Acute Myeloid Leukemia, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Hodgkin Lymphoma, Leukemia, Multiple Myeloma, Myelodysplastic Syndrome, Non-Hodgkin's Lymphoma
Conditions
Keywords
total body irradiation, Allogeneic Peripheral Blood Stem Cell Transplantation, thymoglobulin
Brief summary
One of two different doses of thymoglobulin will allow bone marrow engraftment with minimal Graft-versus-Host Disease and allow adequate immune response to allow the transplanted stem cells to replace the tumor cells.
Detailed description
This randomized phase II trial studies how well giving low dose total-body irradiation (TBI) with anti-thymocyte globulin followed by donor peripheral blood stem cell transplant (PBSCT) works in treating patients with hematologic malignancies. Giving reduced intensity total-body irradiation and anti-thymocyte globulin before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving total-body irradiation together with antithymocyte globulin before transplant may stop this from happening.
Interventions
BIOLOGICALThymoglobulin
Patients eligible for participation in this study will be randomized between receiving rabbit ATG for 3 days. Thymoglobulin will be administered according to VCU BMT standard of care starting day -9 and continued daily through day -7.
RADIATIONTotal-Body Irradiation
Undergo TBI
PROCEDUREAllogeneic PBSCT or BMT
Undergo allogeneic PBSCT or BMT
DRUGTacrolimus
Given PO
DRUGMycophenolate Mofetil
Given PO
Sponsors
Genzyme, a Sanofi Company
Virginia Commonwealth University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Patients with hematological malignancies for which allogeneic stem cell transplantation indicated including non-Hodgkin lymphoma (NHL), multiple myeloma (MM), acute myeloid leukemia (AML), Hodgkin lymphoma (HD), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS) * Patients with HLA compatible related or unrelated stem cell donor, willing and able to serve as an allogenic HSC donor. Unrelated donors have to be matched at HLA-A, B, C and DRB1 loci. A single locus mismatch will be tolerated in the event a more closely matched donor is not available. * Patients age \>/=40 to \</=70 with an ECOG performance status \< 2 * Patients between 18 and 40 years of age will be eligible only if they have co-morbidities precluding conventional allogeneic transplantation with full intensity myeloablative conditioning * Adequate cardiac, pulmonary, renal and hepatic function for transplant * Negative serology for HIV * Negative serum pregnancy test * Patients who have received therapeutic radiation to a localized field will be eligible, provided critical structure tolerance doses have not been exceeded * Patients who have had prior myeloablative autologous transplant will be eligible
Exclusion criteria
* Evidence of uncontrolled viral, fungal, bacterial infection * Evidence of active meningeal or CNS disease * Prior therapy with rabbit ATG, prior treatment with equine ATG is allowed if more than 3 months ago * Breast feeding mothers are excluded
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Comparison of Functional Immune Reconstitution at 6-9 Months Following Transplant as Measured by Antibody Response to Vaccination With Inactivated Hepatitis A or B Vaccine. | Up to 9 months following transplant | A positive test result will indicate immune reconstitution, while a negative test results will indicate lack of immune reconstitution. Participants not done (ND) will be counted with the negative (Neg). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Survival | 2-year survival rate (%) | — |
| Treatment Related Mortality | Day 100 | — |
| Event-free Survival | 2 years | — |
| Engraftment of Donor Hematopoietic Stem Cells, as Measured by Time in Days to Neutrophil and Platelet Count Recovery Following Allogeneic PBSCT. | Up to 52 weeks post transplant. | — |
| Donor Lymphocyte Infusion | 2 year rate of DLI | — |
| Acute Graft-Versus-Host Disease (GVHD) | 2 year rate (%) | — |
| Chronic Graft-Versus-Host Disease (GVHD) | 2 year GVHD rate | — |
| Relapse | 2 year relapse rate (%) | Patients with different disease relapses was determined according to current clinical standards based on the disease. For example, AML or MDS relapse is determined by a bone marrow biopsy. Multiple myeloma relapse requires a number of labs and/or biopsy to diagnose such as SPEP, UPEP, immunofixation, serum and urine light chains. In lymphoma disease is followed using CT and/or PET scans. |
Countries
United States
Participant flow
Recruitment details
Consecutive patients enrolled have recurrent or high-risk hematologic malignancy, adequate end-organ function and performance status. Patient required to have 7/8 or 8/8 mismatched related donor (MRD) or unrelated donor (URD), with high-resolution typing performed for HLA-A, -B, -C, and -DRB1.
Pre-assignment details
Randomized to rabbit ATG (Thymoglobulin; Genzyme, Cambridge, MA), 2.5 or 1.7 mg/kg adjusted ideal body weight/day, followed by TBI to a total dose of 4.5 Gy. Methylprednisolone 2 mg/kg given pre-medication for ATG. GVHD prophylaxis was tacrolimus starting at approximately 12 weeks post transplantation.
