NCT00448201 · REGISTRY CONDITION SEARCH

Reduced-Intensity Busulfan and Fludarabine With or Without Antithymocyte Globulin Followed by Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer or Other Disease

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

Phase: PHASE2
Status at capture: COMPLETED
Registry last update: 2017-05-30

RATIONALE: Giving low doses of chemotherapy, such as busulfan and fludarabine, before a donor stem cell transplant helps stop the growth of cancer and abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer or abnormal cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Immunosuppressive therapy may improve bone marrow function and may be an effective treatment for hematologic cancer or other disease. PURPOSE: This clinical trial is studying the side effects and how well giving busulfan and fludarabine with or without antithymocyte globulin followed by donor stem cell transplant works in treating patients with hematologic cancer or other disease.

Open the original ClinicalTrials.gov record → · Download preserved record

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

Treatment-related Mortality

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outcome · POSTED

Complete Response at 6 and 12 Months Post-transplant

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outcome · POSTED

Complete or Mixed Donor Chimerism at 30, 60, and 90 Days Post-transplant

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outcome · POSTED

5-year Disease-free Survival

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outcome · POSTED

Graft-vs-host Disease at 6 Months Post-transplant

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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: * Histologically confirmed diagnosis of 1 of the following: * Chronic lymphocytic leukemia (CLL), meeting the following criteria: * Absolute lymphocyte count \> 5,000/mm³ * Lymphocytes must appear morphologically mature with \< 55% prolymphocytes * Lymphocyte phenotype with expression of CD19 and cluster of differentiation 5 (CD5) * Prolymphocytic leukemia (PLL), meeting the following criteria: * Absolute lymphocyte count \> 5,000/mm³ * More than 55% prolymphocytes * Morphologically diagnosed * Chronic myelogenous leukemia (CML), meeting the following criteria: * Diagnosis of CML or similar myeloproliferative disorders based on t(9;22) or related t(9;12) cytogenetic abnormalities AND characterized by elevated white blood cell (WBC) counts in peripheral blood or bone marrow * In first chronic phase CML and a candidate for treatment with reduced-dose busulfan * Patients with other cytogenetic abnormalities, such as t(9;12), that are associated with an aggressive clinical course are eligible * Non-Hodgkin's lymphoma (NHL), meeting the following criteria: * Any World Health Organization (WHO) class histologic subtype allowed * Core biopsies are acceptable provided they contain adequate tissue for primary diagnosis and immunophenotyping * Bone marrow biopsies as sole means of diagnosis are not allowed for follicular lymphoma * Hodgkin's lymphoma, meeting the following criteria: * Any WHO class histologic subtype allowed * Core biopsies are acceptable provided they contain adequate tissue for primary diagnosis and immunophenotyping * Multiple myeloma, meeting the following criteria: * Active disease requiring treatment (Durie-Salmon stages I, II, or III) * Acute myeloid leukemia with documented control, defined as \< 10% bone marrow blasts and no circulating blasts * Acute lymphoblastic leukemia, meeting the following criteria: * In early first relapse or beyond OR in first complete remission