for bone marrow with peripheral blood and normal complete blood count (absolute neutrophils > 1000 mL and platelets >= 100,000 mL). | At 1 year |