Busulfan, Cyclophosphamide, and Antithymocyte Globulin Followed by Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Unrelated Donor Allogeneic Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin. |
Biological: anti-thymocyte globulin
Drug: busulfan
Drug: cyclophosphamide
Drug: mycophenolate mofetil
Drug: tacrolimus
Genetic: polymerase chain reaction
Genetic: polymorphism analysis
Other: flow cytometry
Other: laboratory biomarker analysis
Other: pharmacogenomic studies
Other: pharmacological study
Procedure: allogeneic bone marrow transplantation
Procedure: allogeneic hematopoietic stem cell transplantation
Procedure: peripheral blood stem cell transplantation
|
Outcome Measures
Primary Outcome Measures
- Transplantation-related Mortality at 100 Days Post-transplantation [at the 100 days post-transplant]
Secondary Outcome Measures
- 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]
Eligibility Criteria
Criteria
DISEASE CHARACTERISTICS:
-
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
PATIENT CHARACTERISTICS:
-
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
-
No active uncontrolled infection
-
Not pregnant or nursing
-
Negative pregnancy test
-
Fertile patients must use effective contraception
-
No HIV infection
-
No chronic active hepatitis B or C or evidence of cirrhosis on liver biopsy
PRIOR CONCURRENT THERAPY:
- Not specified
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Lori Maness Harris, MD
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Marcel Devetten, MD, University of Nebraska
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 122-05
- P30CA036727
- UNMC-12205
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Unrelated Donor Allogeneic |
|---|---|
| Arm/Group Description | Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin. |
| Period Title: Overall Study | |
| STARTED | 5 |
| COMPLETED | 3 |
| NOT COMPLETED | 2 |
Baseline Characteristics
| Arm/Group Title | Unrelated Donor Allogeneic |
|---|---|
| Arm/Group Description | Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin. |
| Overall Participants | 5 |
| Age (years) [Mean (Full Range) ] | |
| Mean (Full Range) [years] |
50
|
| Sex: Female, Male (Count of Participants) | |
| Female |
1
20%
|
| Male |
4
80%
|
| Race/Ethnicity, Customized (Count of Participants) | |
| Caucasian |
5
100%
|
Outcome Measures
| Title | Transplantation-related Mortality at 100 Days Post-transplantation |
|---|---|
| Description | |
| Time Frame | at the 100 days post-transplant |
Outcome Measure Data
| Analysis Population Description |
|---|
| count of participants reflects number of participants not alive at 100 days post transplant. |
| Arm/Group Title | Unrelated Donor Allogeneic |
|---|---|
| Arm/Group Description | Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin. |
| Measure Participants | 5 |
| Count of Participants [Participants] |
2
40%
|
| Title | Incidence of Grade II-IV Acute Graft-versus-host-disease (GVHD) |
|---|---|
| Description | |
| Time Frame | at day 100 post transplantation |
Outcome Measure Data
| Analysis Population Description |
|---|
| count of participants represents number of participants with documented acute GVHD prior to day 100 post transplant. |
| Arm/Group Title | Unrelated Donor Allogeneic |
|---|---|
| Arm/Group Description | Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin. |
| Measure Participants | 5 |
| Count of Participants [Participants] |
4
80%
|
| Title | Overall Survival |
|---|---|
| Description | |
| Time Frame | 2 years post transplant |
Outcome Measure Data
| Analysis Population Description |
|---|
| Count of participants is the number of participant alive at the 2 year post transplant time point. |
