Combination Chemotherapy With or Without Bone Marrow Transplantation in Treating Children With Acute Myelogenous Leukemia or Myelodysplastic Syndrome

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ClinicalTrials.gov Identifier: NCT00002798

Recruitment Status : Completed

First Posted : January 27, 2003

Last Update Posted : January 16, 2013

Sponsor:

Information provided by (Responsible Party):

National Cancer Institute (NCI)

Study Description

Brief Summary:

Randomized phase III trial to compare the effectiveness of different chemotherapy regimens with or without bone marrow transplantation in treating children who have acute myelogenous leukemia or myelodysplastic syndrome. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with bone marrow transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. It is not yet known which treatment regimen is more effective for acute myelogenous leukemia or myelodysplastic syndrome

Condition or disease	Intervention/treatment	Phase
Childhood Acute Erythroleukemia (M6) Childhood Acute Megakaryocytic Leukemia (M7) Childhood Acute Monoblastic Leukemia (M5a) Childhood Acute Monocytic Leukemia (M5b) Childhood Acute Myeloblastic Leukemia With Maturation (M2) Childhood Acute Myeloblastic Leukemia Without Maturation (M1) Childhood Acute Myelomonocytic Leukemia (M4) Childhood Myelodysplastic Syndromes Chronic Myelomonocytic Leukemia de Novo Myelodysplastic Syndromes Refractory Anemia Refractory Anemia With Excess Blasts Refractory Anemia With Excess Blasts in Transformation Refractory Anemia With Ringed Sideroblasts Secondary Myelodysplastic Syndromes Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies	Drug: asparaginase Drug: daunorubicin hydrochloride Drug: fludarabine phosphate Drug: therapeutic hydrocortisone Procedure: allogeneic bone marrow transplantation Radiation: 3-dimensional conformal radiation therapy Biological: filgrastim Drug: cytarabine Drug: idarubicin Drug: dexamethasone Drug: thioguanine Drug: etoposide Drug: methotrexate Drug: cyclophosphamide Biological: aldesleukin Drug: busulfan	Phase 3

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Detailed Description:

OBJECTIVES:

Increase the remission induction rate to greater than 85% in children with untreated acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) by replacing daunorubicin (DNR) with idarubicin (IDA) in intensively timed DCTER chemotherapy (dexamethasone, cytarabine (ARA-C), thioguanine, etoposide, and daunorubicin) in the first 4 days of each course.

Increase the remission rate further by comparing the efficacy of consolidation chemotherapy with intensively timed IDA DCTER/DCTER vs fludarabine (FAMP), ARA-C, and IDA in maintaining remission and in achieving remission in patients with M2 disease (5%-29% blasts in marrow) at the end of induction chemotherapy.

Compare overall survival, event-free survival, and disease-free survival in patients who receive consolidation with IDA DCTER/DCTER vs FAMP, ARA-C, and IDA.

Compare overall survival, event-free survival, and disease-free survival in patients receiving intensification with the Capizzi II regimen (high-dose ARA-C and asparaginase) vs those receiving a matched-related allogeneic bone marrow transplantation.

Compare overall survival, event-free survival, and disease-free survival in patients treated with interleukin-2 (IL-2) vs standard follow up care after Capizzi II intensification.

Determine whether multichannel flow cytometry detection of residual AML on a companion biologic study protocol CCG-B942 predicts outcome, and determine whether any of these treatment regimens eliminates minimal residual disease more effectively than another.

Register all patients with MDS treated or followed at CCG institutions and capture their biologic, historical and outcome data.

Determine, on a companion biologic study protocol CCG-B972, whether levels of IL-2 soluble receptor (sIL-2R) and absolute lymphocyte count (ALC) before, during, and after therapy correlates with outcome.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to center, diagnosis (acute myelogenous leukemia vs other), and response to induction (partial vs complete remission). After induction, patients with M1/M2 marrow are randomized to arm I or II. Patients in complete remission after consolidation who have an HLA-identical or 1-antigen mismatched sibling or parent donor are randomly assigned to the allogeneic bone marrow transplantation (AlBMT) regimen; all others in complete remission are nonrandomly assigned to the Capizzi II regimen, then are randomly assigned to arms III or IV. Patients with refractory anemia (RA) or RA with ringed sideroblasts with indolent disease may be registered and followed. Other patients with myelodysplastic syndromes may receive 2961 chemotherapy or go directly to AlBMT. Patients with chloromas (granulocytic sarcomas) receive optional radiotherapy on arm V.

