Randomized induction and post induction therapy in adult patients (= 1.5.

Study phase:

phase III.




Study objectives:

Evaluation of the effect of escalated doses of Ara-C in induction cycles I and II. Evaluation of G-CSF priming in induction cycles I and II. Evaluation of the effect of marrow ablative chemotherapy followed by autologous peripheral blood stem cell transplantation in patients with intermediate or poor risk in CR in comparison to conventional consolidation chemotherapy.

Evaluation of the effect of allogeneic sibling or unrelated donor SCT in subgroups of patients with AML of intermediate or poor risk.




Patient population:

patients with AML (except FAB M3 or t(15;17)), RAEB or RAEB-t with IPSS >= 1.5, previously untreated, age 18-60 years (incl.)




Study design:

prospective, multicenter, randomized with randomization up front for induction treatment with conventional dose or high dose Ara-C, and randomization between yes or no G-CSF priming, and randomization of patients in CR with intermediate or poor risk without a suitable donor between auto PBSCT and consolidation chemotherapy.




Duration of treatment:

expected duration of induction cycles I and II inclusive evaluation is about 3 months. Consolidation treatment will take an additional 1-3 months.

The 3 hypotheses to be tested are that the outcome in:

1. The high dose arm B is better than in the low dose arm A;

2. The G-CSF arm is better than in the non-G-CSF arm;

3. The PBSCT arm 2 is better than the chemotherapy cycle III arm 1.

N/A

Patients will be randomized on entry for induction between:

Arm A:

1. Cycle I: idarubicin and conventional dose cytarabine;

2. Cycle II: amsacrine and intermediate dose cytarabine;

Arm B:

1. Cycle I: idarubicin and intermediate dose cytarabine;

2. Cycle II: amsacrine and high dose cytarabine;

A second randomization for induction will involve yes or no priming with G-CSF during chemotherapy of induction cycles I and II.




All CR patients will be distinguished according to good risk, intermediate risk, and poor risk features:

1. Good risk patients will receive a third cycle of chemotherapy (cycle III: mitoxantrone plus etoposide) and will not be randomized.

2. Intermediate or poor risk patients with age below 55 yrs and with a HLA matched family donor will proceed to allogeneic stem cell transplantation.

3. Poor risk patients with age below 50 yrs without a HLA matched sibling donor, but with a phenotypically matched unrelated donor may proceed to marrow ablative treatment and allogeneic stem cell transplantation as soon as they have entered CR. If patients are already distinguished as poor risk following cycle I and logistically there are no impediments the patient may proceed to Allo SCT as soon as possible after cycle I.

4. All other patients in CR, including patients who refuse stem cell transplantation, will undergo stem cell mobilization with G-CSF and stem cell collection.




Patients with an adequate harvest and meeting the eligibility criteria will be randomized between:

1. Arm 1: chemotherapy cycle III: mitoxantrone and etoposide;

2. Arm 2: busulfan-cyclophosphamide ablation + autologous PBSCT.




Patients who are not eligible for Allo SCT or who do not meet the eligibilty criteria for randomization will receive cycle III as consolidation treatment.

Poor risk patients in PR after cycle II with a HLA matched family donor (and patient’s age below 55 yrs) or with a phenotypically matched unrelated donor (and patient’s age below 50 yrs) may proceed to allogeneic stem cell transplantation.