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

Allogeneic Hematopoietic Cell Transplantation for Patients With Hematologic Disorders Who Are Ineligible or Inappropriate for Treatment With a More Intensive Therapeutic Regimen

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.

Study Overview

• Status: Completed
• Conditions: Lymphoma; Myelodysplastic Syndromes; Leukemia; Chronic Myeloproliferative Disorders; Multiple Myeloma and Plasma Cell Neoplasm
• Intervention / Treatment: 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; Biological: anti-thymocyte globulin

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.

• Study Type: Interventional
• Enrollment (Actual): 71
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7295
      • Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Methotrexate Only Arm; GVHD Prophylaxis with Methotrexate	Biological: sargramostim; 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; Biological: therapeutic allogeneic lymphocytes; 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; Drug: busulfan; 6.4 mg/kg by continuous IV infusion over 48 hours on Days -6 and -5; Drug: fludarabine phosphate; fludarabine 30 mg/m^2/day x 5 days IV piggyback (IVPB) over 30 minutes on Days -7 through -3; Drug: methotrexate; Methotrexate 5 mg/m^2 per day on days +1, +3 and +6; Drug: tacrolimus; Suggested starting dose is 0.03 mg/kg po bid starting on Day -1; Procedure: 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; Procedure: 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: 2 Doses ATG + Methotrexate; GVHD prophylaxis with antithymocyte globulin (ATG) + Methotrexate	Biological: sargramostim; 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; Biological: therapeutic allogeneic lymphocytes; 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; Drug: busulfan; 6.4 mg/kg by continuous IV infusion over 48 hours on Days -6 and -5; Drug: fludarabine phosphate; fludarabine 30 mg/m^2/day x 5 days IV piggyback (IVPB) over 30 minutes on Days -7 through -3; Drug: methotrexate; Methotrexate 5 mg/m^2 per day on days +1, +3 and +6; Drug: tacrolimus; Suggested starting dose is 0.03 mg/kg po bid starting on Day -1; Procedure: 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; Procedure: 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; Biological: 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)
Active Comparator: 2 Doses ATG; GVHD prophylaxis with 2 doses ATG	Biological: sargramostim; 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; Biological: therapeutic allogeneic lymphocytes; 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; Drug: busulfan; 6.4 mg/kg by continuous IV infusion over 48 hours on Days -6 and -5; Drug: fludarabine phosphate; fludarabine 30 mg/m^2/day x 5 days IV piggyback (IVPB) over 30 minutes on Days -7 through -3; Drug: tacrolimus; Suggested starting dose is 0.03 mg/kg po bid starting on Day -1; Procedure: 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; Procedure: 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; Biological: 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)
Active Comparator: 3 Doses ATG; GVHD prophylaxis with 3 doses ATG	Biological: sargramostim; 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; Biological: therapeutic allogeneic lymphocytes; 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; Drug: busulfan; 6.4 mg/kg by continuous IV infusion over 48 hours on Days -6 and -5; Drug: fludarabine phosphate; fludarabine 30 mg/m^2/day x 5 days IV piggyback (IVPB) over 30 minutes on Days -7 through -3; Drug: tacrolimus; Suggested starting dose is 0.03 mg/kg po bid starting on Day -1; Procedure: 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; Procedure: 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; Biological: 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment-related Mortality	Treatment related mortality for first 6 months. Defined as the number of treatment related deaths excluding deaths due to disease relapse.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	Days 30, 60, and 90
5-year Disease-free Survival	The length of time post-transplant that the patient survives without any signs or symptoms of that cancer.	Year 5
Graft-vs-host Disease at 6 Months Post-transplant	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.	6 Months

Collaborators and Investigators

• Sponsor: UNC Lineberger Comprehensive Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Thomas C. Shea, MD, UNC Lineberger Comprehensive Cancer Center

Publications and helpful links

Helpful Links

• University of North Carolina (UNC) Lineberger Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): January 7, 2011
• Primary Completion (Actual): January 11, 2011
• Study Completion (Actual): May 23, 2012

Study Registration Dates

• First Submitted: March 14, 2007
• First Submitted That Met QC Criteria: March 15, 2007
• First Posted (Estimate): March 16, 2007

