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

Primary Purpose

Childhood Acute Erythroleukemia (M6), Childhood Acute Megakaryocytic Leukemia (M7), Childhood Acute Monoblastic Leukemia (M5a)

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
asparaginase
daunorubicin hydrochloride
fludarabine phosphate
therapeutic hydrocortisone
allogeneic bone marrow transplantation
3-dimensional conformal radiation therapy
filgrastim
cytarabine
idarubicin
dexamethasone
thioguanine
etoposide
methotrexate
cyclophosphamide
aldesleukin
busulfan
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Childhood Acute Erythroleukemia (M6)

Eligibility Criteria

undefined - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Children's Oncology Group

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Active Comparator

Experimental

Arm Label

Arm I (combination chemotherapy)

Arm II (combination chemotherapy)

Arm III (combination chemotherapy, aldesleukin)

Arm IV (combination chemotherapy)

Arm V (combination chemotherapy, radiotherapy)

Arm Description

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

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

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

No further treatment

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Full Information

First Posted
November 24, 2000
Last Updated
January 15, 2013
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00002798
Brief Title
Combination Chemotherapy With or Without Bone Marrow Transplantation in Treating Children With Acute Myelogenous Leukemia or Myelodysplastic Syndrome
Official Title
A PHASE III STUDY IN CHILDREN WITH UNTREATED ACUTE MYELOGENOUS LEUKEMIA (AML) OR MYELODYSPLASTIC SYNDROME (MDS)
Study Type
Interventional

2. Study Status

Record Verification Date
January 2013
Overall Recruitment Status
Completed
Study Start Date
August 1996 (undefined)
Primary Completion Date
September 2006 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. 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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
880 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I (combination chemotherapy)
Arm Type
Experimental
Arm Description
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
Arm Title
Arm II (combination chemotherapy)
Arm Type
Experimental
Arm Description
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
Arm Title
Arm III (combination chemotherapy, aldesleukin)
Arm Type
Experimental
Arm Description
Patients receive interleukin-2 IV continuously on days 1-4 and 9-18.
Arm Title
Arm IV (combination chemotherapy)
Arm Type
Active Comparator
Arm Description
No further treatment
Arm Title
Arm V (combination chemotherapy, radiotherapy)
Arm Type
Experimental
Arm Description
Patients undergo radiotherapy to the chloroma 5 days a week for 2 weeks.
Intervention Type
Drug
Intervention Name(s)
asparaginase
Other Intervention Name(s)
ASNase, Colaspase, Crasnitin, Elspar, L-ASP
Intervention Type
Drug
Intervention Name(s)
daunorubicin hydrochloride
Other Intervention Name(s)
Cerubidin, Cerubidine, daunomycin hydrochloride, daunorubicin, RP-13057
Intervention Type
Drug
Intervention Name(s)
fludarabine phosphate
Other Intervention Name(s)
2-F-ara-AMP, Beneflur, Fludara
Intervention Type
Drug
Intervention Name(s)
therapeutic hydrocortisone
Other Intervention Name(s)
Aeroseb-HC, Barseb HC, Cetacort, Cort-Dome, Cortef
Intervention Type
Procedure
Intervention Name(s)
allogeneic bone marrow transplantation
Other Intervention Name(s)
bone marrow therapy, allogeneic, bone marrow therapy, allogenic, transplantation, allogeneic bone marrow, transplantation, allogenic bone marrow
Intervention Type
Radiation
Intervention Name(s)
3-dimensional conformal radiation therapy
Other Intervention Name(s)
3D conformal radiation therapy, 3D-CRT
Intervention Type
Biological
Intervention Name(s)
filgrastim
Other Intervention Name(s)
G-CSF, Neupogen
Intervention Description
Given SC
Intervention Type
Drug
Intervention Name(s)
cytarabine
Other Intervention Name(s)
ARA-C, arabinofuranosylcytosine, arabinosylcytosine, Cytosar-U, cytosine arabinoside
Intervention Description
Given IV or IT
Intervention Type
Drug
Intervention Name(s)
idarubicin
Other Intervention Name(s)
4-demethoxydaunorubicin, 4-DMDR, DMDR, IDA
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
dexamethasone
Other Intervention Name(s)
Aeroseb-Dex, Decaderm, Decadron, DM, DXM
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
thioguanine
Other Intervention Name(s)
6-TG
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
etoposide
Other Intervention Name(s)
EPEG, VP-16, VP-16-213
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
methotrexate
Other Intervention Name(s)
amethopterin, Folex, methylaminopterin, Mexate, MTX
Intervention Description
Given IT
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Other Intervention Name(s)
CPM, CTX, Cytoxan, Endoxan, Endoxana
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
aldesleukin
Other Intervention Name(s)
IL-2, Proleukin, recombinant human interleukin-2, recombinant interleukin-2
Intervention Type
Drug
Intervention Name(s)
busulfan
Other Intervention Name(s)
BSF, BU, Misulfan, Mitosan, Myeloleukon
Primary Outcome Measure Information:
Title
Proportions of patients achieving remission rate during induction therapy
Time Frame
Up to 42 days
Title
Proportion of patients dying or with residual disease during induction therapy
Time Frame
Up to 42 days
Title
Time to marrow recovery (induction phase)
Time Frame
Up to 42 days
Title
Frequency of toxicities, including infectious complications (induction phase)
Time Frame
Up to 42 days
Title
Marrow status
Time Frame
At 14 days
Title
Percent of blasts
Time Frame
At the end of induction therapy
Title
Complete remission at the end of consolidation therapy
Time Frame
Up to 5 years
Title
Survival following consolidation
Time Frame
Up to 5 years
Title
Event-free survival following consolidation
Time Frame
Up to 5 years
Title
Overall survival (intensification)
Time Frame
Up to 5 years
Title
EFS (intensification)
Time Frame
Up to 5 years

10. Eligibility

Sex
All
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Beverly Lange
Organizational Affiliation
Children's Oncology Group
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Oncology Group
City
Arcadia
State/Province
California
ZIP/Postal Code
91006-3776
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
20413658
Citation
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.
Results Reference
derived
PubMed Identifier
20056794
Citation
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.
Results Reference
derived
PubMed Identifier
19304957
Citation
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.
Results Reference
derived

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

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