Bu Flu TBI: Busulfan, Fludarabine, and Total-Body Irradiation in Treating Patients Who Are Undergoing a Donor Stem Cell Transplant for Hematologic Cancer
Study Details
Study Description
Brief Summary
RATIONALE: Giving low doses of chemotherapy, such as fludarabine and busulfan, before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system and help destroy any remaining cancer cells (graft-versus-tumor effect). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.
PURPOSE: This phase I/II trial is studying the side effects of giving busulfan and fludarabine together with total-body irradiation and to see how well they work in treating patients who are undergoing a donor stem cell transplant for hematologic cancer.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
OBJECTIVES:
Primary
-
To assess safety and toxicity of the addition of busulfan added to an established fludarabine and low-dose total-body irradiation (TBI) conditioning regimen for non-myeloablative allogeneic transplantation in patients with hematologic malignancies. (Phase I)
-
To assess the non-relapse mortality 1-year after conditioning with busulfan and fludarabine/TBI in patients with hematologic malignancies at moderate to high risk for graft rejection and/or relapse of underlying disease. (Phase II)
Secondary
-
To assess overall survival 1-year survival. (Phase II)
-
To assess the incidence of graft rejection. (Phase II)
-
To assess the incidence of grade II-IV acute graft-vs-host disease (GVHD) and chronic extensive GVHD. (Phase II)
-
To assess rates of disease progression and/or relapse-related mortality. (Phase II)
-
To determine non-hematologic grade III-IV organ specific toxicity. (Phase II)
OUTLINE:
-
Nonmyeloablative-conditioning regimen: Patients receive busulfan IV on day -5 and fludarabine IV over 30 minutes on days -4 to -2. Patients undergo total body irradiation on day 0.
-
Allogeneic peripheral blood stem cell transplantation (PBSC): Patients undergo donor PBSC infusion on day 0.
-
Graft-versus-host disease prophylaxis: Patients receive oral cyclosporine twice daily on days -3 to 56 followed by a taper to day 180. Patients with a related stem cell donor receive oral mycophenolate mofetil twice daily on days 0-28. Patients with an unrelated stem cell donor receive oral mycophenolate mofetil 3 times daily on days 0-28 followed by a taper twice daily to day 56. Patients with evidence of relapse or persistent disease may also receive up to 3 donor lymphocyte infusions.
PROJECTED ACCRUAL: A total of 225 patients will be accrued for this study; 25 patients accrued into the Phase I and 200 patients into Phase II.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI) Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0 |
Biological: therapeutic allogeneic lymphocytes
A population of lymphocytes therapeutically administered to a recipient individual who is genetically distinct from a donor of the same species.
Drug: busulfan
Busulfan is an alkylating chemotherapeutic agent which has been used in many high dose and reduced intensity regimens prior to allogeneic or autologous hematopoietic stem cell transplants. It is active in a wide variety of malignancies and in high-doses it is myeloablative.
IV busulfan is available and diluted and administered per package insert guidelines.
Drug: cyclosporine
Cyclosporine is a cyclic polypeptide immunosuppressive agent. It blocks the calcium-dependent calcineurin-mediated nuclear localization of nuclear factor of activated T cells (NFAT) following T-cell activation, thereby inhibiting transactivation of key T-cell response genes including Interleukin 2 (IL-2) and Interleukin 4 (IL-4).
- Starting on day -3, Cyclosporine (CSP) is given at a dose of 4.0 mg/kg p.o. b.i.d.
Drug: fludarabine phosphate
Fludarabine's active metabolite 2-fluoro-ara-A is an antimetabolite that inhibits DNA primase, DNA polymerase alpha and ribonucleotide nuclease.
Dosing: Days -4, -3 and -2: Fludarabine 30 mg/m2/day IV. Total dose equals 90 mg/m2.
Monitoring: Fludarabine level is not monitored.
Dose Adjustments: There are no provisions for fludarabine dose adjustments.
