NCT00245037 · REGISTRY CONDITION SEARCH

Busulfan, Fludarabine, and Total-Body Irradiation in Treating Patients Who Are Undergoing a Donor Stem Cell Transplant for Hematologic Cancer

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase: PHASE1, PHASE2
Status at capture: COMPLETED
Registry last update: 2017-09-27

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.

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What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Regimen-Related Toxicities

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outcome · POSTED

Non-relapse Mortality

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outcome · POSTED

Overall Survival

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outcome · POSTED

Progression-Free Survival

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outcome · POSTED

Relapse Mortality

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outcome · POSTED

Acute Graft-Versus-Host Disease (aGVHD) Outcome

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outcome · POSTED

Chronic Graft-Versus-Host Disease (cGVHD) Outcome

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility 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
healthy Volunteers: false
maximum Age: 80 Years
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

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
intervention Names
Biological: therapeutic allogeneic lymphocytes
Drug: busulfan
Drug: cyclosporine
Drug: fludarabine phosphate
Drug: mycophenolate mofetil
Procedure: peripheral blood stem cell transplantation
Radiation: Total Body Irradiation (TBI)
Drug: Granulocyte colony-stimulating factor (G-CSF)
Drug: Phenytoin
Drug: Methotrexate
label
Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)
type
EXPERIMENTAL

interventions

arm Group Labels
Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)
description
A population of lymphocytes therapeutically administered to a recipient individual who is genetically distinct from a donor of the same species.
name
therapeutic allogeneic lymphocytes
type
BIOLOGICAL
arm Group Labels
Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)
description
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.
name
busulfan
type
DRUG
arm Group Labels
Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)
description
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.
name
cyclosporine
type
DRUG
arm Group Labels
Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)
description
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.
name
fludarabine phosphate
type
DRUG
arm Group Labels
Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)
description
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).
name
mycophenolate mofetil
type
DRUG
arm Group Labels
Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)
description
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.
name
peripheral blood stem cell transplantation
type
PROCEDURE
arm Group Labels
Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)
description
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.
name
Total Body Irradiation (TBI)
type
RADIATION
arm Group Labels
Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)
description
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).
name
Granulocyte colony-stimulating factor (G-CSF)
type
DRUG
arm Group Labels
Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)
description
This drug is used to prevent seizures while on chemotherapy.
name
Phenytoin
type
DRUG
arm Group Labels
Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)
description
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.
name
Methotrexate
type
DRUG

Study design

allocation

intervention Model

SINGLE_GROUP

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 147
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

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.
measure
Regimen-Related Toxicities
time Frame
5 years post-transplant
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.
measure
Non-relapse Mortality
time Frame
Two years post-transplant

secondary Outcomes

description
The percentage of overall patient survival (out of 147 participants) for Years 1, 2, 3 and 5.
measure
Overall Survival
time Frame
Years 1, 2, 3 and 5
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.
measure
Progression-Free Survival
time Frame
Years 1, 2, 3, and 5
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.
measure
Relapse Mortality
time Frame
Years 1 and 2
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
measure
Acute Graft-Versus-Host Disease (aGVHD) Outcome
time Frame
Day 100, Month 6
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
measure
Chronic Graft-Versus-Host Disease (cGVHD) Outcome
time Frame
Years 1, 2 and 3

Full 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.
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.

Source references

Source notices and limitations

Discovery and provenance

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Preserved source evidence · Not medical advice