and has 1 of the following high-risk features: * t(9;22) or t(4;11) * WBC count \> 30,000/mm³ at presentation * Non-T-cell phenotype * More than 30 years of age * Agnogenic myeloid metaplasia/myelofibrosis * Patients who are transfusion dependent or who have evolving myelodysplastic or leukemic features or high-risk cytogenetic abnormalities are eligible * Myelodysplastic syndromes (MDS) as defined by WHO criteria * Meets 1 of the following criteria: * Over 55 years of age * Ineligible for busulfan-based therapy based on diminished organ function or poor performance status * Indolent and chemotherapy-responsive CLL, low-grade NHL, small lymphocytic lymphoma, or PLL * Patients who have undergone prior autologous stem cell transplantation are preferentially enrolled on clinical trial CALGB-100002, if available and patient is eligible * HLA-matched or mismatched related donor or HLA-matched unrelated donor available * HLA-identical sibling (6/6 or 9/10) (minimal serologic typing required for class I \[A, B\]; molecular typing required for class II (DRB1)) * 9/10 matched unrelated donor (MUD) (molecular analysis at HLA A, B, C, DRB1, and DQB1 by high resolution typing required) * 5/6 MUD (molecular analysis at HLA A, B, and DRB1 required) * No syngeneic donors PATIENT CHARACTERISTICS: * Creatinine clearance ≥ 40 mL/min * Bilirubin ≤ 3 times upper limit of normal (ULN) * aspartate aminotransferase (AST) ≤ 3 times ULN * Diffusing capacity of the lungs for carbon monoxide (DLCO) \> 40% with no symptomatic pulmonary disease * Left ventricular ejection fraction (LVEF) ≥ 30% by multigated acquisition scan (MUGA) * No uncontrolled diabetes mellitus or active serious infection * No known hypersensitivity to Escherichia coli-derived products * No HIV infection * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: * See Disease Characteristics * More than 4 weeks since prior chemotherapy, radiotherapy (except prophylactic cranial x-ray therapy), or surgery
healthy Volunteers: false
minimum Age: 10 Years
sex: ALL
std Ages: CHILD
ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
GVHD Prophylaxis with Methotrexate
intervention Names
Biological: sargramostim
Biological: therapeutic allogeneic lymphocytes
Drug: busulfan
Drug: fludarabine phosphate
Drug: methotrexate
Drug: tacrolimus
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Procedure: peripheral blood stem cell transplantation
label
Methotrexate Only Arm
type
ACTIVE_COMPARATOR
description
GVHD prophylaxis with antithymocyte globulin (ATG) + Methotrexate
intervention Names
Biological: anti-thymocyte globulin
Biological: sargramostim
Biological: therapeutic allogeneic lymphocytes
Drug: busulfan
Drug: fludarabine phosphate
Drug: methotrexate
Drug: tacrolimus
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Procedure: peripheral blood stem cell transplantation
label
2 Doses ATG + Methotrexate
type
ACTIVE_COMPARATOR
description
GVHD prophylaxis with 2 doses ATG
intervention Names
Biological: anti-thymocyte globulin
Biological: sargramostim
Biological: therapeutic allogeneic lymphocytes
Drug: busulfan
Drug: fludarabine phosphate
Drug: tacrolimus
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Procedure: peripheral blood stem cell transplantation
label
2 Doses ATG
type
ACTIVE_COMPARATOR
description
GVHD prophylaxis with 3 doses ATG
intervention Names
Biological: anti-thymocyte globulin
Biological: sargramostim
Biological: therapeutic allogeneic lymphocytes
Drug: busulfan
Drug: fludarabine phosphate
Drug: tacrolimus
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Procedure: peripheral blood stem cell transplantation
label
3 Doses ATG
type
ACTIVE_COMPARATOR

