Effect of Priming During Induction and Consolidations in Younger Acute Myeloid Leukemia (AML)

Effect of Priming With Granulocyte-Macrophage Colony-Stimulating Factor During Chemotherapy and Comparison of Timed Sequential Chemotherapy vs 4 Courses of High Dose Cytarabine as Consolidation in Younger Adults With Newly Diagnosed AML

The purpose of this study is:

1. To compare priming with Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) during induction and consolidation courses versus no priming.
2. To compare as consolidation timed sequential chemotherapy versus four courses of high dose cytarabine.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: GM-CSF

Detailed Description

Patients aged 15-50 are enrolled and randomly assigned to receive GM-CSF or no GM-CSF during all remission-induction and consolidation courses of chemotherapy. Induction chemotherapy consists of a timed-sequential chemotherapy including a first sequence of chemotherapy combining daunorubicin, 80 mg/m2 per day, administered IV as a short infusion over 3 days (days 1-3), and cytarabine, 500 mg/m2 per day IV as a continuous infusion over the same period. The second sequence, administered after 4-day free interval, consists of mitoxantrone, 12 mg/m2 per day, administered IV as a short infusion over 2 days (days 8 and 9), and cytarabine, 500 mg/m2/12h, administered as a 3-hour infusion for 3 days (days 8-10). Salvage therapy consists of cytarabine, 3 g/m2/12h on days 1,3,5,7, combined with amsacrine, 100mg/m2 per day on days 1 to 3. GM-CSF (Leucomax, recombinant human GM-CSF from Escherichia Coli, Schering Plough, Kenilworth,N.J., USA) is given at a dose of 5µg/kg per day, intravenously beginning at day 1 of each chemotherapy course and continuing until the last day of chemotherapy of each course.

Patients who achieve CR after induction chemotherapy or salvage therapy are randomly assigned to consolidation courses consisting of either a timed sequential chemotherapy similar to that of the ALFA-9000 trial (P2 arm) or the CALGB postremission chemotherapy (P1 arm), which includes 4 cycles of high-dose cytarabine, followed by 4 additional maintenance courses.

• Study Type: Interventional
• Enrollment (Actual): 473
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 50 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• A morphologically proven diagnosis of AML according to the WHO classification
• Serum creatinine < 2N; AST and ALT < 2.5N; total bilirubin < 2N (unless related to the underlying disease).
• ECOG performance status 0 to 2.
• Women of child-bearing must use acceptable contraceptive methods, and must have a negative serum or urine pregnancy test within 2 weeks prior the beginning treatment on this trial.
• Must be able and willing to give written informed consent

Exclusion Criteria:

• Patients with M3-AML. Patient with AML following diagnosed myeloproliferation or patient with prior history of MDS known for more than 3 months. Patients with AML secondary to previous treatment with cytotoxic chemotherapy or radiotherapy (therapy-related AML).
• Patient presenting any diagnosis of uncontrolled or metastatic tumor.
• Patients with uncontrolled severe infection,

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

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: EMA+GM-CSF; Daunorubicine (CérubidineR) : 80 mg/m2/jour IV over 30 min from day 1 to day 3,; AraC (AracytineR) : 500 mg/m2/jour IV from day 1 to day 3,; Mitoxantrone (NovantroneR) : 12 mg/m2/jour IV over 30 min from day 8 to 9; AraC (AracytineR) : 500 mg/m2/12h IV over 3 hours from day 8 to day10.; GM-CSF (LeucomaxR): 5 µg/kg/jour IV over 6 hours from day 1 to day 10.	Drug: GM-CSF; Randomization 1: GM-CSF (5micogram/Kg/d) versus no GM-CSF during induction chemotherapy and all consolidation courses. Randomiization 2: Consolidation high dose AraC versus consolidation EMA; Other Names: GM-CSF: molgramostim; AraC: Cytarabine; Daunorubicine: Cerubidine; EMA: etoposide, mitoxantrone, cytarabine
Active Comparator: EMA without GM-CSF; Daunorubicine (CérubidineR) : 80 mg/m2/jour IV over 30 min from day 1 to day 3,; AraC (AracytineR) : 500 mg/m2/jour IV from day 1 to day 3,; Mitoxantrone (NovantroneR) : 12 mg/m2/jour IV over 30 min from day 8 to 9; AraC (AracytineR) : 500 mg/m2/12h IV over 3 hours from day 8 to day10.	Drug: GM-CSF; Randomization 1: GM-CSF (5micogram/Kg/d) versus no GM-CSF during induction chemotherapy and all consolidation courses. Randomiization 2: Consolidation high dose AraC versus consolidation EMA; Other Names: GM-CSF: molgramostim; AraC: Cytarabine; Daunorubicine: Cerubidine; EMA: etoposide, mitoxantrone, cytarabine
Experimental: HD AraC+ GM-CSF; AraC (Aracytine) : 3 g/m2/12h IV (3 hours) on days 1, 3 , 5; GM-CSF :5 µg/kg/d IV (6 hours) from day1 to day 5	Drug: GM-CSF; Randomization 1: GM-CSF (5micogram/Kg/d) versus no GM-CSF during induction chemotherapy and all consolidation courses. Randomiization 2: Consolidation high dose AraC versus consolidation EMA; Other Names: GM-CSF: molgramostim; AraC: Cytarabine; Daunorubicine: Cerubidine; EMA: etoposide, mitoxantrone, cytarabine
Active Comparator: HD-AraC without GM-CSF; - AraC (Aracytine) : 3 g/m2/12h IV (3 hours) on days 1, 3 , 5	Drug: GM-CSF; Randomization 1: GM-CSF (5micogram/Kg/d) versus no GM-CSF during induction chemotherapy and all consolidation courses. Randomiization 2: Consolidation high dose AraC versus consolidation EMA; Other Names: GM-CSF: molgramostim; AraC: Cytarabine; Daunorubicine: Cerubidine; EMA: etoposide, mitoxantrone, cytarabine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Assessing the potential value of the daily administration of GM-CSF during induction chemotherapy and post-induction for analyzing and comparing the arms with and without GM-CSF: EFS, % of CR, duration of remission, OS and toxicity of each treatment.	72 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Evaluate the effectiveness on DFS of a single course of consolidation using a very intensive sequential chemotherapy with mitoxantrone, AraC and etoposide feasible compared to 4 courses of high dose AraC followed of 4 courses of maintenance.	72 months

