Combination Chemotherapy Regimens Followed by CNS Radiation Therapy, Thioguanine, and Cytarabine in Treating Young Patients With Standard-Risk or High-Risk Acute Myeloid Leukemia

Condition(s) targeted: Leukemia

Intervention: busulfan (Drug); cladribine (Drug); cyclophosphamide (Drug); cytarabine (Drug); etoposide phosphate (Drug); idarubicin (Drug); liposomal daunorubicin citrate (Drug); mitoxantrone hydrochloride (Drug); thioguanine (Drug); tretinoin (Drug); allogeneic hematopoietic stem cell transplantation (Procedure); biological therapy (Procedure); chemotherapy (Procedure); high-dose chemotherapy (Procedure); intrathecal therapy (Procedure); radiation therapy (Procedure)

Phase: Phase 2/Phase 3

Status: Recruiting

Sponsored by: Medizinische Klinik und Poliklinik A - Universitaetsklinikum Muenster

Official(s) and/or principal investigator(s):
Ursula Creutzig, MD, Study Chair, Affiliation: Medizinische Klinik und Poliklinik A - Universitaetsklinikum Muenster

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. Radiation therapy uses high-energy x-rays to kill cancer cells. Giving thioguanine and cytarabine after combination chemotherapy and radiation therapy may help these treatments keep working. It is not yet known which combination chemotherapy regimen and which dose of radiation therapy is most effective in treating patients with acute myeloid leukemia.

PURPOSE: This randomized phase II/III trial is studying different combination chemotherapy regimens followed by CNS radiation therapy, thioguanine, and cytarabine to compare how well they work in treating young patients with standard-risk or high-risk acute myeloid leukemia.

Official title: Multicenter Therapy-Optimization Trial AML-BFM 2004 for the Treatment of Acute Myeloid Leukemias in Children and Adolescents

Study design: Interventional, Treatment, Randomized, Open Label, Active Control

Primary outcome:

Event-free and overall survival

Disease-free survival

Secondary outcome: Cardiotoxicity

Detailed description: OBJECTIVES:

Primary

* Compare the improvement of prognosis in pediatric patients with acute myeloid leukemia treated with intensified cytostatic induction therapy comprising cytarabine, etoposide phosphate, and liposomal daunorubicin citrate vs standard induction therapy comprising cytarabine, etoposide phosphate, and idarubicin.

* Compare the improvement of prognosis in high-risk patients treated with consolidation therapy comprising cytarabine and idarubicin with vs without cladribine.

* Determine the efficacy of 2 different doses of prophylactic CNS irradiation in these patients.

* Compare the incidence of cardiotoxicity in patients treated with these regimens.

Secondary

* Compare the incidence of infection-caused deaths in patients treated with these regimens.

* Determine the prognostic relevance of minimal residual disease, in terms of recognizing recurrence risk early, in patients treated with these regimens.

OUTLINE: This is a controlled, open-label, parallel-group, randomized, multicenter study. Patients are stratified according to risk (standard vs high) and disease. Patients may be randomized at 3 different time points during the study.

Patients with large leukemia cell mass (primary WBC > 50,000/mm^3) or substantial organ enlargement receive oral thioguanine and cytarabine IV or subcutaneously (SC) for 3-7 days as preliminary cytoreduction before beginning induction therapy.

Patients with acute myeloid leukemia (AML) FAB M3 receive oral tretinoin on days 3-11 for the first course and then on days 1-14 (except during intrathecal [IT] treatment) for all other courses. Treatment repeats every 3 weeks for at least 3 courses (during induction, consolidation, and intensification therapies).

* Induction therapy 1: Patients are randomized to 1 of 2 induction therapy arms.

- Arm I (ADxE): Patients receive cytarabine IV over 48 hours on days 1 and 2 and then IV over 2 hours twice daily on days 3-8; liposomal daunorubicin citrate IV over 2 hours on days 3, 5, and 7; etoposide phosphate IV over 1 hour on days 6-8; and cytarabine IT on days 1 and 8.

- Arm II (AIE): Patients receive cytarabine IV and IT and etoposide phosphate as in arm I. Patients also receive idarubicin IV over 4 hours on days 3, 5, and 7.

Beginning 4 weeks after completion of induction therapy 1, patients with standard-risk disease proceed to consolidation therapy block 1. Patients with high-risk disease proceed to induction therapy 2.

* Induction therapy 2 (HAM): Patients receive induction therapy 2 comprising high-dose cytarabine IV over 3 hours twice daily on days 1-3; mitoxantrone IV over 30 minutes on day 3; and cytarabine IT on day 1.

Beginning 4 weeks after completion of induction therapy 2, patients proceed to consolidation therapy block 1.

* Consolidation therapy block 1: Standard-risk patients (including those with AML M3) are assigned to arm II; high-risk patients are randomized to arm I or II.