interventions

arm Group Labels
2 Doses ATG
2 Doses ATG + Methotrexate
3 Doses ATG
description
0.5 mg/kg on day -3, 2.5 mg/kg on day -2 (groups 2, 3 and 4) and 3 mg/kg on day -1 (group 4 only)
name
anti-thymocyte globulin
type
BIOLOGICAL
arm Group Labels
2 Doses ATG
2 Doses ATG + Methotrexate
3 Doses ATG
Methotrexate Only Arm
description
GM-CSF 500 ug everyday (QD) subcutaneously will be given to recipients who remain with an Absolute neutrophil count (ANC) \< 1000/microliter (uL) past day 20
name
sargramostim
type
BIOLOGICAL
arm Group Labels
2 Doses ATG
2 Doses ATG + Methotrexate
3 Doses ATG
Methotrexate Only Arm
description
A minimum total cluster of differentiation 34 (CD34)+ cell dose of 3 x 10\^6 cells/kg and a maximum 8 x 10\^6 cells/kg will be infused on day 0
name
therapeutic allogeneic lymphocytes
type
BIOLOGICAL
arm Group Labels
2 Doses ATG
2 Doses ATG + Methotrexate
3 Doses ATG
Methotrexate Only Arm
description
6.4 mg/kg by continuous IV infusion over 48 hours on Days -6 and -5
name
busulfan
type
DRUG
arm Group Labels
2 Doses ATG
2 Doses ATG + Methotrexate
3 Doses ATG
Methotrexate Only Arm
description
fludarabine 30 mg/m\^2/day x 5 days IV piggyback (IVPB) over 30 minutes on Days -7 through -3
name
fludarabine phosphate
type
DRUG
arm Group Labels
2 Doses ATG + Methotrexate
Methotrexate Only Arm
description
Methotrexate 5 mg/m\^2 per day on days +1, +3 and +6
name
methotrexate
type
DRUG
arm Group Labels
2 Doses ATG
2 Doses ATG + Methotrexate
3 Doses ATG
Methotrexate Only Arm
description
Suggested starting dose is 0.03 mg/kg po bid starting on Day -1
name
tacrolimus
type
DRUG
arm Group Labels
2 Doses ATG
2 Doses ATG + Methotrexate
3 Doses ATG
Methotrexate Only Arm
description
Minimum total CD34+ cells of 3 x 10\^6 cells/kg and a maximum of 8 x 10\^6 cells/kg will be infused on Day 0
name
nonmyeloablative allogeneic hematopoietic stem cell transplantation
type
PROCEDURE
arm Group Labels
2 Doses ATG
2 Doses ATG + Methotrexate
3 Doses ATG
Methotrexate Only Arm
description
Minimum total CD34+ cells of 3 x 10\^6 cells/kg and a maximum of 8 x 10\^6 cells/kg will be infused on Day 0
name
peripheral blood stem cell transplantation
type
PROCEDURE

Study design

allocation

NON_RANDOMIZED

intervention Model

SINGLE_GROUP

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 71
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
Treatment related mortality for first 6 months. Defined as the number of treatment related deaths excluding deaths due to disease relapse.
measure
Treatment-related Mortality
time Frame
6 months

secondary Outcomes

measure
Complete Response at 6 and 12 Months Post-transplant
time Frame
6 and 12 months
description
Complete chimerism is defined as 100% donor cells detected, suggesting complete hematopoietic replacement. Mixed donor chimerism means host cells are detected in particular cells like lymphocytes. Five to 90% donor cells set the criteria for mixed chimerism (MC). Chimerism was not tabulated on day 30.
measure
Complete or Mixed Donor Chimerism at 30, 60, and 90 Days Post-transplant
time Frame
Days 30, 60, and 90
description
The length of time post-transplant that the patient survives without any signs or symptoms of that cancer.
measure
5-year Disease-free Survival
time Frame
Year 5
description
Graft-vs-host disease (GVHD) can be mild, moderate or severe depending on the differences in tissue type between patient and donor. Its symptoms can include: * Rashes, which include burning and redness, that erupt on the palms or soles and may spread to the trunk and eventually to the entire body * Blistering, causing the exposed skin surface to flake off in severe cases * Nausea, vomiting, abdominal cramps, diarrhea and loss of appetite, which can indicate that the gastrointestinal (digestive) tract is affected * Jaundice, or a yellowing of the skin, which can indicate liver damage * Excessive dryness of the mouth and throat, leading to ulcers * Dryness of the lungs, vagina and other surfaces Acute GVHD - Can occur soon after the transplanted cells begin to appear in the recipient. Acute GVHD ranges from mild, moderate or severe, and can be life-threatening if its effects are not controlled. Extensive chronic GVHD - Usually occurs at about three months post-transplant.
measure
Graft-vs-host Disease at 6 Months Post-transplant
time Frame
6 Months