| Arm/Group Title | Unrelated Donor Allogeneic |
|---|---|
| Arm/Group Description | Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin. |
| Measure Participants | 5 |
| Count of Participants [Participants] |
2
40%
|
| Title | Event-free Survival |
|---|---|
| Description | |
| Time Frame | 2 years post transplant |
Outcome Measure Data
| Analysis Population Description |
|---|
| Number of participants at 2 years that experienced event-free survival. |
| Arm/Group Title | Unrelated Donor Allogeneic |
|---|---|
| Arm/Group Description | Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin. |
| Measure Participants | 5 |
| Count of Participants [Participants] |
2
40%
|
Adverse Events
| Time Frame | Adverse events are collected from the time of consent until day plus 100 from transplant. | |
|---|---|---|
| Adverse Event Reporting Description | Grade 4 anemia, thrombocytopenia, and leucopenia, grade 3 dysphagia, and grade 3 infertility are routinely expected for all patients participating in this protocol, so these events were not reported. Multiple grade 1 and grade 2 toxicities are also expected for all patients participating in this protocol; these events will not routinely be reported. All other toxicities > grade 3 will be reported. | |
| Arm/Group Title | Unrelated Donor Allogeneic | |
| Arm/Group Description | Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin. | |
All Cause Mortality |
||
| Unrelated Donor Allogeneic | ||
| Affected / at Risk (%) | # Events | |
| Total | 2/5 (40%) | |
Serious Adverse Events |
||
| Unrelated Donor Allogeneic | ||
| Affected / at Risk (%) | # Events | |
| Total | 3/5 (60%) | |
| Infections and infestations | ||
| Lung infection | 1/5 (20%) | 1 |
| Infections and infestations - Other | 1/5 (20%) | 1 |
| Investigations | ||
| Blood bilirubin increased | 1/5 (20%) | 1 |
| Investigations - Other | 1/5 (20%) | 1 |
| Metabolism and nutrition disorders | ||
| hyperglycemia | 1/5 (20%) | 1 |
| Psychiatric disorders | ||
| confusion | 1/5 (20%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| Unrelated Donor Allogeneic | ||
| Affected / at Risk (%) | # Events | |
| Total | 5/5 (100%) | |
| Blood and lymphatic system disorders | ||
| Blood and lymphatic system - Other | 1/5 (20%) | 1 |
| Febrile Neutropenia | 4/5 (80%) | 4 |
| anemia | 1/5 (20%) | 1 |
| Cardiac disorders | ||
| acute coronary syndrome | 1/5 (20%) | 1 |
| Gastrointestinal disorders | ||
| Diarrhea | 3/5 (60%) | 3 |
| General disorders | ||
| Fatigue | 2/5 (40%) | 2 |
| Immune system disorders | ||
| Serum sickness | 2/5 (40%) | 2 |
| Infections and infestations | ||
| Infections and infestations - Other | 1/5 (20%) | 1 |
| Encephalitis infection | 1/5 (20%) | 1 |
| Encephalitis infection | 1/5 (20%) | 1 |
| Endocarditis infective | 1/5 (20%) | 1 |
| Investigations | ||
| Blood bilirubin increased | 3/5 (60%) | 3 |
| Platelet count decreased | 2/5 (40%) | 2 |
| Neutrophil count decreased | 1/5 (20%) | 1 |
| Metabolism and nutrition disorders | ||
| Hypoalbuminemia | 1/5 (20%) | 1 |
| Hyperglycemia | 3/5 (60%) | 3 |
| hypocalcemia | 1/5 (20%) | 1 |
| Anorexia | 1/5 (20%) | 1 |
| hypernatremia | 1/5 (20%) | 1 |
| hyponatremia | 1/5 (20%) | 1 |
| Nervous system disorders | ||
| syncope | 1/5 (20%) | 1 |
| Seizure | 1/5 (20%) | 1 |
| nervous system - Other | 1/5 (20%) | 1 |
| Psychiatric disorders | ||
| confusion | 1/5 (20%) | 1 |
| Renal and urinary disorders | ||
| Renal and Urinary disorders - Other | 2/5 (40%) | 2 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Lori Maness-Harris, MD |
|---|---|
| Organization | University of Nebraska Medical Center |
| Phone | 402-559-3848 |
| lmaness@unmc.edu |
- 122-05
- P30CA036727
- UNMC-12205