Participants by arm
| Arm | Count |
|---|---|
| A:Thymoglobulin: 1.7 mg/kg/Day 1.7 mg/kg/d thymoglobulin IV d-9 to -7 | 19 |
| B:Thymoglobulin: 2.5 mg/kg/Day 2.5 mg/kg/d thymoglobulin IV d-9 to d-7 | 23 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Unable to proceed to transplant | 0 | 1 |
Baseline characteristics
| Characteristic | A:Thymoglobulin: 1.7 mg/kg/Day | B:Thymoglobulin: 2.5 mg/kg/Day | Total |
|---|---|---|---|
| Age, Continuous | 57 years | 57 years | 57 years |
| Region of Enrollment United States | 19 participants | 23 participants | 42 participants |
| Sex: Female, Male Female | 7 Participants | 8 Participants | 15 Participants |
| Sex: Female, Male Male | 12 Participants | 15 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 19 / 19 | 22 / 22 |
| serious Total, serious adverse events | 7 / 19 | 12 / 22 |
Outcome results
Primary
The Comparison of Functional Immune Reconstitution at 6-9 Months Following Transplant as Measured by Antibody Response to Vaccination With Inactivated Hepatitis A or B Vaccine.
A positive test result will indicate immune reconstitution, while a negative test results will indicate lack of immune reconstitution. Participants not done (ND) will be counted with the negative (Neg).
Time frame: Up to 9 months following transplant
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| A:Thymoglobulin: 1.7 mg/kg/Day | The Comparison of Functional Immune Reconstitution at 6-9 Months Following Transplant as Measured by Antibody Response to Vaccination With Inactivated Hepatitis A or B Vaccine. | Positive | 8 participants |
| A:Thymoglobulin: 1.7 mg/kg/Day | The Comparison of Functional Immune Reconstitution at 6-9 Months Following Transplant as Measured by Antibody Response to Vaccination With Inactivated Hepatitis A or B Vaccine. | Negative/Not Done | 11 participants |
| B:Thymoglobulin: 2.5 mg/kg/Day | The Comparison of Functional Immune Reconstitution at 6-9 Months Following Transplant as Measured by Antibody Response to Vaccination With Inactivated Hepatitis A or B Vaccine. | Positive | 3 participants |
| B:Thymoglobulin: 2.5 mg/kg/Day | The Comparison of Functional Immune Reconstitution at 6-9 Months Following Transplant as Measured by Antibody Response to Vaccination With Inactivated Hepatitis A or B Vaccine. | Negative/Not Done | 19 participants |
Secondary
Acute Graft-Versus-Host Disease (GVHD)
Time frame: 2 year rate (%)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A:Thymoglobulin: 1.7 mg/kg/Day | Acute Graft-Versus-Host Disease (GVHD) | 27.2 percentage of participant |
| B:Thymoglobulin: 2.5 mg/kg/Day | Acute Graft-Versus-Host Disease (GVHD) | 4.5 percentage of participant |
Secondary
Chronic Graft-Versus-Host Disease (GVHD)
Time frame: 2 year GVHD rate
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A:Thymoglobulin: 1.7 mg/kg/Day | Chronic Graft-Versus-Host Disease (GVHD) | 23.8 percentage of participants |
| B:Thymoglobulin: 2.5 mg/kg/Day | Chronic Graft-Versus-Host Disease (GVHD) | 31.8 percentage of participants |
Secondary
Donor Lymphocyte Infusion
Time frame: 2 year rate of DLI
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A:Thymoglobulin: 1.7 mg/kg/Day | Donor Lymphocyte Infusion | 8.9 percentage of participants |
| B:Thymoglobulin: 2.5 mg/kg/Day | Donor Lymphocyte Infusion | 45.5 percentage of participants |
Secondary
Engraftment of Donor Hematopoietic Stem Cells, as Measured by Time in Days to Neutrophil and Platelet Count Recovery Following Allogeneic PBSCT.
Time frame: Up to 52 weeks post transplant.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A:Thymoglobulin: 1.7 mg/kg/Day | Engraftment of Donor Hematopoietic Stem Cells, as Measured by Time in Days to Neutrophil and Platelet Count Recovery Following Allogeneic PBSCT. | 12 Days |
| B:Thymoglobulin: 2.5 mg/kg/Day | Engraftment of Donor Hematopoietic Stem Cells, as Measured by Time in Days to Neutrophil and Platelet Count Recovery Following Allogeneic PBSCT. | 12 Days |
Secondary
Event-free Survival
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A:Thymoglobulin: 1.7 mg/kg/Day | Event-free Survival | 62.2 percentage of participants |
| B:Thymoglobulin: 2.5 mg/kg/Day | Event-free Survival | 44.5 percentage of participants |
Secondary
Relapse
Patients with different disease relapses was determined according to current clinical standards based on the disease. For example, AML or MDS relapse is determined by a bone marrow biopsy. Multiple myeloma relapse requires a number of labs and/or biopsy to diagnose such as SPEP, UPEP, immunofixation, serum and urine light chains. In lymphoma disease is followed using CT and/or PET scans.
Time frame: 2 year relapse rate (%)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A:Thymoglobulin: 1.7 mg/kg/Day | Relapse | 28 Percent patients relapsing |
| B:Thymoglobulin: 2.5 mg/kg/Day | Relapse | 50 Percent patients relapsing |
Secondary
Survival
Time frame: 2-year survival rate (%)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A:Thymoglobulin: 1.7 mg/kg/Day | Survival | 71.3 percentage of patient surviving |
| B:Thymoglobulin: 2.5 mg/kg/Day | Survival | 62.4 percentage of patient surviving |
Secondary
Treatment Related Mortality
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A:Thymoglobulin: 1.7 mg/kg/Day | Treatment Related Mortality | 0 percentage of patients |
| B:Thymoglobulin: 2.5 mg/kg/Day | Treatment Related Mortality | 0 percentage of patients |