Leukemia
Conditions
Keywords
Chronic Myelogenous Leukemia, Allogeneic Stem Cell Transplantation, Leukemia, Imatinib Mesylate, Gleevec, Busulfan, Busulfex, Myleran, Fludarabine, ATG, STI571, Antithymocyte Globulin, Thymoglobulin
Brief summary
Primary Objective: To estimate the probability of molecular complete remission at one year for the described sequential treatment approach, with nonablative hematopoietic transplantation, post transplant imatinib mesylate and donor lymphocyte infusion, in patients with Ph-positive Chronic Myelogenous Leukemia (CML) not in blastic transformation. Secondary Objective: Response to post transplant Imatinib mesylate therapy for 12 weeks as treatment of residual disease, response to donor lymphocyte infusion (DLI) for residual disease following imatinib mesylate therapy, as well as engraftment, toxicity, disease free survival and survival, effect of busulfan pharmacokinetics on study outcome.
Detailed description
Patients will have blood and bone marrow tests performed as well as chest and sinus X-rays and tests of their heart and lung function. Approximately 5 tablespoons of blood will be drawn. All patients in this study will receive imatinib mesylate by mouth for 9 days, unless the patient is known to be allergic or have symptomatic intolerance to the drug, or if the leukemia has failed to respond to imatinib. Fludarabine 40 mg/m2 by vein for 4 days (days -5 to -2), busulfan 130 mg/m2 by vein for 2 days (days -3 and -2), and ATG (Antithymocyte Globulin) 2.5 mg/kg by vein for 3 days (-3,-2 and -1). Patients will then receive the donor bone marrow or blood stem cells by vein over approximately one hour on day 0. After the infusion of the donor cells, you will receive immunosuppressive therapy with tacrolimus and methotrexate to decrease the risk of developing graft-vs-host disease (GvHD). Patients will need frequent blood tests to monitor their counts and blood chemistries. This is generally done daily while in hospital and at least twice per week for the first 100 days post transplant. You may need frequent blood transfusions and may have to be admitted to the hospital to receive antibiotics if they develop fever. Bone marrow will be examined frequently beginning four weeks after treatment to evaluate response to treatment; Blood and bone marrow exams are to be performed at one, two three, six, 12 and 18 months post transplant and yearly thereafter for 5 years. To collect a bone marrow sample, an area of the hip or chest bone is numbed with anesthetic and a small amount of bone marrow is withdrawn through a large needle. Patients in whom treatment produces a remission, in which no sign of the leukemia can be detected, will receive no further therapy unless the leukemia recurs. Patients with evidence of leukemia after 3 months from the transplant will receive additional treatment with imatinib mesylate; those with detectable leukemia after an additional 3 months may receive an infusion of immune cells from the transplant donor. If there is evidence of leukemia after the transplant, you will receive additional treatment with imatinib mesylate. If leukemia cells can still be detected, additional donor immune cells will be given to you by vein. Patients are considered on the study for 5 years after the transplant. A total of 90 patients will take part in this study. All will be enrolled at M. D. Anderson.
Interventions
DRUGImatinib Mesylate
400 mg by mouth twice daily for 9 Days
40 mg/m\^2 by vein daily for 4 Days
DRUGBusulfan
130 mg/m\^2 by vein daily for 2 Days
2.5 mg/kg by vein daily for 3 Days
DRUGTacrolimus
Tacrolimus levels maintained between 5-15 ng/dl, first as continuous IV infusion, and converted to oral every 12 hour dosing as tolerated. Starting day -2 until day 180.
DRUGMethotrexate
5 mg/m2 on days 1, 3, 6 and 11.
PROCEDUREDonor lymphocyte infusion (DLI)
Infusion of lymphocytes from the original bone marrow donor by vein if relapse after \>4 weeks of imatinib.
PROCEDUREStem Cell Transplant
Infusion of donor bone marrow or blood stem cells by vein over approximately one hour on day 0.
Sponsors
National Cancer Institute (NCI)
M.D. Anderson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of Ph+ chronic myelogenous leukemia (CML) in first chronic phase without a complete hematologic response after 3 months of Imatinib mesylate therapy, or \>=35% Ph+ cells despite \> 6 months of Imatinib mesylate treatment, or after disease progression from a complete or partial response. Any patient with accelerated phase or blast crisis who achieves a subsequent chronic phase is eligible. Patients must have an HLA matched related or unrelated donor or one antigen mismatched related donor. 2. Patients should be less than 70 years of age. Patients less than 30 years of age who achieve a hematologic remission with imatinib therapy are eligible regardless of cytogenetic response. 3. Patients are stratified as Group 1: First chronic phase, Group 2 Accelerated phase or blast crisis that achieved a hematologic remission with imatinib mesylate-based treatment.