Drug: mycophenolate mofetil
Mycophenolate mofetil (MMF) is the morpholinyl ethyl ester of mycophenolic acid (MPA) and reversibly inhibits inosine monophosphate dehydrogenase, particularly the type II isoform that is more prominent in activated lymphocytes. As a result of the inhibition of de novo purine synthesis, proliferation of B- and T-lymphocytes is blocked and antibody production is inhibited.
Related Donors: MMF will be given daily at 15mg/kg q 12 hrs until day +28, then stop without tapering. Doses will be rounded to the nearest 250 mg (capsules are 250 mg).
Unrelated Donors: MMF will be given daily at 15mg/kg q 8 hrs until day +28, then given daily at 15mg/kg q 12 hours until day +56, then stop without tapering. Doses will be rounded to the nearest 250 mg (capsules are 250 mg).
Procedure: peripheral blood stem cell transplantation
Bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) are procedures that restore stem cells that have been destroyed by high doses of chemotherapy and/or radiation therapy. There are three types of transplants:
In autologous transplants, patients receive their own stem cells.
In syngeneic transplants, patients receive stem cells from their identical twin.
In allogeneic transplants, patients receive stem cells from their brother, sister, or parent. A person who is not related to the patient (an unrelated donor) also may be used.
Radiation: Total Body Irradiation (TBI)
TBI is a form of radiotherapy used primarily as part of the preparative regimen for haematopoietic stem cell (or bone marrow) transplantation. As the name implies, TBI involves irradiation of the entire body, though in modern practice the lungs are often partially shielded to lower the risk of radiation-induced lung injury.
Toxicities: At the dosage used, side effects are not expected. Nevertheless, there may be fever, alopecia, parotitis, diarrhea, reversible skin pigmentation, mucositis and late effects including cataract formation, pulmonary damage, carcinogenesis, and sterilization.
Dosing: TBI will be given in one 200 cGy fraction from linear accelerator at a rate of 15-19 cGy/min.
Drug: Granulocyte colony-stimulating factor (G-CSF)
Granulocyte colony-stimulating factor (G-CSF or GCSF) is a colony-stimulating factor hormone. G-CSF is also known as colony-stimulating factor 3 (CSF 3).
It is a glycoprotein, growth factor and cytokine produced by a number of different tissues to stimulate the bone marrow to produce granulocytes and stem cells. G-CSF then stimulates the bone marrow to release them into the blood.
Toxicities: At the dosage used, the most common side effect will be medullary bone pain.
Dosing: 5 mcg/kg/day given per institutional standards (on approximately days 10-15 or not at all).
Drug: Phenytoin
This drug is used to prevent seizures while on chemotherapy.
Drug: Methotrexate
Methotrexate is used to treat severe psoriasis (a skin disease in which red, scaly patches form on some areas of the body) that cannot be controlled by other treatments.
|
Outcome Measures
Primary Outcome Measures
- Regimen-Related Toxicities [5 years post-transplant]
Non-hematologic toxicities and adverse experiences ≥ Grade 3 occurrences measured up to day +100 using the NCI Common Toxicity Criteria for Adverse Events v3.0 (CTCAE). Infections and GVHD will be assessed up to 5 years post transplant. The following data represents the number of regimen-related, grade 3 and 4 toxicities that occurred in each category.
- Non-relapse Mortality [Two years post-transplant]
Percent of subjects with non-relapse mortality two years after conditioning with busulfan with fludarabine/200 cGy TBI in patients with hematologic malignancies at moderate to high risk for graft rejection and/or relapse of underlying disease.
Secondary Outcome Measures
- Overall Survival [Years 1, 2, 3 and 5]
The percentage of overall patient survival (out of 147 participants) for Years 1, 2, 3 and 5.
