Clinical trial NCT00049517
Conditions: Leukemia
Keywords: acute myeloid leukemia autologous transplantation gemtuzumab ozogamicin
Sponsor: Eastern Cooperative Oncology Group
Start date: 2002-12-19; Completion date: 2019-12-01
Enrollment: 657 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
RATIONALE: Giving combination chemotherapy before a stem cell transplant helps stop the growth of cancer cells. It also helps stop the patient's immune system from rejecting the transplanted stem cells. When the healthy stem cells are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. If the patient's stem cells are to be transplanted, the patient is also treated with a monoclonal antibody, such as gemtuzumab ozogamicin, to kill any remaining cancer cells or deliver cancer-killing substances to them without harming normal cells. It is not yet known whether combination chemotherapy is more effective with or without gemtuzumab ozogamicin followed by stem cell transplant in treating acute myeloid leukemia.

PURPOSE: This randomized phase III trial is studying combination chemotherapy, gemtuzumab ozogamicin, and stem cell transplant to see how well they work compared to combination chemotherapy and peripheral stem cell transplant alone in treating patients with acute myeloid leukemia.

Detailed description:
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.

Arms: arm 1: Induction: Patients receive standard-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course.

Consolidation/Transplant:

Before initiating consolidation therapy, patients with CR were randomized to a standard or an investigational arm. All patients received 2 cycles of high-dose cytarabine therapy (3 g/m2 given IV over a 3-hour period every 12 hours every other day for a total of 6 doses), followed by sargramostim 250 μg/m2 until recovery of blood counts.

The patients undergoing autologous hematopoietic cell transplantation (HCT) received intravenous busulfan 0.8 mg/kg every 6 hours for 16 doses (without pharmacokinetic sampling) followed by intravenous cyclophosphamide 60 mg/kg daily for 2 days. arm 2: Induction: Patients receive high-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course.

Consolidation/Transplant:

Before initiating consolidation therapy, patients with CR were randomized to a standard or an investigational arm. All patients received 2 cycles of high-dose cytarabine therapy (3 g/m2 given IV over a 3-hour period every 12 hours every other day for a total of 6 doses), followed by sargramostim 250 μg/m2 until recovery of blood counts.

The patients undergoing autologous hematopoietic cell transplantation (HCT) received intravenous busulfan 0.8 mg/kg every 6 hours for 16 doses (without pharmacokinetic sampling) followed by intravenous cyclophosphamide 60 mg/kg daily for 2 days. arm 3: Induction: Patients receive standard-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course.

Consolidation/Transplant:

Before initiating consolidation therapy, patients with CR were randomized to a standard or an investigational arm. All patients received 2 cycles of high-dose cytarabine therapy (3 g/m2 given IV over a 3-hour period every 12 hours every other day for a total of 6 doses), followed by sargramostim 250 μg/m2 until recovery of blood counts. patients randomized to the investigational arm received a single dose of Gemtuzumab ozogamicin (GO) at 6 mg/m2 followed by sargramostim 250 μ/m2 until recovery of counts.

The patients undergoing autologous HCT received intravenous busulfan 0.8 mg/kg every 6 hours for 16 doses followed by intravenous cyclophosphamide 60 mg/kg daily for 2 days. arm 4: Induction: Patients receive high-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course.

Consolidation/Transplant:

Before initiating consolidation therapy, patients with CR were randomized to a standard or an investigational arm. All patients received 2 cycles of high-dose cytarabine therapy (3 g/m2 given IV over a 3-hour period every 12 hours every other day for a total of 6 doses), followed by sargramostim 250 μg/m2 until recovery of blood counts. patients randomized to the investigational arm received a single dose of Gemtuzumab ozogamicin (GO) at 6 mg/m2 followed by sargramostim 250 μ/m2 until recovery of counts.

The patients undergoing autologous HCT received intravenous busulfan 0.8 mg/kg every 6 hours for 16 doses followed by intravenous cyclophosphamide 60 mg/kg daily for 2 days. arm 5: Induction: Patients receive standard-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course.

Consolidation/Transplant:

Patients without CR did not receive any consolidation treatment. Patients in CR with an unfavorable cytogenetic profile or an initial white blood cell count \> 100,000/μL were to proceed to allogeneic HCT if they had a suitable human leukocyte antigen (HLA)-matched sibling donor available. arm 6: Induction: Patients receive high-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course.

Consolidation/Transplant:

Patients without CR did not receive any consolidation treatment. Patients in CR with an unfavorable cytogenetic profile or an initial white blood cell count \> 100,000/μL were to proceed to allogeneic HCT if they had a suitable human leukocyte antigen (HLA)-matched sibling donor available.
Interventions: intervention 1: sargramostim intervention 2: busulfan intervention 3: cyclophosphamide intervention 4: cytarabine intervention 5: gemtuzumab ozogamicin (GO) intervention 6: Daunorubicin intervention 7: Autologous HCT intervention 8: Allogeneic HCT
Intervention descriptions: intervention 1: Given IV or as an injection intervention 2: Given IV intervention 3: Given IV intervention 4: Given as a continuous infusion intervention 5: Given IV intervention 6: Given intravenously daily for 3 days at a dose of either 45 or 90 mg/m2. intervention 7: Autologous hematopoietic cell transplantation intervention 8: Allogeneic hematopoietic cell transplantation

Protocol documents: