Combination Chemotherapy in Treating Children With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome

Sponsor

European Organisation for Research and Treatment of Cancer - EORTC (Other)

Overall Status

Completed

CT.gov ID

NCT00002517

Collaborator

(none)

Locations

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug may kill more cancer cells. It is not yet known which regimen of combination chemotherapy is more effective for acute myeloid leukemia or myelodysplastic syndrome.

PURPOSE: Randomized phase III trial to compare the effectiveness of different combination chemotherapy regimens in treating children who have newly diagnosed acute myeloid leukemia or myelodysplastic syndrome.

Condition or Disease	Intervention/Treatment	Phase
Leukemia Myelodysplastic Syndromes	Drug: cytarabine Drug: daunorubicin hydrochloride Drug: dexamethasone Drug: etoposide Drug: idarubicin Drug: mitoxantrone hydrochloride Drug: thioguanine Procedure: allogeneic bone marrow transplantation Radiation: radiation therapy	Phase 3

Detailed Description

OBJECTIVES:

Compare the efficacy of idarubicin vs mitoxantrone in induction and first intensification in terms of achieving and maintaining complete remissions in children with acute myeloid leukemia or myelodysplastic syndrome.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to center and disease type (de novo acute myeloid leukemia (AML) vs AML secondary to myelodysplastic syndrome (MDS) vs MDS).

Induction: Patients are randomized to 1 of 2 treatment arms.
Arm I: Patients receive cytarabine (ARA-C) IV continuously on days 1 and 2 and then IV over 30 minutes every 12 hours on days 3-8, mitoxantrone IV on days 3-5, etoposide (VP-16) IV over 1 hour on days 6-8, and ARA-C intrathecally (IT) on days 1 and 8.
Arm II: Patients receive ARA-C and VP-16 as in arm I and idarubicin IV on days 3-5.

Patients on both arms with CNS disease at presentation receive ARA-C IT every 3 days until the CSF clears and then weekly until the first intensification. After induction, patients on both arms proceed to first intensification, regardless of response.

First intensification: When blood counts recover and within 40 days after initiating induction, patients are randomized to 1 of 2 treatment arms.
Arm III: Patients receive high-dose ARA-C IV over 3 hours every 12 hours on days 1-3 (if allogeneic bone marrow transplantation (BMT) is planned) or days 1-4 (if allogeneic BMT is not planned) and mitoxantrone IV on days 7-9.
Arm IV: Patients receive high-dose ARA-C as in arm III and idarubicin IV on days 7-9.
Patients who achieve complete remission (CR) after first intensification and have an HLA-identical, chronic myelomonocytic leukemia-nonreactive, sibling donor undergo allogeneic BMT. Patients who achieve CR after intensification and have no suitable donor receive intensive chemotherapy as defined below. All patients with chloroma at presentation undergo local radiotherapy beginning after final intensification.
Second intensification: When blood counts recover, patients receive daunorubicin IV continuously, ARA-C IV continuously, VP-16 IV continuously, oral thioguanine, and oral dexamethasone on days 1-4 and 11-14 and ARA-C IT on days 1, 4, 11, and 14.
Third intensification: When blood counts recover, patients receive high-dose ARA-C IV over 3 hours every 12 hours on days 1-3 and VP-16 IV over 1 hour on days 2-5. When blood counts recover, autologous bone marrow is harvested in the event of subsequent relapse.
Maintenance: When blood counts recover, patients receive oral thioguanine daily and ARA-C subcutaneously 4 days a month for 1 year.

PROJECTED ACCRUAL: A total of 310 patients will be accrued for this study within 5 years.

Study Design

Study Type:

Interventional

Allocation:

Randomized

Primary Purpose:

Treatment

Official Title:

IDA VS MTZ IN INDUCTION AND INTENSIFICATION TREATMENT OF AML OR MDS IN CHILDREN, A PHASE III RANDOMIZED STUDY

Study Start Date :

Mar 1, 1993

Actual Primary Completion Date :

May 1, 2010

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 14 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Newly diagnosed acute myeloid leukemia (AML) based on the cytological, cytochemical, and immunological criteria of the FAB classification
Must meet 1 of the following criteria:
More than 30% blasts in marrow (calculation based on the total number of nucleated cells except lymphocytes and plasmocytes)
Presence of granulocytic sarcoma (chloroma)
Disease must be associated with at least 1 of the following:
More than 3% myeloperoxidase- or Sudan black-positive blasts
More than 3% platelet peroxidase-positive blasts
More than 20% esterase-positive blasts
Immunological markers compatible with a myeloid differentiation, including 1 of the following criteria:
Blasts positive for myeloid-associated antigen and negative for B- or T-lymphocyte antigens
Blasts positive for at least 2 myeloid antigens (except CD3 and CD8)
A cytogenetic abnormality associated with AML OR
Newly diagnosed myelodysplastic syndrome (MDS) based on the cytological and cytochemical criteria of the FAB classification
Eligible subtypes:
Refractory anemia with excess blasts (RAEB)
RAEB in transformation
Chronic myelomonocytic leukemia
No promyelocytic leukemia (M3 or M3v) treated with tretinoin (protocol EORTC-06915)
No AML secondary to hematologic or malignant disease other than MDS
Registration must occur within 48 hours of diagnosis

PATIENT CHARACTERISTICS:

Age:

Under 15

Performance status:

Not specified

Life expectancy:

Not specified

Hematopoietic:

See Disease Characteristics
No uncontrolled bleeding disorder

Hepatic:

Not specified

Renal:

No renal failure

Cardiovascular:

No congenital heart disease

Other:

No encephalopathy
No genetic disorders
No uncontrolled infection

PRIOR CONCURRENT THERAPY:

Biologic therapy:

Not specified

Chemotherapy:

Not specified

Endocrine therapy:

Not specified

Radiotherapy:

Not specified

Surgery:

Not specified

Other:

No prior antileukemic therapy

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Algemeen Ziekenhuis Middelheim	Antwerp	Belgium	2020
2	Hopital Universitaire Des Enfants Reine Fabiola	Brussels	Belgium	1020
3	Academisch Ziekenhuis der Vrije Universiteit Brussel	Brussels	Belgium	1090
4	Universitair Ziekenhuis Gent	Ghent	Belgium	B-9000
5	U.Z. Gasthuisberg	Leuven	Belgium	B-3000
6	Centre Hospitalier Regional de la Citadelle	Liege	Belgium	4000
7	Clinique de l'Esperance	Montegnee	Belgium	4420
8	Centre Hospitalier Regional et Universitaire d'Angers	Angers	France	49033
9	CHR de Besancon - Hopital Saint-Jacques	Besancon	France	25030
10	CHU de Caen	Caen	France	14033
11	CHR de Grenoble - La Tronche	Grenoble	France	38043
12	Centre Hospitalier Regional de Lille	Lille	France	59037
13	Hopital Debrousse	Lyon	France	69322
14	Hopital Arnaud de Villeneuve	Montpellier	France	34295
15	CHR Hotel Dieu	Nantes	France	44093
16	Centre Antoine Lacassagne	Nice	France	06189
17	Hopital Robert Debre	Paris	France	75019
18	Institut Curie - Section Medicale	Paris	France	75248
19	Hopital Jean Bernard	Poitiers	France	86021
20	Hopital Americain	Reims	France	51092
21	Hopital Universitaire Hautepierre	Strasbourg	France	67098
22	Hopital des Enfants (Purpan Enfants)	Toulouse	France	31026
23	Hospital Escolar San Joao	Porto	Portugal	4200