- Progression-Free Survival [Years 1, 2, 3, and 5]
The percentage of progression-free patients (out of 147 participants) at Years 1, 2, 3, and 5. Definition of Disease Progression: MM/Plasma Cell: Increasing bone pain or increase in serum/urine monoclonal protein by 25%. CLL/NHL/HD: New sites of lymphadenopathy; ≥ 25% increase in lymph node size; Blood or bone marrow involvement with clonal B-cells; Increase of ≥ 25% bone marrow involvement; ≥ 25% increase in blood involvement with clonal B-cells. AML/ALL: Any incidence of relapse (>5% blasts) by evaluation of the bone marrow aspirate. CML: Inability to control platelet or granulocyte counts; Increase in baseline number of metaphases demonstrating the Ph+ chromosome by >25%; Any other new cytogenetic abnormality; Transformation to accelerated phase or blast crisis. MDS/MPD: Any evidence by morphologic or flow cytometric evaluation of the bone marrow aspirate of new blasts (>5%) or worsening cytopenia or cytogenetic evidence of recurrence.
- Relapse Mortality [Years 1 and 2]
The percentage of patients (out of 147 participants) who relapsed at Years 1 and 2. Relapse is defined as the presence of >5% blasts by morphology on a post-transplant bone marrow aspirate.
- Acute Graft-Versus-Host Disease (aGVHD) Outcome [Day 100, Month 6]
Grading of Acute GVHD: Severity of Individual Organ Involvement: Skin 1 a maculopapular eruption involving less than 25% of the body surface 2 a maculopapular eruption involving 25-50% of the body surface 3 generalized erythroderma 4 generalized erythroderma with bullous formation and/or with desquamation Liver 1 bilirubin 2.0-3.0mg/100mL 2 bilirubin 3-5.9mg/100mL 3 bilirubin 6-14.9mg/100mL 4 bilirubin >15mg/100mL Gut Diarrhea is graded +1 to +4 in severity. Nausea/vomiting and/or anorexia caused by GVHD is assigned as +1 in severity Diarrhea 1 <1000mL of liquid stool/day 2 >1,000mL of stool/day 3 >1,500mL of stool/day 4 2,000mL of stool/day, severe abdominal pain, with or without ileus Severity of GVHD: Grade 1 +1 to +2 skin rash; No gut or liver involvement Grade 2 +1 to +3 skin rash;+1 GI involvement and/or +1 liver
- Chronic Graft-Versus-Host Disease (cGVHD) Outcome [Years 1, 2 and 3]
Grading of Chronic GVHD: Limited: Localized skin involvement and/or hepatic dysfunction due to chronic GVHD Extensive: One or more of the following: Generalized skin involvement Liver histology showing chronic aggressive hepatitis, bridging necrosis or cirrhosis Involvement of the eye: Schirmer's test with <5 mm wetting Involvement of minor salivary glands or oral mucosa demonstrated on labial biopsy Involvement of any other target organ Chronic GVHD Severity: Mild: Signs and symptoms of cGVHD do not interfere substantially with function and do not progress once appropriately treated with local therapy or standard systemic therapy. Moderate: Signs and symptoms of cGVHD interfere somewhat with function despite appropriate therapy or are progressive through first line systemic therapy. Severe: Signs and symptoms of cGVHD limit function substantially despite appropriate therapy or are progressive through second line systemic therapy
Eligibility Criteria
Criteria
DISEASE CHARACTERISTICS:
-
Diagnosis of a hematologic malignancy of 1 of the following high-risk types:
-
Acute lymphoblastic leukemia
-
Acute myeloid leukemia
-
Chronic myelogenous leukemia
-
Chronic lymphocytic leukemia
-
Myelodysplastic syndromes
-
Myeloproliferative disorder
-
Multiple myeloma
-
Plasma cell dyscrasias
-
Non-Hodgkin lymphoma
-
Hodgkin disease
PATIENT CHARACTERISTICS:
Performance status
- Karnofsky 50-100%
Life expectancy
- Not specified
Hematopoietic
- Not specified
Hepatic
-
No liver failure
-
No cirrhosis with evidence of portal hypertension
-
No alcoholic hepatitis
-
No esophageal varices
-
No chronic hepatitis
-
No other liver disease
Renal
- Not specified
Cardiovascular
-
Left Ventricular Ejection Fraction (LVEF) > 35%
-
No symptomatic coronary artery disease or cardiac failure requiring therapy
Pulmonary
-