Induction: Patients receive idarubicin IV over 30 minutes on days 0-3, cytarabine and etoposide IV continuously on days 0-3, and oral thioguanine twice a day and oral dexamethasone 3 times a day on days 0-3. Patients then begin course 2, which consists of cytarabine, etoposide, thioguanine, and dexamethasone on days 10-13, daunorubicin IV continuously on days 10-13, and filgrastim (G-CSF) subcutaneously (SC) beginning on day 16 and continuing until blood counts recover. Patients also receive CNS prophylaxis/therapy consisting of cytarabine intrathecally (IT) on days 0 and 14 (if no CNS disease at entry) or on days 0, 5, and 7 (if CNS disease present at entry). Disease is reassessed on day 28-42. Patients with M1 or M2 marrow proceed to consolidation while those with M3 marrow or progressive disease go off study.

Consolidation:

Arm I: Patients receive treatment as in induction therapy, plus G-CSF SC beginning on day 16 and continuing until blood counts recover. If CSF is clear by day 10 of induction, patients receive cytarabine IT on days 0, 10, and 35. If CSF is not clear, patients receive triple intrathecal therapy (TIT; cytarabine, hydrocortisone, methotrexate) on days 0 and 10.

Arm II: Patients receive fludarabine IV over 24 hours on days 0 and 1, cytarabine IV over 72 hours on days 2-4, and idarubicin IV over 15 minutes on days 0-2. G-CSF begins on day 6 and continues until blood counts recover. Patients also receive TIT on days -1 and 7, if CSF is not clear on day 10 of induction. Patients on both arms are reassessed on day 35. Those patients with M1 marrow proceed to intensification; all others are removed from the study.

Intensification:

Capizzi II regimen: Course 1: Patients receive cytarabine IV over 3 hours every 12 hours on days 0, 1, 7, and 8 and asparaginase IM on days 1 and 8. Course 2: Patients also receive cytarabine IT or TIT on days 0, 7, and 14.AlBMT regimen: Therapy begins within 2-8 weeks of hematologic recovery. Patients may receive interim therapy consisting of oral thioguanine for about 2 weeks. Patients then receive oral busulfan every 6 hours on days -9 to -6 and cyclophosphamide IV over 1 hour on days -5 to -2. AlBMT is infused over 4 hours beginning 36-48 hours after the last dose of cyclophosphamide. Patients in complete remission after completing the Capizzi II regimen proceed to maintenance therapy on arm III.

Arm III: Patients receive interleukin-2 IV continuously on days 1-4 and 9-18.

Arm IV: No further treatment.

Arm V: Patients undergo radiotherapy to the chloroma 5 days a week for 2 weeks.

Patients are followed monthly for 18 months, every 3 months for 1 year, and then every 6 months until 5 years from diagnosis.

PROJECTED ACCRUAL: Approximately 880 patients with de novo acute myelogenous leukemia will be accrued for this study within 4 years. It is expected that 178 patients per year will be randomly assigned for consolidation, that 39 patients per year will undergo allogeneic bone marrow transplantation while 120 patients per year will receive chemotherapy as intensification, and that 102 patients per year will be randomly assigned for polychemotherapy immunomodulation. An additional 80 patients with myelodysplastic syndromes will be accrued for this study.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	880 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A PHASE III STUDY IN CHILDREN WITH UNTREATED ACUTE MYELOGENOUS LEUKEMIA (AML) OR MYELODYSPLASTIC SYNDROME (MDS)
Study Start Date :	August 1996
Actual Primary Completion Date :	September 2006

Resource links provided by the National Library of Medicine

Genetics Home Reference related topics: Core binding factor acute myeloid leukemia Cytogenetically normal acute myeloid leukemia Familial acute myeloid leukemia with mutated CEBPA