Collaborators and Investigators

• Sponsor: Acute Leukemia French Association
• Collaborators: Hospices Civils de Lyon
• Investigators: Principal Investigator: XAVIER THOMAS, MD, PhD, Hospices Civils de Lyon

Publications and helpful links

General Publications

• Boissel N, Nibourel O, Renneville A, Gardin C, Reman O, Contentin N, Bordessoule D, Pautas C, de Revel T, Quesnel B, Huchette P, Philippe N, Geffroy S, Terre C, Thomas X, Castaigne S, Dombret H, Preudhomme C. Prognostic impact of isocitrate dehydrogenase enzyme isoforms 1 and 2 mutations in acute myeloid leukemia: a study by the Acute Leukemia French Association group. J Clin Oncol. 2010 Aug 10;28(23):3717-23. doi: 10.1200/JCO.2010.28.2285. Epub 2010 Jul 12.
• Thomas X, Raffoux E, Botton Sd, Pautas C, Arnaud P, de Revel T, Reman O, Terre C, Corront B, Gardin C, Le QH, Quesnel B, Cordonnier C, Bourhis JH, Elhamri M, Fenaux P, Preudhomme C, Michallet M, Castaigne S, Dombret H. Effect of priming with granulocyte-macrophage colony-stimulating factor in younger adults with newly diagnosed acute myeloid leukemia: a trial by the Acute Leukemia French Association (ALFA) Group. Leukemia. 2007 Mar;21(3):453-61. doi: 10.1038/sj.leu.2404521. Epub 2007 Jan 25.
• Thomas X, Elhamri M, Raffoux E, Renneville A, Pautas C, de Botton S, de Revel T, Reman O, Terre C, Gardin C, Chelghoum Y, Boissel N, Quesnel B, Hicheri Y, Bourhis JH, Fenaux P, Preudhomme C, Michallet M, Castaigne S, Dombret H. Comparison of high-dose cytarabine and timed-sequential chemotherapy as consolidation for younger adults with AML in first remission: the ALFA-9802 study. Blood. 2011 Aug 18;118(7):1754-62. doi: 10.1182/blood-2011-04-349258. Epub 2011 Jun 20.

Study record dates

Study Major Dates

• Study Start: March 1, 1999
• Primary Completion (Actual): September 1, 2006
• Study Completion (Actual): September 1, 2006

Study Registration Dates

• First Submitted: April 8, 2009
• First Submitted That Met QC Criteria: April 10, 2009
• First Posted (Estimate): April 13, 2009

Study Record Updates

• Last Update Posted (Estimate): April 13, 2009
• Last Update Submitted That Met QC Criteria: April 10, 2009
• Last Verified: April 1, 2009

More Information

Terms related to this study

• Keywords: Prognosis; Acute myeloid leukemia; GM-CSF; Priming; Timed-sequential chemotherapy
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Etoposide; Cytarabine; Daunorubicin; Mitoxantrone; Sargramostim; Molgramostim
• Other Study ID Numbers: ALFA 9802