Study Record Updates

• Last Update Posted (Actual): May 30, 2017
• Last Update Submitted That Met QC Criteria: May 23, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: primary myelofibrosis; stage III adult diffuse large cell lymphoma; stage III adult immunoblastic large cell lymphoma; stage III adult Burkitt lymphoma; stage IV grade 3 follicular lymphoma; stage IV adult diffuse large cell lymphoma; stage IV adult immunoblastic large cell lymphoma; stage IV adult Burkitt lymphoma; recurrent grade 3 follicular lymphoma; recurrent adult diffuse large cell lymphoma; recurrent adult immunoblastic large cell lymphoma; recurrent adult Burkitt lymphoma; recurrent childhood small noncleaved cell lymphoma; recurrent childhood large cell lymphoma; de novo myelodysplastic syndromes; previously treated myelodysplastic syndromes; secondary myelodysplastic syndromes; adult acute myeloid leukemia with 11q23 (MLL) abnormalities; adult acute myeloid leukemia with inv(16)(p13;q22); adult acute myeloid leukemia with t(15;17)(q22;q12); adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with t(8;21)(q22;q22); secondary acute myeloid leukemia; childhood acute lymphoblastic leukemia in remission; childhood acute myeloid leukemia in remission; chronic phase chronic myelogenous leukemia; childhood chronic myelogenous leukemia; childhood myelodysplastic syndromes; recurrent adult acute myeloid leukemia; adult acute myeloid leukemia in remission; recurrent adult Hodgkin lymphoma; recurrent/refractory childhood Hodgkin lymphoma; recurrent adult diffuse small cleaved cell lymphoma; recurrent adult diffuse mixed cell lymphoma; blastic phase chronic myelogenous leukemia; relapsing chronic myelogenous leukemia; Waldenstrom macroglobulinemia; stage III grade 1 follicular lymphoma; stage III grade 2 follicular lymphoma; stage III grade 3 follicular lymphoma; stage III adult diffuse small cleaved cell lymphoma; stage III adult diffuse mixed cell lymphoma; stage IV grade 1 follicular lymphoma; stage IV grade 2 follicular lymphoma; stage IV adult diffuse small cleaved cell lymphoma; stage IV adult diffuse mixed cell lymphoma; stage III mantle cell lymphoma; stage IV mantle cell lymphoma; stage II multiple myeloma; stage III multiple myeloma; recurrent grade 1 follicular lymphoma; recurrent grade 2 follicular lymphoma; noncontiguous stage II grade 1 follicular lymphoma; noncontiguous stage II grade 2 follicular lymphoma; noncontiguous stage II adult diffuse small cleaved cell lymphoma; noncontiguous stage II small lymphocytic lymphoma; noncontiguous stage II marginal zone lymphoma; recurrent marginal zone lymphoma; recurrent small lymphocytic lymphoma; stage III small lymphocytic lymphoma; stage III marginal zone lymphoma; stage IV small lymphocytic lymphoma; stage IV marginal zone lymphoma; extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue; nodal marginal zone B-cell lymphoma; splenic marginal zone lymphoma; stage I multiple myeloma; recurrent adult lymphoblastic lymphoma; recurrent mantle cell lymphoma; refractory chronic lymphocytic leukemia; stage III chronic lymphocytic leukemia; stage IV chronic lymphocytic leukemia; stage III adult Hodgkin lymphoma; stage IV adult Hodgkin lymphoma; recurrent cutaneous T-cell non-Hodgkin lymphoma; stage III adult lymphoblastic lymphoma; stage IV adult lymphoblastic lymphoma; recurrent mycosis fungoides/Sezary syndrome; recurrent adult grade III lymphomatoid granulomatosis; refractory multiple myeloma; recurrent adult acute lymphoblastic leukemia; prolymphocytic leukemia; recurrent childhood acute lymphoblastic leukemia; noncontiguous stage II mantle cell lymphoma; noncontiguous stage II adult diffuse large cell lymphoma; noncontiguous stage II adult diffuse mixed cell lymphoma; noncontiguous stage II adult lymphoblastic lymphoma; noncontiguous stage II grade 3 follicular lymphoma; accelerated phase chronic myelogenous leukemia; adult acute lymphoblastic leukemia in remission; recurrent childhood acute myeloid leukemia; noncontiguous stage II adult Burkitt lymphoma; noncontiguous stage II adult immunoblastic large cell lymphoma; recurrent childhood lymphoblastic lymphoma; adult nasal type extranodal natural killer (NK)/T-cell lymphoma
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Precancerous Conditions; Lymphoma; Syndrome; Myelodysplastic Syndromes; Multiple Myeloma; Neoplasms, Plasma Cell; Leukemia; Preleukemia; Plasmacytoma; Myeloproliferative Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Calcineurin Inhibitors; Fludarabine; Fludarabine phosphate; Methotrexate; Tacrolimus; Busulfan; Sargramostim; Antilymphocyte Serum
• Other Study ID Numbers: LCCC 0306; P30CA016086 (U.S. NIH Grant/Contract)