Diffusing capacity of lung for carbon monoxide (DLCO) > 30%
-
Total lung capacity > 30%
-
Forced expiratory volume in 1 second (FEV_1) > 30%
-
No supplementary continuous oxygen
Other
-
HIV negative
-
No active nonhematologic malignancy except localized skin cancer
-
No overt organ dysfunction
PRIOR CONCURRENT THERAPY:
- Not specified
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Knight Cancer Institute at Oregon Health and Science University | Portland | Oregon | United States | 97239-3098 |
Sponsors and Collaborators
- OHSU Knight Cancer Institute
- National Cancer Institute (NCI)
Investigators
- Study Chair: Richard Maziarz, MD, OHSU Knight Cancer Institute
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- IRB00000210
- P30CA016058
- OHSU-HEM-05011-L
- OHSU-210
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI) |
|---|---|
| Arm/Group Description | Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0 Therapeutic allogeneic lymphocytes: A population of lymphocytes therapeutically administered to a recipient individual who is genetically distinct from a donor of the same species. Busulfan: Busulfan is an alkylating chemotherapeutic agent which has been used in many high dose and reduced intensity regimens prior to allogeneic or autologous hematopoietic stem cell transplants. It is active in a wide variety of malignancies and in high-doses it is myeloablative. IV Busulfan is available and diluted and administered per package insert guidelines. Cyclosporine: Cyclosporine is a cyclic polypeptide immunosuppressive agent. It blocks the calcium-dependent calcineurin-mediated nuclear localization of nuclear factor of activated T cells (NFAT) following T-cell activation, thereby inhibiting transactivation of key T-cell response genes including |
| Period Title: Overall Study | |
| STARTED | 147 |
| COMPLETED | 130 |
| NOT COMPLETED | 17 |
Baseline Characteristics
| Arm/Group Title | Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI) |
|---|---|
| Arm/Group Description | Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0 Therapeutic allogeneic lymphocytes: A population of lymphocytes therapeutically administered to a recipient individual who is genetically distinct from a donor of the same species. Busulfan: Busulfan is an alkylating chemotherapeutic agent which has been used in many high dose and reduced intensity regimens prior to allogeneic or autologous hematopoietic stem cell transplants. It is active in a wide variety of malignancies and in high-doses it is myeloablative. IV Busulfan is available and diluted and administered per package insert guidelines. Cyclosporine: Cyclosporine is a cyclic polypeptide immunosuppressive agent. It blocks the calcium-dependent calcineurin-mediated nuclear localization of nuclear factor of activated T cells (NFAT) following T-cell activation, thereby inhibiting transactivation of key T-cell response genes including |
| Overall Participants | 147 |
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
81
55.1%
|
| >=65 years |
66
44.9%
|
| Sex: Female, Male (Count of Participants) | |
| Female |
49
33.3%
|
| Male |
98
66.7%
|
| Karnofsky Performance Score (KPS) (Count of Participants) | |
| KPS ≥ 90 |
91
61.9%
|
| KPS < 90 |
48
32.7%
|
| Pre-Transplant Disease Status (Count of Participants) | |
| In Complete Remission |
85
57.8%
|
| Not in Complete Remission |
62
42.2%
|
| Disease Risk Index (DRI) (Count of Participants) | |
| Low or intermediate |
93
63.3%
|
| High or Very High |
51
34.7%
|
| HLA Match (Count of Participants) | |
| 8/8 |
135
91.8%
|
| 7/8 |
12
8.2%
|
| Donor Relation (Count of Participants) | |
| Related Sibling Donor |
39
26.5%
|
| Unrelated Donor |
108
73.5%
|
| Cytomegalovirus (CMV) Status (Count of Participants) | |
| -/- recipient/donor |
22
15%
|
| All other combinations |
118
80.3%
|
| Donor/Recipient Gender (Count of Participants) | |
| F/F, M/M, M/F |
117
79.6%
|
| F/M |
30
20.4%
|
Outcome Measures
| Title | Regimen-Related Toxicities |
|---|---|
