Randomized study to assess the added value of Laromustine in combination with standard remission-induction chemotherapy in patients aged 18-65 years with previously untreated acute myeloid leukemia (AML) or myelodysplasia (MDS) (RAEB with IPSS >= 1.5)

Study phase:

phase III

Study objective:

Part A:

To determine the feasibility of Laromustine when given at three possible dose levels together with standard induction cycles I and II in patients with AML/ RAEB with IPSS >= 1.5 in a prospective comparison to standard induction cycles I and II without Laromustine


Part B:

To evaluate the effect of Laromustine at the selected feasible dose level when combined with remission induction chemotherapy cycles I and II as regards clinical outcome (event-free survival) in comparison to remission induction cycles I and II with no addition of Laromustine in a phase III study



Patient population:

Patients with previously untreated AML (except acute promyelocytic leukemia) or MDS RAEB with IPSS >= 1.5, age 18-65 years.



Study design:

Part A:

Comparative, randomized feasibility study of remission induction chemotherapy combined with Laromustine at three possible dose levels 200, 300, 400 mg/m2.

Part B:

Multicenter, phase III study at the selected feasible dose level of Laromustine in a prospective randomized approach between Laromustine combined with two induction cycles of chemotherapy versus the same chemotherapy with no addition of Laromustine



Duration of treatment:

Expected duration of 2 induction cycles inclusive evaluation is approximately 3 months. Consolidation treatment will take an additional 1-3 months. All patients will be followed until 10 years after randomization.

The hypothesis to be tested is that arm B is tolerable and that the outcome in arm B is better than in arm A.

-At entry

-After each induction cycle

-After cycle III, autoSCT or alloSCT

-During follow up: every 6 months

Patients will be randomized on entry for induction between:

Arm A:

Cycle I: idarubicin and conventional dose cytarabine

Cycle II: amsacrine and intermediate dose cytarabine


Arm B:

Cycle I: idarubicin, conventional dose cytarabine and assigned dose of Laromustine

Cycle II: amsacrine, conventional dose cytarabine and assigned dose Laromustine



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

- Good risk patients will receive a third cycle of chemotherapy (cycle III: mitoxantrone plus etoposide).

- Intermediate or poor risk patients with a HLA matched family donor will proceed to allogeneic stem cell transplantation.

- Poor risk patients 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.

- 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 who are not eligible for Allo SCT or auto SCT will receive cycle III as consolidation treatment.



Poor risk patients in PR after cycle II with a HLA matched family donor or with a phenotypically matched unrelated donor may proceed to allogeneic stem cell transplantation.