MedlinePlus related topics: Acute Myeloid Leukemia Bone Marrow Transplantation Leukemia Myelodysplastic Syndromes

Genetic and Rare Diseases Information Center resources: Myeloid Leukemia Acute Myeloid Leukemia Acute Non Lymphoblastic Leukemia Myelodysplastic Syndromes Chronic Myelomonocytic Leukemia Juvenile Myelomonocytic Leukemia Acute Megakaryoblastic Leukemia Acute Erythroid Leukemia Di Guglielmo's Syndrome Myelodysplastic Syndrome With Excess Blasts Acute Myeloblastic Leukemia Without Maturation Acute Myeloblastic Leukemia With Maturation Acute Myelomonocytic Leukemia Acute Monoblastic Leukemia Sideroblastic Anemia Pyridoxine-refractory Autosomal Recessive Myelodysplastic/myeloproliferative Disease Chronic Myeloproliferative Disorders

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm I (combination chemotherapy) Patients receive treatment as in induction therapy, plus G-CSF SC beginning on day 16 and continuing until blood counts recover. If CSF is clear by day 10 of induction, patients receive cytarabine IT on days 0, 10, and 35. If CSF is not clear, patients receive triple intrathecal therapy (TIT; cytarabine, hydrocortisone, methotrexate) on days 0 and 10. See Detailed Description	Drug: daunorubicin hydrochloride Other Names: Cerubidin Cerubidine daunomycin hydrochloride daunorubicin RP-13057 Drug: therapeutic hydrocortisone Other Names: Aeroseb-HC Barseb HC Cetacort Cort-Dome Cortef Procedure: allogeneic bone marrow transplantation Other Names: bone marrow therapy, allogeneic bone marrow therapy, allogenic transplantation, allogeneic bone marrow transplantation, allogenic bone marrow Biological: filgrastim Given SC Other Names: G-CSF Neupogen Drug: cytarabine Given IV or IT Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside Drug: idarubicin Given IV Other Names: 4-demethoxydaunorubicin 4-DMDR DMDR IDA Drug: dexamethasone Given PO Other Names: Aeroseb-Dex Decaderm Decadron DM DXM Drug: thioguanine Given PO Other Name: 6-TG Drug: etoposide Given IV Other Names: EPEG VP-16 VP-16-213 Drug: methotrexate Given IT Other Names: amethopterin Folex methylaminopterin Mexate MTX
Experimental: Arm II (combination chemotherapy) Patients receive fludarabine IV over 24 hours on days 0 and 1, cytarabine IV over 72 hours on days 2-4, and idarubicin IV over 15 minutes on days 0-2. G-CSF begins on day 6 and continues until blood counts recover. Patients also receive TIT on days -1 and 7, if CSF is not clear on day 10 of induction. Patients on both arms are reassessed on day 35. Those patients with M1 marrow proceed to intensification; all others are removed from the study. Intensification: See Detailed Description	Drug: asparaginase Other Names: ASNase Colaspase Crasnitin Elspar L-ASP Drug: fludarabine phosphate Other Names: 2-F-ara-AMP Beneflur Fludara Drug: therapeutic hydrocortisone Other Names: Aeroseb-HC