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

A PHASE III STUDY IN CHILDREN WITH UNTREATED ACUTE MYELOGENOUS LEUKEMIA (AML) OR MYELODYSPLASTIC SYNDROME (MDS)

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

Study Overview

• Status: Completed
• Conditions: Chronic Myelomonocytic Leukemia; 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; Secondary Myelodysplastic Syndromes; de Novo Myelodysplastic Syndromes; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies; Refractory Anemia With Ringed Sideroblasts
• Intervention / Treatment: Biological: aldesleukin; Drug: asparaginase; Drug: daunorubicin hydrochloride; Drug: therapeutic hydrocortisone; Drug: fludarabine phosphate; Procedure: allogeneic bone marrow transplantation; Drug: cyclophosphamide; Drug: busulfan; Drug: etoposide; Drug: methotrexate; Biological: filgrastim; Drug: dexamethasone; Drug: cytarabine; Radiation: 3-dimensional conformal radiation therapy; Drug: idarubicin; Drug: thioguanine

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 Type: Interventional
• Enrollment (Actual): 880
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / 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; RP-13057; daunomycin hydrochloride; daunorubicin; 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; Drug: etoposide; Given IV; Other Names: EPEG; VP-16; VP-16-213; Drug: methotrexate; Given IT; Other Names: amethopterin; Folex; methylaminopterin; Mexate; MTX; Biological: filgrastim; Given SC; Other Names: G-CSF; Neupogen; Drug: dexamethasone; Given PO; Other Names: Aeroseb-Dex; Decaderm; Decadron; DM; DXM; Drug: cytarabine; Given IV or IT; Other Names: Cytosar-U; cytosine arabinoside; ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Drug: idarubicin; Given IV; Other Names: IDA; 4-demethoxydaunorubicin; 4-DMDR; DMDR; Drug: thioguanine; Given PO; Other Names: 6-TG
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: Elspar; Colaspase; L-ASP; ASNase; Crasnitin; Drug: therapeutic hydrocortisone; Other Names: Aeroseb-HC; Barseb HC; Cetacort; Cort-Dome; Cortef; Drug: fludarabine phosphate; Other Names: 2-F-ara-AMP; Beneflur; Fludara; Procedure: allogeneic bone marrow transplantation; Other Names: bone marrow therapy, allogeneic; bone marrow therapy, allogenic; transplantation, allogeneic bone marrow; transplantation, allogenic bone marrow; Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Drug: busulfan; Other Names: BSF; BU; Misulfan; Mitosan; Myeloleukon; Drug: methotrexate; Given IT; Other Names: amethopterin; Folex; methylaminopterin; Mexate; MTX; Biological: filgrastim; Given SC; Other Names: G-CSF; Neupogen; Drug: cytarabine; Given IV or IT; Other Names: Cytosar-U; cytosine arabinoside; ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Drug: idarubicin; Given IV; Other Names: IDA; 4-demethoxydaunorubicin; 4-DMDR; DMDR; Drug: thioguanine; Given PO; Other Names: 6-TG
Experimental: Arm III (combination chemotherapy, aldesleukin); Patients receive interleukin-2 IV continuously on days 1-4 and 9-18.	Biological: aldesleukin; Other Names: Proleukin; IL-2; recombinant human interleukin-2; recombinant interleukin-2; Drug: daunorubicin hydrochloride; Other Names: Cerubidin; Cerubidine; RP-13057; daunomycin hydrochloride; daunorubicin; Drug: etoposide; Given IV; Other Names: EPEG; VP-16; VP-16-213; Biological: filgrastim; Given SC; Other Names: G-CSF; Neupogen; Drug: dexamethasone; Given PO; Other Names: Aeroseb-Dex; Decaderm; Decadron; DM; DXM; Drug: cytarabine; Given IV or IT; Other Names: Cytosar-U; cytosine arabinoside; ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Drug: idarubicin; Given IV; Other Names: IDA; 4-demethoxydaunorubicin; 4-DMDR; DMDR; Drug: thioguanine; Given PO; Other Names: 6-TG
Active Comparator: Arm IV (combination chemotherapy); No further treatment	Drug: daunorubicin hydrochloride; Other Names: Cerubidin; Cerubidine; RP-13057; daunomycin hydrochloride; daunorubicin; Drug: etoposide; Given IV; Other Names: EPEG; VP-16; VP-16-213; Biological: filgrastim; Given SC; Other Names: G-CSF; Neupogen; Drug: dexamethasone; Given PO; Other Names: Aeroseb-Dex; Decaderm; Decadron; DM; DXM; Drug: cytarabine; Given IV or IT; Other Names: Cytosar-U; cytosine arabinoside; ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Drug: idarubicin; Given IV; Other Names: IDA; 4-demethoxydaunorubicin; 4-DMDR; DMDR; Drug: thioguanine; Given PO; Other Names: 6-TG
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; RP-13057; daunomycin hydrochloride; daunorubicin; Drug: etoposide; Given IV; Other Names: EPEG; VP-16; VP-16-213; Biological: filgrastim; Given SC; Other Names: G-CSF; Neupogen; Drug: dexamethasone; Given PO; Other Names: Aeroseb-Dex; Decaderm; Decadron; DM; DXM; Drug: cytarabine; Given IV or IT; Other Names: Cytosar-U; cytosine arabinoside; ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Radiation: 3-dimensional conformal radiation therapy; Other Names: 3D-CRT; 3D conformal radiation therapy; Drug: idarubicin; Given IV; Other Names: IDA; 4-demethoxydaunorubicin; 4-DMDR; DMDR; Drug: thioguanine; Given PO; Other Names: 6-TG

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Beverly Lange, Children's Oncology Group

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: August 1, 1996
• Primary Completion (Actual): September 1, 2006

Study Registration Dates

• First Submitted: November 24, 2000
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): January 16, 2013
• Last Update Submitted That Met QC Criteria: January 15, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Leukemia, Myelomonocytic, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Anemia; Leukemia, Monocytic, Acute; Leukemia, Megakaryoblastic, Acute; Leukemia, Erythroblastic, Acute; Anemia, Refractory, with Excess of Blasts; Anemia, Refractory; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Antibiotics, Antineoplastic; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Dexamethasone; Aldesleukin; Cyclophosphamide; Etoposide; Etoposide phosphate; Fludarabine; Fludarabine phosphate; Cytarabine; Methotrexate; Daunorubicin; Asparaginase; Idarubicin; Busulfan; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Thioguanine; Interleukin-2
• Other Study ID Numbers: NCI-2012-01834; U10CA098543 (U.S. NIH Grant/Contract); 2961; CDR0000064883 (Registry Identifier: PDQ (Physician Data Query))