Overview

This trial is active, not recruiting.

Conditions chronic myeloproliferative disorders, leukemia, lymphoma, multiple myeloma and plasma cell neoplasm, myelodysplastic syndromes
Treatments anti-thymocyte globulin, sargramostim, therapeutic allogeneic lymphocytes, busulfan, fludarabine phosphate, methotrexate, tacrolimus, nonmyeloablative allogeneic hematopoietic stem cell transplantation, peripheral blood stem cell transplantation
Phase phase 2
Sponsor UNC Lineberger Comprehensive Cancer Center
Collaborator National Cancer Institute (NCI)
Start date November 2003
End date December 2016
Trial size 70 participants
Trial identifier NCT00448201, CDR0000549851, LCCC 0306, P30CA016086, UNC-LCCC-0306

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation non-randomized
Intervention model single group assignment
Masking open label
Primary purpose treatment
Arm
(Active Comparator)
GVHD Prophylaxis with Methotrexate
sargramostim
GM-CSF 500 ug QD subcutaneously will be given to recipients who remain with an ANC < 1000/uL past day 20
therapeutic allogeneic lymphocytes
A minimum total 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
busulfan
6.4 mg/kg by continuous IV infusion over 48 hours on Days -6 and -5
fludarabine phosphate
fludarabine 30 mg/m^2/day x 5 days IVPB over 30 minutes on Days -7 through -3
methotrexate
Methotrexate 5 mg/m^2 per day on days +1, +3 and +6
tacrolimus
Suggested starting dose is 0.03 mg/kg po bid starting on Day -1
nonmyeloablative allogeneic hematopoietic stem cell transplantation
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
peripheral blood stem cell transplantation
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
(Active Comparator)
GVHD prophylaxis with ATG + Methotrexate
anti-thymocyte globulin
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)
sargramostim
GM-CSF 500 ug QD subcutaneously will be given to recipients who remain with an ANC < 1000/uL past day 20
therapeutic allogeneic lymphocytes
A minimum total 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
busulfan
6.4 mg/kg by continuous IV infusion over 48 hours on Days -6 and -5
fludarabine phosphate
fludarabine 30 mg/m^2/day x 5 days IVPB over 30 minutes on Days -7 through -3
methotrexate
Methotrexate 5 mg/m^2 per day on days +1, +3 and +6
tacrolimus
Suggested starting dose is 0.03 mg/kg po bid starting on Day -1
nonmyeloablative allogeneic hematopoietic stem cell transplantation
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
peripheral blood stem cell transplantation
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
(Active Comparator)
GVHD prophylaxis with 2 doses ATG
anti-thymocyte globulin
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)
sargramostim
GM-CSF 500 ug QD subcutaneously will be given to recipients who remain with an ANC < 1000/uL past day 20
therapeutic allogeneic lymphocytes
A minimum total 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
busulfan
6.4 mg/kg by continuous IV infusion over 48 hours on Days -6 and -5
fludarabine phosphate
fludarabine 30 mg/m^2/day x 5 days IVPB over 30 minutes on Days -7 through -3
tacrolimus
Suggested starting dose is 0.03 mg/kg po bid starting on Day -1
nonmyeloablative allogeneic hematopoietic stem cell transplantation
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
peripheral blood stem cell transplantation
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
(Active Comparator)
GVHD prophylaxis with 3 doses ATG
anti-thymocyte globulin
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)
sargramostim
GM-CSF 500 ug QD subcutaneously will be given to recipients who remain with an ANC < 1000/uL past day 20
therapeutic allogeneic lymphocytes
A minimum total 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
busulfan
6.4 mg/kg by continuous IV infusion over 48 hours on Days -6 and -5
fludarabine phosphate
fludarabine 30 mg/m^2/day x 5 days IVPB over 30 minutes on Days -7 through -3
tacrolimus
Suggested starting dose is 0.03 mg/kg po bid starting on Day -1
nonmyeloablative allogeneic hematopoietic stem cell transplantation
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
peripheral blood stem cell transplantation
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

Primary Outcomes

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
Complete or mixed donor chimerism at 30, 60, and 90 days post-transplant
time frame: Days 30, 60, and 90
5-year disease-free survival
time frame: Year 5
Graft-vs-host disease at 6 months post-transplant
time frame: 6 Months

Eligibility Criteria

Male or female participants at least 10 years old.

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 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 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 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) - AST ≤ 3 times ULN - DLCO > 40% with no symptomatic pulmonary disease - LVEF ≥ 30% by 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

Additional Information

Official title Allogeneic Hematopoietic Cell Transplantation for Patients With Hematologic Disorders Who Are Ineligible or Inappropriate for Treatment With a More Intensive Therapeutic Regimen
Principal investigator Thomas C. Shea, MD
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 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 CD3 positivity, B-cells as defined by CD19 positivity, and myeloid cells as defined by CD14 and 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.
Trial information was received from ClinicalTrials.gov and was last updated in November 2015.
Information provided to ClinicalTrials.gov by UNC Lineberger Comprehensive Cancer Center.