Exclusion criteria
1. Zubrod Performance Scale (PS) \>=2, uncontrolled infection, Creatinine \> 2.0 mg/dl; Ejection fraction \< 40%; Carbon Monoxide Diffusing Capacity (DLCO) \< 45% of predicted; Serum bilirubin \> 2 gm/dl; GPT (Glutamic-pyruvic transaminase) or GOT (glutamic-oxaloacetic transaminase)\> 3 times normal values. Patients should not be human immunodeficiency virus (HIV) seropositive or pregnant. 2. Patients should not have progressed to accelerated phase or blast crisis while receiving imatinib mesylate containing therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants in Complete Molecular Remission at 1 Year | Baseline to 1 year | Participants at 1 year in molecular remission, post transplant, post imatinib mesylate and donor lymphocyte infusion (DLI). Molecular remission is a complete remission with no evidence of disease in the blood cells and/or bone marrow using sensitive polymerase chain reaction (PCR) tests (this test is most commonly used in clinical trials). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Participants' With mCR Response to Post Transplant Imatinib Mesylate Therapy | 1 Year | Number of participants with response of molecular complete remission (mCR) to Imatinib Mesylate therapy as treatment for residual disease after transplant. Molecular remission is a complete remission with no evidence of disease in the blood cells and/or bone marrow using sensitive polymerase chain reaction (PCR) tests. |
| Participants' With mCR Response to Post Transplant DLI | 1 year | Number of participants with response of molecular complete remission (mCR) to DLI as treatment for residual disease after transplant. Molecular remission is a complete remission with no evidence of disease in the blood cells and/or bone marrow using sensitive polymerase chain reaction (PCR) tests. |
Countries
United States
Participant flow
Recruitment details
Recruitment Period: 02/12/03 to 01/15/09. All patients were recruited at UT MD Anderson Cancer Center.
Pre-assignment details
One patient registered for transplant became ineligible before any treatment due to infection and was taken off study; 41 patients received the transplant regimen and an Allogeneic transplant.
Participants by arm
| Arm | Count |
|---|---|
| Mesylate, Busulfan, Fludarabine + Antithymocyte Globulin Oral Imatinib Mesylate 400 mg twice a day for 9 Days; Busulfan 130 mg/m\^2 by vein (IV) daily for 2 Days; Fludara 40 mg/m\^2 IV daily for 4 Days; Antithymocyte Globulin (ATG) 2.5 mg/kg IV daily for 3 Days; Tacrolimus levels maintained between 5-15 ng/dl, Day -2 to Day 180; Methotrexate 5 mg/m2 on days 1, 3, 6 and 11; and Donor bone marrow or blood stem cells infused on day 0 with possible donor lymphocyte infusion (DLI) for progressive disease. | 42 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Infection prior to treatment | 1 |
Baseline characteristics
| Characteristic | Mesylate, Busulfan, Fludarabine + Antithymocyte Globulin |
|---|---|
| Age, Categorical <=18 years | 1 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 39 Participants |
| Age Continuous | 42.2 years FULL_RANGE 42 |
| Region of Enrollment United States | 42 participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 37 / 41 |
| serious Total, serious adverse events | 12 / 41 |
Outcome results
Primary
Number of Participants in Complete Molecular Remission at 1 Year
Participants at 1 year in molecular remission, post transplant, post imatinib mesylate and donor lymphocyte infusion (DLI). Molecular remission is a complete remission with no evidence of disease in the blood cells and/or bone marrow using sensitive polymerase chain reaction (PCR) tests (this test is most commonly used in clinical trials).
Time frame: Baseline to 1 year
Population: Analysis was per protocol. One patient did not receive treatment and was excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mesylate, Busulfan, Fludarabine + Antithymocyte Globulin | Number of Participants in Complete Molecular Remission at 1 Year | 21 participants |
Secondary
Participants' With mCR Response to Post Transplant DLI
Number of participants with response of molecular complete remission (mCR) to DLI as treatment for residual disease after transplant. Molecular remission is a complete remission with no evidence of disease in the blood cells and/or bone marrow using sensitive polymerase chain reaction (PCR) tests.
Time frame: 1 year
Population: Only 8 participants having the post-transplant DLI out of the 41 participants treated were analyzed for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mesylate, Busulfan, Fludarabine + Antithymocyte Globulin | Participants' With mCR Response to Post Transplant DLI | 4 Participants |
Secondary
Participants' With mCR Response to Post Transplant Imatinib Mesylate Therapy
Number of participants with response of molecular complete remission (mCR) to Imatinib Mesylate therapy as treatment for residual disease after transplant. Molecular remission is a complete remission with no evidence of disease in the blood cells and/or bone marrow using sensitive polymerase chain reaction (PCR) tests.
Time frame: 1 Year
Population: Analysis was per protocol. Only 19 participants having the post transplant Imatinib Mesylate Therapy out of the 41 participants treated were analyzed for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mesylate, Busulfan, Fludarabine + Antithymocyte Globulin | Participants' With mCR Response to Post Transplant Imatinib Mesylate Therapy | 10 Participants |