Trial Information

A Phase III Trial in Adult Acute Myeloid Leukemia: Daunorubicin Dose-Intensification Prior to Risk-Allocated Autologous Stem Cell Transplantation

OBJECTIVES:

- To compare the overall survival (OS) between two induction regimens (standard versus
dose intense daunorubicin and cytarabine) in patients with de novo AML.

- To compare disease-free survival (DFS) between two consolidation regimens.

- To compare overall survival between two consolidation regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to
induction therapy (standard-dose daunorubicin vs high-dose daunorubicin).

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

- Standard: Patients receive standard-dose daunorubicin IV over 10-15 minutes on
days 1-3 and cytarabine IV continuously on days 1-7.

- High dose: Patients receive high-dose daunorubicin IV over 10-15 minutes on days
1-3 and cytarabine as in arm I.

Patients in both arms may receive a second course of induction therapy if complete remission
(CR) is not achieved after the first course. The second course is administered as in arm I
to all patients. Patients who don't achieve CR after 2 courses of induction therapy are
removed from study.

Patients who achieve CR after induction therapy proceed to post-remission therapy with
EITHER allogeneic transplantation only (on or off study) OR consolidation therapy and
autologous transplantation (on study), according to risk status and donor status.

Patients who are considered at intermediate or high risk for relapse (unfavorable
cytogenetics/high WBC) and have a suitable related donor undergo an allogeneic
transplantation. Patients with intermediate-risk cytogenetics, WBC no greater than
100,000/mm^3, and appropriate donors have the option of undergoing allogeneic
transplantation.

- Allogeneic transplantation: Within 1-3 months after recovery from induction therapy,
patients receive busulfan IV every 6 hours on days -7 to -4 and cyclophosphamide IV
over 4 hours on days -3 and -2. Allogeneic bone marrow or peripheral blood stem cells
(PBSCs) are infused on day 0. Patients receive graft-vs-host disease (GVHD) prophylaxis
comprising cyclosporine IV over 1-4 hours beginning on day -1 and then orally (when
tolerated) twice daily until day 180. Alternatively, patients may receive tacrolimus IV
over 24 hours beginning on day -1 and then orally twice daily until day 180. Patients
also receive methotrexate IV on days 1, 3, 6, and 11.

Patients who do not meet the criteria for allogeneic transplantation (i.e., are favorable
risk or do not have a matching related donor) or who opt not to undergo allogeneic
transplantation proceed to consolidation therapy followed by randomization to 1 of 2
autologous transplantation arms.

- Consolidation therapy: Beginning 2-8 weeks after recovery from induction therapy,
patients receive high-dose cytarabine IV over 3 hours every 12 hours on days 1, 3, and
5. A second course is administered 3 weeks after blood recovery. Patients receive
filgrastim (G-CSF) subcutaneously (SC) daily for 4 days and then autologous PBSCs are
harvested by leukapheresis.

- Autologous stem cell transplantation: Patients are randomized to 1 of 2 autologous
transplantation arms.

- Arm I: Within 1 month after PBSC collection, patients receive conditioning
comprising busulfan IV every 6 hours on days -7 to -4 and cyclophosphamide IV over
2 hours on days -3 and -2. Patients then undergo autologous PBSC transplantation
on day 0. Patients receive sargramostim (GM-CSF) or G-CSF IV or SC beginning on
day 0 and continuing until blood counts recover.

- Arm II (closed to accrual as of 10/4/2007): Within 2-4 weeks after PBSC
collection, patients receive gemtuzumab ozogamicin IV over 2 hours on day 1 and
GM-CSF SC or IV beginning on day 10 and continuing until blood counts recover.
Within 2-3 weeks after blood count recovery, patients receive conditioning and
undergo autologous PBSC transplantation as in arm I.

Patients are followed monthly for 1 year, every 2 months for 1 year, and then every 3 months
for up to 7 years.

ACTUAL ACCRUAL: A total of 657 patients were accrued for this study.