Graft Versus Host Disease, Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic/Myeloproliferative Diseases, Myelodysplastic Syndromes, Secondary Myelofibrosis
Conditions
Keywords
graft versus host disease, adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(15;17)(q22;q12), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), recurrent adult acute myeloid leukemia, untreated adult acute myeloid leukemia, untreated adult acute lymphoblastic leukemia, accelerated phase chronic myelogenous leukemia, blastic phase chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia, relapsing chronic myelogenous leukemia, stage III multiple myeloma, refractory multiple myeloma, de novo myelodysplastic syndromes, myelodysplastic/myeloproliferative disease, unclassifiable, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, secondary myelofibrosis, secondary acute myeloid leukemia, recurrent adult Burkitt lymphoma, recurrent adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse small cleaved cell lymphoma, recurrent adult Hodgkin lymphoma, recurrent adult immunoblastic large cell lymphoma, recurrent adult lymphoblastic lymphoma, recurrent adult T-cell leukemia/lymphoma, recurrent cutaneous T-cell non-Hodgkin lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle cell lymphoma, recurrent marginal zone lymphoma, recurrent small lymphocytic lymphoma, recurrent adult acute lymphoblastic leukemia, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma, adult nasal type extranodal NK/T-cell lymphoma, stage III adult Hodgkin lymphoma, stage IV adult Hodgkin lymphoma, stage III adult T-cell leukemia/lymphoma, stage IV adult T-cell leukemia/lymphoma, stage III adult Burkitt lymphoma, stage IV adult Burkitt lymphoma, stage III adult diffuse large cell lymphoma, stage IV adult diffuse large cell lymphoma, stage III adult diffuse mixed cell lymphoma, stage IV adult diffuse mixed cell lymphoma, stage III adult immunoblastic large cell lymphoma, stage IV adult immunoblastic large cell lymphoma, stage III adult lymphoblastic lymphoma, stage IV adult lymphoblastic lymphoma, stage III grade 1 follicular lymphoma, stage III grade 2 follicular lymphoma, stage III grade 3 follicular lymphoma, stage IV grade 1 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage IV grade 3 follicular lymphoma, stage III mantle cell lymphoma, stage IV mantle cell lymphoma, stage III marginal zone lymphoma, stage IV marginal zone lymphoma, stage III small lymphocytic lymphoma, stage IV small lymphocytic lymphoma, stage III adult diffuse small cleaved cell lymphoma, stage IV adult diffuse small cleaved cell lymphoma, adult acute lymphoblastic leukemia in remission, adult acute myeloid leukemia in remission, atypical chronic myeloid leukemia, noncontiguous stage II adult Burkitt lymphoma, noncontiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse mixed cell lymphoma, noncontiguous stage II adult diffuse small cleaved cell lymphoma, noncontiguous stage II adult immunoblastic large cell lymphoma, noncontiguous stage II adult lymphoblastic lymphoma, noncontiguous stage II grade 1 follicular lymphoma, noncontiguous stage II grade 2 follicular lymphoma, noncontiguous stage II grade 3 follicular lymphoma, noncontiguous stage II mantle cell lymphoma, noncontiguous stage II marginal zone lymphoma, noncontiguous stage II small lymphocytic lymphoma, refractory hairy cell leukemia, stage I multiple myeloma, stage II multiple myeloma
Brief summary
RATIONALE: Giving chemotherapy before a donor bone marrow transplant or peripheral stem cell transplant helps stop the growth of cancer cells and helps stop the patient's immune system from rejecting the donor's stem cells. When certain 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 tacrolimus and mycophenolate mofetil after the transplant may stop this from happening. PURPOSE: This phase II trial is studying how well giving busulfan together with cyclophosphamide and antithymocyte globulin followed by donor stem cell transplant works in treating patients with hematologic cancer.
Detailed description
OBJECTIVES: Primary * To determine the incidence of grade II-IV acute graft-versus-host disease in patients with hematologic cancer or other diseases treated with a myeloablative conditioning regimen comprising targeted (steady-state concentration of 800-1,000 ng/mL) busulfan, cyclophosphamide, and anti-thymocyte globulin followed by matched unrelated donor allogeneic hematopoietic stem cell transplantation. * To determine the day +100 transplantation-related mortality in these patients. Secondary * To determine the effect of cyclophosphamide pharmacokinetic parameters on day +100 transplantation-related mortality in these patients. * To determine the ability of low-dose anti-thymocyte globulin administered on day +5 to induce activation-induced cell death of activated donor lymphocytes. * To determine the incidence of chronic graft-versus-host disease in patients treated with this regimen. * To determine event-free and overall survival of patients treated with this regimen. * To evaluate pharmacogenomic associations between genetic polymorphisms in drug disposition enzymes with the pharmacokinetics of busulfan and cyclophosphamide. OUTLINE: * Myeloablative conditioning regimen: Patients receive busulfan IV over 2 hours on days -8 to -5; cyclophosphamide IV over 4 hours on days -3 to -2; and anti-thymocyte globulin IV over 6 hours on day -3 and then over 4 hours on days -2, -1, and 5. * Allogeneic hematopoietic stem cell transplantation: Patients undergo allogeneic bone marrow or peripheral blood stem cell infusion on day 0. * Graft-versus-host-disease prophylaxis: Patients receive tacrolimus IV continuously or orally on days 6 to150, followed by an even taper to day 180 in the absence of graft-versus-host-disease. Patients also receive mycophenolate mofetil IV or orally beginning on day 6 and continuing to day 28. Patients undergo blood collection periodically during study for pharmacokinetic, pharmacogenomic, and other translational studies. Genomic DNA extracted from blood samples is analyzed by polymerase chain reaction for genetic polymorphisms in cyclophosphamide/busulfan disposition enzymes. Activated donor lymphocytes are assessed using flow cytometry to measure activation-induced cell death, as reflected by apoptosis in activated T cells. Chimerism on or around day 100 is also assessed using fluorescence in situ hybridization analysis and DNA fingerprinting. After completion of study treatment, patients are followed periodically.