Barseb HC Cetacort Cort-Dome Cortef Procedure: allogeneic bone marrow transplantation Other Names: bone marrow therapy, allogeneic bone marrow therapy, allogenic transplantation, allogeneic bone marrow transplantation, allogenic bone marrow Biological: filgrastim Given SC Other Names: G-CSF Neupogen Drug: cytarabine Given IV or IT Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside Drug: idarubicin Given IV Other Names: 4-demethoxydaunorubicin 4-DMDR DMDR IDA Drug: thioguanine Given PO Other Name: 6-TG Drug: methotrexate Given IT Other Names: amethopterin Folex methylaminopterin Mexate MTX Drug: cyclophosphamide Given IV Other Names: CPM CTX Cytoxan Endoxan Endoxana Drug: busulfan Other Names: BSF BU Misulfan Mitosan Myeloleukon
Experimental: Arm III (combination chemotherapy, aldesleukin) Patients receive interleukin-2 IV continuously on days 1-4 and 9-18.	Drug: daunorubicin hydrochloride Other Names: Cerubidin Cerubidine daunomycin hydrochloride daunorubicin RP-13057 Biological: filgrastim Given SC Other Names: G-CSF Neupogen Drug: cytarabine Given IV or IT Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside Drug: idarubicin Given IV Other Names: 4-demethoxydaunorubicin 4-DMDR DMDR IDA Drug: dexamethasone Given PO Other Names: Aeroseb-Dex Decaderm Decadron DM DXM Drug: thioguanine Given PO Other Name: 6-TG Drug: etoposide Given IV Other Names: EPEG VP-16 VP-16-213 Biological: aldesleukin Other Names: IL-2 Proleukin recombinant human interleukin-2 recombinant interleukin-2
Active Comparator: Arm IV (combination chemotherapy) No further treatment	Drug: daunorubicin hydrochloride Other Names: Cerubidin Cerubidine daunomycin hydrochloride daunorubicin RP-13057 Biological: filgrastim Given SC Other Names: G-CSF Neupogen Drug: cytarabine Given IV or IT Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside Drug: idarubicin Given IV Other Names: 4-demethoxydaunorubicin 4-DMDR DMDR IDA Drug: dexamethasone Given PO Other Names: Aeroseb-Dex Decaderm Decadron DM DXM Drug: thioguanine Given PO Other Name: 6-TG Drug: etoposide Given IV Other Names: EPEG VP-16 VP-16-213
Experimental: Arm V (combination chemotherapy, radiotherapy) Patients undergo radiotherapy to the chloroma 5 days a week for 2 weeks.	Drug: daunorubicin hydrochloride Other Names: Cerubidin Cerubidine daunomycin hydrochloride daunorubicin RP-13057 Radiation: 3-dimensional conformal radiation therapy Other Names: 3D conformal radiation therapy 3D-CRT Biological: filgrastim Given SC Other Names: G-CSF Neupogen Drug: cytarabine Given IV or IT Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside Drug: idarubicin Given IV Other Names: 4-demethoxydaunorubicin 4-DMDR DMDR IDA Drug: dexamethasone Given PO Other Names: Aeroseb-Dex Decaderm Decadron DM DXM Drug: thioguanine Given PO Other Name: 6-TG Drug: etoposide Given IV Other Names: EPEG VP-16 VP-16-213

