Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Related Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs No phase specified Treatment Active 10 and over NCI UNC-LCCC-0306 LCCC 0306, NCT00448201

Objectives

Primary

1. 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.
2. Determine the feasibility of this regimen in these patients.
3. Establish a treatment-related mortality during the first 6 months that is less than 20% in patients treated with this regimen.

Secondary

1. Determine the response rates (disease-specific partial response and complete response) in patients treated with this regimen.
2. Determine overall and progression-free survival of patients treated with this regimen.
3. Determine the percent donor chimerism and immunologic recovery, including dendritic cell recovery, in patients treated with this regimen.
4. Determine the risk of acute and chronic graft-versus-host disease and other toxicities in patients treated with this regimen.
5. 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.

Entry 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 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

Prior/Concurrent Therapy:

• See Disease Characteristics
• More than 4 weeks since prior chemotherapy, radiotherapy (except prophylactic cranial x-ray therapy), or surgery

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

Expected Enrollment

Outcomes

Treatment-related mortality

Complete response at 6 and 12 months post-transplant
Complete or mixed donor chimerism at 30, 60, and 90 days post-transplant
5-year disease-free survival
Graft-vs-host disease at 6 months post-transplant

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 180, 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 completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for at least 5 years.

Trial Contact Information

Trial Lead Organizations

Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill

Thomas Shea, MD, Principal investigator		Ph: 919-966-7746 Email: sheaT@med.unc.edu

U.S.A.
North Carolina
	Chapel Hill
	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
		Clinical Trials Office - Lineberger Comprehensive Cancer Center	Ph:  877-668-0683; 919-966-4432

Related Information

PDQ® clinical trial CALGB-100002

Registry 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
Trial Start Date		2003-11-01
Registered in ClinicalTrials.gov		NCT00448201
Date Submitted to PDQ		2007-05-04
Information Last Verified		2008-07-27
NCI Grant/Contract Number		CA16086

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