Full study description

brief Summary: RATIONALE: Giving low doses of chemotherapy, such as busulfan and fludarabine, before a donor stem cell transplant helps stop the growth of cancer and abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer or abnormal cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Immunosuppressive therapy may improve bone marrow function and may be an effective treatment for hematologic cancer or other disease. PURPOSE: This clinical trial is studying the side effects and how well giving busulfan and fludarabine with or without antithymocyte globulin followed by donor stem cell transplant works in treating patients with hematologic cancer or other disease.
detailed Description: OBJECTIVES: Primary * Determine the clinical efficacy and toxicity profiles of a nonmyeloablative preparative regimen comprising busulfan and fludarabine with or without anti-thymocyte globulin followed by allogeneic hematopoietic stem cell transplantation in patients with hematologic cancers or other diseases. * Determine the feasibility of this regimen in these patients. * Establish a treatment-related mortality during the first 6 months that is less than 20% in patients treated with this regimen. Secondary * Determine the response rates (disease-specific partial response and complete response) in patients treated with this regimen. * Determine overall and progression-free survival of patients treated with this regimen. * Determine the percent donor chimerism and immunologic recovery, including dendritic cell recovery, in patients treated with this regimen. * Determine the risk of acute and chronic graft-versus-host disease and other toxicities in patients treated with this regimen. * Assess the overall nonhematologic grades 3 and 4 toxicity of this regimen, including the incidence of veno-occlusive disease and pulmonary toxicity, in these patients. OUTLINE: Patients are assigned to 1 of 4 treatment groups according to disease type and donor type. * Preparative regimen: * Group 1 (patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), IPSS (International Prognostic Scoring System score) high-risk myelodysplastic syndromes (HR MDS), or chronic myelogenous leukemia (CML) with an human leukocyte antigen (HLA)-matched related donor (MRD): Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3 and busulfan IV continuously over 48 hours on days -6 and -5. * Group 2 (patients with AML, ALL, IPSS HR MDS, or CML with an HLA-matched unrelated donor (MUD) or mismatched related donor (MMRD)): Patients receive fludarabine phosphate and busulfan as in group 1 and anti-thymocyte globulin IV over 4 hours on day -8. * Group 3 (patients with all other diseases with a MRD): Patients receive fludarabine phosphate and busulfan as in group 1 and anti-thymocyte globulin as in group 2. * Group 4 (patients with all other disease with a MUD or MMRD): Patients receive fludarabine phosphate and busulfan as in group 1 and anti-thymocyte globulin IV over 4 hours on days -8 and -7. * Allogeneic stem cell transplantation: All patients undergo allogeneic peripheral blood stem cell transplantation on day 0. Patients then receive sargramostim (GM-CSF) subcutaneously once daily beginning on day 5 (groups 1 and 2) or day 7 (groups 3 and 4) and continuing until blood counts recover. * Graft-vs-host disease (GVHD) prophylaxis: All patients receive oral tacrolimus twice daily on days -1 to 120 followed by a taper until day 180. Patients in groups 1 and 2 also receive methotrexate IV on days 1, 3, and 6. * Donor lymphocyte infusion (DLI): After day 120, patients with progressive disease or stable disease while off immunosuppression and with no evidence of active GVHD may receive DLI. Treatment with DLI may repeat every 8 weeks for up to 3 total infusions in the absence of disease response or GVHD. Peripheral blood and/or bone marrow samples are collected at baseline and then at 30, 60, 90, 120, and 180 days post-transplantation. Chimerism (including the following subsets: whole blood, T-cells as defined by cluster of differentiation 3 (CD3) positivity, B-cells as defined by Cluster of Differentiation 19 (CD19) positivity, and myeloid cells as defined by Cluster of Differentiation 14 (CD14) and Cluster of Differentiation 15 (CD15) positivity is analyzed by polymerase chain reaction technology. After restaging between Days 90 and 100 and between Days 150 to 180, patients are followed every 6 months for 1 years and then yearly for a maximum of 5 years from study entry.

Source references