| Description | Non-hematologic toxicities and adverse experiences ≥ Grade 3 occurrences measured up to day +100 using the NCI Common Toxicity Criteria for Adverse Events v3.0 (CTCAE). Infections and GVHD will be assessed up to 5 years post transplant. The following data represents the number of regimen-related, grade 3 and 4 toxicities that occurred in each category. |
| Time Frame | 5 years post-transplant |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI) |
|---|---|
| Arm/Group Description | Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0 Therapeutic allogeneic lymphocytes: A population of lymphocytes therapeutically administered to a recipient individual who is genetically distinct from a donor of the same species. Busulfan: Busulfan is an alkylating chemotherapeutic agent which has been used in many high dose and reduced intensity regimens prior to allogeneic or autologous hematopoietic stem cell transplants. It is active in a wide variety of malignancies and in high-doses it is myeloablative. IV Busulfan is available and diluted and administered per package insert guidelines. Cyclosporine: Cyclosporine is a cyclic polypeptide immunosuppressive agent. It blocks the calcium-dependent calcineurin-mediated nuclear localization of nuclear factor of activated T cells (NFAT) following T-cell activation, thereby inhibiting transactivation of key T-cell response genes including |
| Measure Participants | 147 |
| Cardiac Disorders |
21
|
| Renal Disorders |
10
|
| Respiratory Disorders |
8
|
| CNS Disorders |
16
|
| Hepatic Disorders |
39
|
| General Disorders |
30
|
| Title | Non-relapse Mortality |
|---|---|
| Description | Percent of subjects with non-relapse mortality two years after conditioning with busulfan with fludarabine/200 cGy TBI in patients with hematologic malignancies at moderate to high risk for graft rejection and/or relapse of underlying disease. |
| Time Frame | Two years post-transplant |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI) |
|---|---|
| Arm/Group Description | Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0 Therapeutic allogeneic lymphocytes: A population of lymphocytes therapeutically administered to a recipient individual who is genetically distinct from a donor of the same species. Busulfan: Busulfan is an alkylating chemotherapeutic agent which has been used in many high dose and reduced intensity regimens prior to allogeneic or autologous hematopoietic stem cell transplants. It is active in a wide variety of malignancies and in high-doses it is myeloablative. IV Busulfan is available and diluted and administered per package insert guidelines. Cyclosporine: Cyclosporine is a cyclic polypeptide immunosuppressive agent. It blocks the calcium-dependent calcineurin-mediated nuclear localization of nuclear factor of activated T cells (NFAT) following T-cell activation, thereby inhibiting transactivation of key T-cell response genes including |
| Measure Participants | 147 |
| Year 1 |
27
18.4%
|
| Year 2 |
33
22.4%
|
| Title | Overall Survival |
|---|---|
| Description | The percentage of overall patient survival (out of 147 participants) for Years 1, 2, 3 and 5. |
| Time Frame | Years 1, 2, 3 and 5 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI) |
|---|---|
| Arm/Group Description | Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0 Therapeutic allogeneic lymphocytes: A population of lymphocytes therapeutically administered to a recipient individual who is genetically distinct from a donor of the same species. Busulfan: Busulfan is an alkylating chemotherapeutic agent which has been used in many high dose and reduced intensity regimens prior to allogeneic or autologous hematopoietic stem cell transplants. It is active in a wide variety of malignancies and in high-doses it is myeloablative. IV Busulfan is available and diluted and administered per package insert guidelines. Cyclosporine: Cyclosporine is a cyclic polypeptide immunosuppressive agent. It blocks the calcium-dependent calcineurin-mediated nuclear localization of nuclear factor of activated T cells (NFAT) following T-cell activation, thereby inhibiting transactivation of key T-cell response genes including |