Interventions
BIOLOGICALanti-thymocyte globulin
DRUGbusulfan
DRUGcyclophosphamide
DRUGmycophenolate mofetil
DRUGtacrolimus
GENETICpolymerase chain reaction
GENETICpolymorphism analysis
OTHERflow cytometry
OTHERlaboratory biomarker analysis
OTHERpharmacogenomic studies
OTHERpharmacological study
PROCEDUREallogeneic bone marrow transplantation
PROCEDUREallogeneic hematopoietic stem cell transplantation
PROCEDUREperipheral blood stem cell transplantation
Sponsors
National Cancer Institute (NCI)
University of Nebraska
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Pathologically confirmed diagnosis of 1 of the following: * Acute myeloid leukemia * Acute lymphocytic leukemia * Chronic myelogenous leukemia beyond first chronic phase (i.e., 2nd chronic phase, accelerated phase, or blast crisis) * Multiple myeloma * Myelodysplastic syndromes * Malignant lymphoma * Myelofibrosis * Requirement for myeloablative conditioning regimen confirmed by attending physician * Available donor must meet the following criteria: * HLA phenotypically identical unrelated donor by low, intermediate, or high resolution for HLA class I antigens, and by high resolution for HLA class II antigens * Matched at the A, B, and DRβ1 loci * Single HLA-A or HLA-B antigen mismatch allowed * Meets all National Marrow Donor Program or foreign registry criteria for allogeneic bone marrow/stem cell donors * Peripheral blood stem cells are the preferred product on this study but bone marrow is allowed * Karnofsky performance status 70-100% * DLCO ≥ 50% predicted * LVEF ≥ 45% * Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 65 mL/min * Serum total bilirubin ≤ 2.0 mg/dL * Fertile patients must use effective contraception
Exclusion criteria
* No active uncontrolled infection * Not pregnant or nursing/negative pregnancy test * No HIV infection * No chronic active hepatitis B or C or evidence of cirrhosis on liver biopsy
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Transplantation-related Mortality at 100 Days Post-transplantation | at the 100 days post-transplant |
Secondary
| Measure | Time frame |
|---|---|
| Incidence of Grade II-IV Acute Graft-versus-host-disease (GVHD) | at day 100 post transplantation |
| Overall Survival | 2 years post transplant |
| Event-free Survival | 2 years post transplant |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Unrelated Donor Allogeneic Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin. | 5 |
| Total | 5 |
Baseline characteristics
| Characteristic | Unrelated Donor Allogeneic |
|---|---|
| Age, Continuous | 50 years |
| Race/Ethnicity, Customized Caucasian | 5 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 5 |
| other Total, other adverse events | 5 / 5 |
| serious Total, serious adverse events | 3 / 5 |
Outcome results
Primary
Transplantation-related Mortality at 100 Days Post-transplantation
Time frame: at the 100 days post-transplant
Population: count of participants reflects number of participants not alive at 100 days post transplant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Unrelated Donor Allogeneic | Transplantation-related Mortality at 100 Days Post-transplantation | 2 Participants |
Secondary
Event-free Survival
Time frame: 2 years post transplant
Population: Number of participants at 2 years that experienced event-free survival.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Unrelated Donor Allogeneic | Event-free Survival | 2 Participants |
Secondary
Incidence of Grade II-IV Acute Graft-versus-host-disease (GVHD)
Time frame: at day 100 post transplantation
Population: count of participants represents number of participants with documented acute GVHD prior to day 100 post transplant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Unrelated Donor Allogeneic | Incidence of Grade II-IV Acute Graft-versus-host-disease (GVHD) | 4 Participants |
Secondary
Overall Survival
Time frame: 2 years post transplant
Population: Count of participants is the number of participant alive at the 2 year post transplant time point.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Unrelated Donor Allogeneic | Overall Survival | 2 Participants |