- Arm I (AI/2-CDA): Patients receive cytarabine IV over 96 hours on days 1-4; cladribine IV over 30 minutes on days 1 and 3; idarubicin IV over 1 hour on days 3 and 5; and cytarabine IT on days 1 and 6.

- Arm II (AI): Patients receive cytarabine IV over 96 hours on days 1-4; idarubicin IV over 1 hour on days 3 and 5; and cytarabine IT on days 1 and 6.

Beginning 4 weeks after completion of consolidation therapy block 1, patients in both arms proceed to consolidation therapy block 2.

* Consolidation therapy block 2 (HAM): Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1-3; mitoxantrone IV over 30 minutes on days 3 and 4; and cytarabine IT on days 1 and 6.

Beginning 2-4 weeks after completion of consolidation therapy block 2, patients who do not have a planned allogeneic stem cell transplant (SCT) proceed to intensification therapy. High-risk patients with available sibling donor proceed to matched sibling donor SCT. Other high-risk patients who exhibit a nonresponse or an enduring aplasia without signs of hematologic regeneration (at least 4 weeks after consolidation therapy block 2) proceed to matched family donor SCT or matched unrelated donor SCT.

* Allogeneic SCT: Patients receive conditioning therapy comprising oral busulfan every 6 hours on days - 7 to -4 and cyclophosphamide IV on days -3 and -2. Patients undergo allogeneic SCT on day 0.

* Intensification therapy (HAE): Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1-3; etoposide phosphate IV over 1 hour on days 2-5; and cytarabine IT on day 1.

Beginning at least 4 weeks after completion of intensification therapy, patients proceed to CNS treatment/prophylaxis.

* CNS treatment/prophylaxis: Patients with primary CNS involvement receive cytarabine IT weekly for at least 3 weeks until cerebral spinal fluid stabilization and then undergo CNS irradiation* for 2-3 weeks. Patients without CNS involvement are randomized to receive 1 of 2 dose levels of prophylactic CNS irradiation**.

- Arm I: Patients receive prophylactic CNS irradiation.

- Arm II: Patients receive prophylactic CNS irradiation at a higher dose. NOTE: *Patients with Down syndrome or who are less than 1 ¼ years of age do not receive CNS irradiation.

NOTE: **Patients who have undergone planned allogeneic SCT do not receive prophylactic CNS irradiation.

All patients then proceed to maintenance therapy.

* Maintenance therapy: Beginning 4 weeks after completion of intensification therapy and CNS irradiation, patients receive oral thioguanine daily on days 1-28; cytarabine SC on days 1-4; and cytarabine IT* weekly. Treatment repeats every 4 weeks for up to 1 year. Patients with AML M3 also receive oral tretinoin on days 1-14 of the first course and then every 3 months for 14 days for 3 courses.

NOTE: *Patients with Down syndrome do not receive cytarabine IT.

After completion of study therapy, patients are followed periodically.

PROJECTED ACCRUAL: A total of 550 patients will be accrued for this study.

Maximum age: 18 Years. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

* Diagnosis of de novo acute myeloid leukemia (AML), including isolated myelosarcoma or acute mixed lineage leukemia/biphenotypic leukemia (predominantly myeloid)

* Patients with Down syndrome are eligible

* No secondary AML

* No preexisting syndromes (e. g., Fanconi's anemia)

* Diagnosis falls into 1 of the following risk groups:

- Standard risk

+ AML FAB M3 [t(15;17)]

+ AML with Down syndrome

+ AML FAB M1 or M2 with auer rods*

+ AML FAB M4 eosinophil*

+ AML with t(8;21)*

+ AML with inv(16)*

- High risk

+ AML FAB M0

+ AML FAB M1 or M2 without auer rods

+ AML FAB M4 with > 5% blasts on day 15 (after 1 induction therapy)

+ AML FAB M5

+ AML FAB M6

+ AML FAB M7 NOTE: * Reassigned to high-risk group if FLT-3 ITD mutation is demonstrated

PATIENT CHARACTERISTICS:

* No other concurrent disease that would preclude study treatment

* Not pregnant

* Negative pregnancy test

PRIOR CONCURRENT THERAPY:

* More than 14 days since prior intensive induction therapy

Medizinische Hochschule Hannover, Hannover D-30625, Germany; Recruiting
Dirk Reinhardt, MD, Phone: 49-511-532-9123, Email: AML-BFM@MH-Hannover.de

Medizinische Klinik und Poliklinik A - Universitaetsklinikum Muenster, Muenster D-48149, Germany; Recruiting
Ursula Creutzig, MD, Phone: 49-511-532-9123, Email: AML-BFM@MH-Hannover.de

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: March 2004
Last updated: May 23, 2007