| Measure Participants | 147 |
| Year 1 |
60
40.8%
|
| Year 2 |
48
32.7%
|
| Year 3 |
42
28.6%
|
| Year 5 |
29
19.7%
|
| Title | Progression-Free Survival |
|---|---|
| Description | The percentage of progression-free patients (out of 147 participants) at Years 1, 2, 3, and 5. Definition of Disease Progression: MM/Plasma Cell: Increasing bone pain or increase in serum/urine monoclonal protein by 25%. CLL/NHL/HD: New sites of lymphadenopathy; ≥ 25% increase in lymph node size; Blood or bone marrow involvement with clonal B-cells; Increase of ≥ 25% bone marrow involvement; ≥ 25% increase in blood involvement with clonal B-cells. AML/ALL: Any incidence of relapse (>5% blasts) by evaluation of the bone marrow aspirate. CML: Inability to control platelet or granulocyte counts; Increase in baseline number of metaphases demonstrating the Ph+ chromosome by >25%; Any other new cytogenetic abnormality; Transformation to accelerated phase or blast crisis. MDS/MPD: Any evidence by morphologic or flow cytometric evaluation of the bone marrow aspirate of new blasts (>5%) or worsening cytopenia or cytogenetic evidence of recurrence. |
| Time Frame | Years 1, 2, 3, and 5 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI) |
|---|---|
| Arm/Group Description | Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0 Therapeutic allogeneic lymphocytes: A population of lymphocytes therapeutically administered to a recipient individual who is genetically distinct from a donor of the same species. Busulfan: Busulfan is an alkylating chemotherapeutic agent which has been used in many high dose and reduced intensity regimens prior to allogeneic or autologous hematopoietic stem cell transplants. It is active in a wide variety of malignancies and in high-doses it is myeloablative. IV Busulfan is available and diluted and administered per package insert guidelines. Cyclosporine: Cyclosporine is a cyclic polypeptide immunosuppressive agent. It blocks the calcium-dependent calcineurin-mediated nuclear localization of nuclear factor of activated T cells (NFAT) following T-cell activation, thereby inhibiting transactivation of key T-cell response genes including |
| Measure Participants | 147 |
| Year 1 |
48
32.7%
|
| Year 2 |
39
26.5%
|
| Year 3 |
35
23.8%
|
| Year 5 |
29
19.7%
|
| Title | Relapse Mortality |
|---|---|
| Description | The percentage of patients (out of 147 participants) who relapsed at Years 1 and 2. Relapse is defined as the presence of >5% blasts by morphology on a post-transplant bone marrow aspirate. |
| Time Frame | Years 1 and 2 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI) |
|---|---|
| Arm/Group Description | Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0 Therapeutic allogeneic lymphocytes: A population of lymphocytes therapeutically administered to a recipient individual who is genetically distinct from a donor of the same species. Busulfan: Busulfan is an alkylating chemotherapeutic agent which has been used in many high dose and reduced intensity regimens prior to allogeneic or autologous hematopoietic stem cell transplants. It is active in a wide variety of malignancies and in high-doses it is myeloablative. IV Busulfan is available and diluted and administered per package insert guidelines. Cyclosporine: Cyclosporine is a cyclic polypeptide immunosuppressive agent. It blocks the calcium-dependent calcineurin-mediated nuclear localization of nuclear factor of activated T cells (NFAT) following T-cell activation, thereby inhibiting transactivation of key T-cell response genes including |
| Measure Participants | 147 |
| Year 1 |
13
8.8%
|
| Year 2 |
20
13.6%
|
| Title | Acute Graft-Versus-Host Disease (aGVHD) Outcome |
|---|---|