Outcome Measures

Primary Outcome Measures :

Proportions of patients achieving remission rate during induction therapy [ Time Frame: Up to 42 days ]
Proportion of patients dying or with residual disease during induction therapy [ Time Frame: Up to 42 days ]
Time to marrow recovery (induction phase) [ Time Frame: Up to 42 days ]
Frequency of toxicities, including infectious complications (induction phase) [ Time Frame: Up to 42 days ]
Marrow status [ Time Frame: At 14 days ]
Percent of blasts [ Time Frame: At the end of induction therapy ]
Complete remission at the end of consolidation therapy [ Time Frame: Up to 5 years ]
Survival following consolidation [ Time Frame: Up to 5 years ]
Event-free survival following consolidation [ Time Frame: Up to 5 years ]
Overall survival (intensification) [ Time Frame: Up to 5 years ]
EFS (intensification) [ Time Frame: Up to 5 years ]

Eligibility Criteria

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Ages Eligible for Study:	up to 21 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Histologically confirmed previously untreated acute myeloid leukemia (AML) in patients 1 month to 21 years of age
- Infants under 1 month with progressive disease eligible
  - Supportive care may be given to confirm that the leukemia is not regressing prior to entry
- No acute promyelocytic leukemia (FAB M3)
- No acute undifferentiated leukemia (FAB M0)
Histochemical verification of AML required by the following stains:
- Wright or Giemsa
- Peroxidase
- PAS
- Chloroacetate esterase
- Sudan black
- Nonspecific esterase (NSE) with and without fluoride (NaF) inhibition
- Combined NSE/NaF and butyrate inhibition or diagnosis of megakaryoblasticleukemia (FAB M7) should be supported by one of the following:
  - CD41 reactivity
  - Glycoprotein 1b reactivity
  - Factor VIII-related antigen reactivity
  - Platelet peroxidase on electron microscopy
The following are also eligible:
- Myelodysplastic syndromes, including:
  - Refractory anemia (RA) *
  - RA with ringed sideroblasts (RARS) *
  - RA with excess blasts (RAEB)
  - RAEB in transformation (RAEBt)
  - Chronic myelomonocytic leukemia (CMML)
- AML with monosomy 7
- Granulocytic sarcoma (chloroma) with or without marrow involvement
- Mixed lineage leukemia with 2 morphologically defined populations provided the predominant population is myeloid
No Downs syndrome
No juvenile chronic myelogenous leukemia
No Fanconi's anemia
No secondary AML
Performance status - Not specified
No prior anticancer chemotherapy
Prior topical or inhaled steroids for nonmalignant conditions allowed
No prior anticancer radiotherapy
No prior antileukemic therapy

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00002798

Locations

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United States, California
Children's Oncology Group
Arcadia, California, United States, 91006-3776

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

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Principal Investigator:	Beverly Lange	Children's Oncology Group

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Ho PA, Zeng R, Alonzo TA, Gerbing RB, Miller KL, Pollard JA, Stirewalt DL, Heerema NA, Raimondi SC, Hirsch B, Franklin JL, Lange B, Meshinchi S. Prevalence and prognostic implications of WT1 mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group. Blood. 2010 Aug 5;116(5):702-10. doi: 10.1182/blood-2010-02-268953. Epub 2010 Apr 22.

Pollard JA, Alonzo TA, Gerbing RB, Ho PA, Zeng R, Ravindranath Y, Dahl G, Lacayo NJ, Becton D, Chang M, Weinstein HJ, Hirsch B, Raimondi SC, Heerema NA, Woods WG, Lange BJ, Hurwitz C, Arceci RJ, Radich JP, Bernstein ID, Heinrich MC, Meshinchi S. Prevalence and prognostic significance of KIT mutations in pediatric patients with core binding factor AML enrolled on serial pediatric cooperative trials for de novo AML. Blood. 2010 Mar 25;115(12):2372-9. doi: 10.1182/blood-2009-09-241075. Epub 2010 Jan 7.

Ho PA, Alonzo TA, Gerbing RB, Pollard J, Stirewalt DL, Hurwitz C, Heerema NA, Hirsch B, Raimondi SC, Lange B, Franklin JL, Radich JP, Meshinchi S. Prevalence and prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group. Blood. 2009 Jun 25;113(26):6558-66. doi: 10.1182/blood-2008-10-184747. Epub 2009 Mar 20.

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Responsible Party:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00002798
Other Study ID Numbers:	NCI-2012-01834 2961 U10CA098543 ( U.S. NIH Grant/Contract ) CDR0000064883 ( Registry Identifier: PDQ (Physician Data Query) )
First Posted:	January 27, 2003 Key Record Dates
Last Update Posted:	January 16, 2013
Last Verified:	January 2013

Additional relevant MeSH terms:

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Leukemia Leukemia, Myeloid, Acute Preleukemia Leukemia, Myeloid Leukemia, Myelomonocytic, Acute Leukemia, Myelomonocytic, Chronic Leukemia, Myelomonocytic, Juvenile Leukemia, Monocytic, Acute Leukemia, Erythroblastic, Acute Leukemia, Megakaryoblastic, Acute Anemia Myelodysplastic Syndromes Anemia, Refractory Anemia, Refractory, with Excess of Blasts Syndrome	Disease Pathologic Processes Neoplasms by Histologic Type Neoplasms Hematologic Diseases Bone Marrow Diseases Precancerous Conditions Myelodysplastic-Myeloproliferative Diseases Myeloproliferative Disorders Cytarabine Aldesleukin Dexamethasone Hydrocortisone Hydrocortisone 17-butyrate 21-propionate Hydrocortisone acetate

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