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

Phase 2

Completed

Conditions: Chronic Myeloproliferative Disorders
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes

Interventions: Biological: sargramostim
Biological: anti-thymocyte globulin
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

Registration Number: NCT00448201

Lead Sponsor: UNC Lineberger Comprehensive Cancer Center

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 71

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Methotrexate Only Arm	sargramostim	GVHD Prophylaxis with Methotrexate
Methotrexate Only Arm	therapeutic allogeneic lymphocytes	GVHD Prophylaxis with Methotrexate
Methotrexate Only Arm	peripheral blood stem cell transplantation	GVHD Prophylaxis with Methotrexate
2 Doses ATG + Methotrexate	anti-thymocyte globulin	GVHD prophylaxis with antithymocyte globulin (ATG) + Methotrexate
2 Doses ATG + Methotrexate	sargramostim	GVHD prophylaxis with antithymocyte globulin (ATG) + Methotrexate
2 Doses ATG + Methotrexate	therapeutic allogeneic lymphocytes	GVHD prophylaxis with antithymocyte globulin (ATG) + Methotrexate
Methotrexate Only Arm	tacrolimus	GVHD Prophylaxis with Methotrexate
Methotrexate Only Arm	nonmyeloablative allogeneic hematopoietic stem cell transplantation	GVHD Prophylaxis with Methotrexate
2 Doses ATG + Methotrexate	nonmyeloablative allogeneic hematopoietic stem cell transplantation	GVHD prophylaxis with antithymocyte globulin (ATG) + Methotrexate
2 Doses ATG + Methotrexate	peripheral blood stem cell transplantation	GVHD prophylaxis with antithymocyte globulin (ATG) + Methotrexate
2 Doses ATG	anti-thymocyte globulin	GVHD prophylaxis with 2 doses ATG
2 Doses ATG	sargramostim	GVHD prophylaxis with 2 doses ATG
2 Doses ATG	therapeutic allogeneic lymphocytes	GVHD prophylaxis with 2 doses ATG
2 Doses ATG	busulfan	GVHD prophylaxis with 2 doses ATG
2 Doses ATG	nonmyeloablative allogeneic hematopoietic stem cell transplantation	GVHD prophylaxis with 2 doses ATG
2 Doses ATG	peripheral blood stem cell transplantation	GVHD prophylaxis with 2 doses ATG
3 Doses ATG	anti-thymocyte globulin	GVHD prophylaxis with 3 doses ATG
3 Doses ATG	sargramostim	GVHD prophylaxis with 3 doses ATG
3 Doses ATG	therapeutic allogeneic lymphocytes	GVHD prophylaxis with 3 doses ATG
3 Doses ATG	busulfan	GVHD prophylaxis with 3 doses ATG
3 Doses ATG	fludarabine phosphate	GVHD prophylaxis with 3 doses ATG
3 Doses ATG	tacrolimus	GVHD prophylaxis with 3 doses ATG
3 Doses ATG	nonmyeloablative allogeneic hematopoietic stem cell transplantation	GVHD prophylaxis with 3 doses ATG
3 Doses ATG	peripheral blood stem cell transplantation	GVHD prophylaxis with 3 doses ATG
Methotrexate Only Arm	fludarabine phosphate	GVHD Prophylaxis with Methotrexate
Methotrexate Only Arm	busulfan	GVHD Prophylaxis with Methotrexate
Methotrexate Only Arm	methotrexate	GVHD Prophylaxis with Methotrexate
2 Doses ATG + Methotrexate	busulfan	GVHD prophylaxis with antithymocyte globulin (ATG) + Methotrexate
2 Doses ATG + Methotrexate	fludarabine phosphate	GVHD prophylaxis with antithymocyte globulin (ATG) + Methotrexate
2 Doses ATG + Methotrexate	methotrexate	GVHD prophylaxis with antithymocyte globulin (ATG) + Methotrexate
2 Doses ATG + Methotrexate	tacrolimus	GVHD prophylaxis with antithymocyte globulin (ATG) + Methotrexate
2 Doses ATG	fludarabine phosphate	GVHD prophylaxis with 2 doses ATG
2 Doses ATG	tacrolimus	GVHD prophylaxis with 2 doses ATG

Primary Outcome Measures

Name	Time	Method
Treatment-related Mortality	6 months	Treatment related mortality for first 6 months. Defined as the number of treatment related deaths excluding deaths due to disease relapse.

Secondary Outcome Measures

Name	Time	Method
5-year Disease-free Survival	Year 5	The length of time post-transplant that the patient survives without any signs or symptoms of that cancer.
Complete Response at 6 and 12 Months Post-transplant	6 and 12 months
Complete or Mixed Donor Chimerism at 30, 60, and 90 Days Post-transplant	Days 30, 60, and 90	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.
Graft-vs-host Disease at 6 Months Post-transplant	6 Months	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.