| Description | Grading of Acute GVHD: Severity of Individual Organ Involvement: Skin 1 a maculopapular eruption involving less than 25% of the body surface 2 a maculopapular eruption involving 25-50% of the body surface 3 generalized erythroderma 4 generalized erythroderma with bullous formation and/or with desquamation Liver 1 bilirubin 2.0-3.0mg/100mL 2 bilirubin 3-5.9mg/100mL 3 bilirubin 6-14.9mg/100mL 4 bilirubin >15mg/100mL Gut Diarrhea is graded +1 to +4 in severity. Nausea/vomiting and/or anorexia caused by GVHD is assigned as +1 in severity Diarrhea 1 <1000mL of liquid stool/day 2 >1,000mL of stool/day 3 >1,500mL of stool/day 4 2,000mL of stool/day, severe abdominal pain, with or without ileus Severity of GVHD: Grade 1 +1 to +2 skin rash; No gut or liver involvement Grade 2 +1 to +3 skin rash;+1 GI involvement and/or +1 liver |
| Time Frame | Day 100, Month 6 |
Outcome Measure Data
| Analysis Population Description |
|---|
| This is cumulative incidence of grades 2-4 aGVHD at 100 days and at 6 months. Out of the total number of participants, grades 2-4 aGVHD occurred in 79 patients. |
| Arm/Group Title | Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI) |
|---|---|
| Arm/Group Description | Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0 Therapeutic allogeneic lymphocytes: A population of lymphocytes therapeutically administered to a recipient individual who is genetically distinct from a donor of the same species. Busulfan: Busulfan is an alkylating chemotherapeutic agent which has been used in many high dose and reduced intensity regimens prior to allogeneic or autologous hematopoietic stem cell transplants. It is active in a wide variety of malignancies and in high-doses it is myeloablative. IV Busulfan is available and diluted and administered per package insert guidelines. Cyclosporine: Cyclosporine is a cyclic polypeptide immunosuppressive agent. It blocks the calcium-dependent calcineurin-mediated nuclear localization of nuclear factor of activated T cells (NFAT) following T-cell activation, thereby inhibiting transactivation of key T-cell response genes including |
| Measure Participants | 147 |
| Day 100 |
55
37.4%
|
| Month 6 |
60
40.8%
|
| Title | Chronic Graft-Versus-Host Disease (cGVHD) Outcome |
|---|---|
| Description | Grading of Chronic GVHD: Limited: Localized skin involvement and/or hepatic dysfunction due to chronic GVHD Extensive: One or more of the following: Generalized skin involvement Liver histology showing chronic aggressive hepatitis, bridging necrosis or cirrhosis Involvement of the eye: Schirmer's test with <5 mm wetting Involvement of minor salivary glands or oral mucosa demonstrated on labial biopsy Involvement of any other target organ Chronic GVHD Severity: Mild: Signs and symptoms of cGVHD do not interfere substantially with function and do not progress once appropriately treated with local therapy or standard systemic therapy. Moderate: Signs and symptoms of cGVHD interfere somewhat with function despite appropriate therapy or are progressive through first line systemic therapy. Severe: Signs and symptoms of cGVHD limit function substantially despite appropriate therapy or are progressive through second line systemic therapy |
| Time Frame | Years 1, 2 and 3 |
Outcome Measure Data
| Analysis Population Description |
|---|
| This is a cumulative incidence of cGVHD at 1 year, 2 years, and 3 years. A total of 99 patients (out of 147) developed cGVHD, 86 patients (87%) with extensive stage cGVHD and 13 patients (13%) with limited stage cGVHD. |
| Arm/Group Title | Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI) |
|---|---|
| Arm/Group Description | Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0 Therapeutic allogeneic lymphocytes: A population of lymphocytes therapeutically administered to a recipient individual who is genetically distinct from a donor of the same species. Busulfan: Busulfan is an alkylating chemotherapeutic agent which has been used in many high dose and reduced intensity regimens prior to allogeneic or autologous hematopoietic stem cell transplants. It is active in a wide variety of malignancies and in high-doses it is myeloablative. IV Busulfan is available and diluted and administered per package insert guidelines. Cyclosporine: Cyclosporine is a cyclic polypeptide immunosuppressive agent. It blocks the calcium-dependent calcineurin-mediated nuclear localization of nuclear factor of activated T cells (NFAT) following T-cell activation, thereby inhibiting transactivation of key T-cell response genes including |
| Measure Participants | 147 |
| Year 1 |
64.6
43.9%
|
| Year 2 |
66
44.9%
|
| Year 3 |
67.3
45.8%
|
Adverse Events
| Time Frame | Non-hematologic toxicities and adverse experiences ≥ Grade 3 will be assessed up to day +100 using the NCI Common Toxicity Criteria for Adverse Events v3.0 (CTCAE). Infections and GVHD will be assessed up to 5 years post transplant. | |
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI) | |
| Arm/Group Description | Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0 Therapeutic allogeneic lymphocytes: A population of lymphocytes therapeutically administered to a recipient individual who is genetically distinct from a donor of the same species. Busulfan: Busulfan is an alkylating chemotherapeutic agent which has been used in many high dose and reduced intensity regimens prior to allogeneic or autologous hematopoietic stem cell transplants. It is active in a wide variety of malignancies and in high-doses it is myeloablative. IV Busulfan is available and diluted and administered per package insert guidelines. Cyclosporine: Cyclosporine is a cyclic polypeptide immunosuppressive agent. It blocks the calcium-dependent calcineurin-mediated nuclear localization of nuclear factor of activated T cells (NFAT) following T-cell activation, thereby inhibiting transactivation of key T-cell response genes including | |
All Cause Mortality |
||
| Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI) | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI) | ||
| Affected / at Risk (%) | # Events | |
| Total | 59/147 (40.1%) | |
| Cardiac disorders | ||
| Left ventricular systolic dysfunction | 1/147 (0.7%) | |
| Pericardial effusion | 2/147 (1.4%) | |
| Atrial fibrillation/flutter | 3/147 (2%) | |
| Left ventricular dysfunction | 1/147 (0.7%) | |
| Respiratory pulseless electrical activity (PEA) arrest | 1/147 (0.7%) | |
| General disorders | ||
| Iron overload | 1/147 (0.7%) | |
| Steroid myopathy | 3/147 (2%) | |
| Hemolysis | 5/147 (3.4%) | |
| ABO incompatability | 1/147 (0.7%) | |
| Bleeding | 2/147 (1.4%) | |
| Thrombosis/deep vein thrombosis | 5/147 (3.4%) | |
| Thrombotic thrombocytopenic purpura (TTP) | 1/147 (0.7%) | |
| Refractory ascites | 1/147 (0.7%) | |
| Ogilvie's syndrome | 1/147 (0.7%) | |
| Hepatobiliary disorders | ||
| Veno-occlusive disease | 1/147 (0.7%) | |
| Infections and infestations | ||
| Death Caused by Bacterial Infection | 7/147 (4.8%) | |
| Death Caused by Fungal Infection | 3/147 (2%) | |
| Death Caused by Sepsis/Septic Shock | 3/147 (2%) | |
| Death Caused by Viral Infection | 3/147 (2%) | |
| Death Caused by Nonspecified Pneumonia | 1/147 (0.7%) | |
| Musculoskeletal and connective tissue disorders | ||
| Fractures/musculoskeletal | 3/147 (2%) | |
| Nervous system disorders | ||
| CsA toxicity | 5/147 (3.4%) | |
| Posterior-reversible encephalopathy syndrome | 2/147 (1.4%) | |
| Renal and urinary disorders | ||
| Event associated with CsA | 1/147 (0.7%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Cryptogenic organizing pneumonia | 1/147 (0.7%) | |
| Eosinophilic pneumonia | 1/147 (0.7%) | |
Other (Not Including Serious) Adverse Events |
||
| Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI) | ||
| Affected / at Risk (%) | # Events | |
| Total | 52/147 (35.4%) | |
| Hepatobiliary disorders | ||
| Hyperbilirubinemia or transaminitis | 38/147 (25.9%) | |
| Infections and infestations | ||
| Neutropenic fever | 14/147 (9.5%) | |
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 | Richard T. Maziarz, MD |
|---|---|
| Organization | Oregon Health and Science University |
| Phone | 503-494-6345 |
| maziarzr@ohsu.edu |
- IRB00000210
- P30CA016058
- OHSU-HEM-05011-L
- OHSU-210