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Fludarabine and Cyclophosphamide in Treating Patients Who Are Undergoing Donor Stem Cell Transplant for Chronic Lymphocytic Leukemia or Waldenstrom's Macroglobulinemia

This study has been completed.
Information provided by:
German CLL Study Group Identifier:
First received: January 24, 2006
Last updated: February 23, 2017
Last verified: April 2007

RATIONALE: Giving chemotherapy before a donor bone marrow transplant helps stop the growth of cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. Also, monoclonal antibodies, such as alemtuzumab, can find cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving methotrexate, cyclosporine and mycophenolate mofetil after the transplant may stop this from happening. Once the donated stem cells begin working, the patient's immune system may see the remaining cancer cells as not belonging in the patient's body and destroy them (called graft-versus-tumor effect). Giving an infusion of the donor's white blood cells (donor lymphocyte infusion) may boost this effect.

PURPOSE: This phase I/II trial is studying the side effects of giving fludarabine together with cyclophosphamide and to see how well they work in treating patients who are undergoing donor stem cell transplant for B-cell chronic lymphocytic leukemia or Waldenström's macroglobulinemia.

Condition Intervention Phase
Chronic Lymphocytic Leukemia
Biological: alemtuzumab
Biological: anti-thymocyte globulin
Biological: filgrastim
Biological: rituximab
Biological: therapeutic allogeneic lymphocytes
Drug: busulfan
Drug: cyclophosphamide
Drug: cyclosporine
Drug: fludarabine phosphate
Drug: methotrexate
Drug: mycophenolate mofetil
Procedure: peripheral blood stem cell transplantation
Radiation: radiation therapy
Phase 1
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Pilot Study on Allogeneic Stem Cell Transplantation Following Conditioning With Fludarabine and an Alkylating Agent in Patients With High-Risk Chronic Lymphocytic Leukemia

Resource links provided by NLM:

Further study details as provided by German CLL Study Group:

Primary Outcome Measures:
  • Feasibility as measured by the proportion of eligible patients completing the transplant procedure successfully
  • Safety as measured by a treatment-related mortality of < 25% at 2 years following transplant

Secondary Outcome Measures:
  • Clinical remission rate by NIH criteria at 12 months following transplant
  • Minimal residual disease negativity rate as measured by high-resolution flow or CDR PCR at 12 months following transplant
  • Chimerism as measured by STR-PCR at 12 months following transplant
  • Event-free and overall survival at 5 years following transplant

Enrollment: 100
Study Start Date: June 2000
Study Completion Date: July 2010
Arms Assigned Interventions
Experimental: Allogeneic stem cell transplantation
  1. Cytoreductive therapy for inducing a state of partial remission:

    FC or FC-R or alternative salvage regimens (e.g. Alemtuzumab)

  2. Conditioning regimen:

    FC +/- ATG (Arm A) or FC/Busulfan +/- ATG (Arm C: refractory patients only)

  3. allogeneic-PBSCT (from HLA-identical donor)
  4. GVHD prophylaxis: CSA + MTX or MMF
  5. +/- DLI (Donor lymphocyte infusions)
Biological: alemtuzumab Biological: anti-thymocyte globulin Biological: filgrastim Biological: rituximab Biological: therapeutic allogeneic lymphocytes Drug: busulfan Drug: cyclophosphamide Drug: cyclosporine Drug: fludarabine phosphate Drug: methotrexate Drug: mycophenolate mofetil Procedure: peripheral blood stem cell transplantation Radiation: radiation therapy

Detailed Description:



  • Determine the feasibility and safety of induction therapy comprising fludarabine and cyclophosphamide followed by allogeneic stem cell transplantation in patients with high-risk B-cell chronic lymphocytic leukemia or lymphoplasmocytic lymphoma (Waldenstrom's macroglobulinemia).


  • Determine the incidence and kinetics of clinical and molecular remissions in patients treated with this regimen.
  • Determine event-free and overall survival of patients treated with this regimen.
  • Determine the duration of clinical and molecular remission in relation to the underlying cytogenetic deviation in patients treated with this regimen.
  • Determine the kinetics and extent of lympho-hematopoietic donor chimerism in patients treated with this regimen.

OUTLINE: This is a multicenter, open-label, nonrandomized, pilot study.

  • Cytoreductive therapy: Patients receive up to 3 courses of cytoreductive therapy comprising fludarabine IV and cyclophosphamide IV on days 1-3 (with or without rituximab IV on day 1). Patients refractory to fludarabine-containing therapy may receive alemtuzumab IV for 12 weeks OR any other cytotoxic salvage regimen for cytoreduction.
  • Conditioning regimen: Patients receive 1 of the following conditioning regimens*:

NOTE: *Patients who did not achieve partial response after cytoreductive therapy receive regimen 3.

  • Regimen 1: Patients receive fludarabine IV and cyclophosphamide IV on days -7 to -3. If stem cells are collected from an unrelated donor, patients also receive anti-thymocyte globulin (ATG) IV on days -4 to -1.
  • Regimen 2: Patients undergo total-body irradiation on day -9. Patients then receive alemtuzumab IV on days -8 to -4 and fludarabine IV and cyclophosphamide IV on days -6 to -2.
  • Regimen 3: Patients receive fludarabine IV on days -7 to -3, busulfan IV or orally on days -7 to -5, and cyclophosphamide IV on days -3 to -2. If stem cells are collected from an unrelated donor, patients also receive ATG on days -3 to -1.

    • Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo allogeneic PBSCT on day 0. Patients receive filgrastim (G-CSF) subcutaneously daily starting on day 5 and continuing until blood count recover.
    • Graft-versus-host-disease (GVHD) prophylaxis: Patients receive cyclosporine IV beginning on day -1 and continuing until approximately day 100. Patients treated with conditioning regimen 1 or 3 also receive methotrexate IV on days 1, 3, and 6 OR oral mycophenolate mofetil twice daily on days 0-50. Patients with evidence of residual disease at least 4 weeks after completion of cyclosporine undergo donor lymphocyte infusion (DLI).
    • DLI: The donor T-lymphocytes are collected from the PBSCT donor without prior G-CSF mobilization. Patients receive DLI every 8 weeks in the presence of residual disease and the absence of GVHD.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 70 patients will be accrued for this study.


Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • Diagnosis of B-cell chronic lymphocytic leukemia or lymphoplasmocytic lymphoma (Waldenstrom's macroglobulinemia)

    • Must have poor prognostic features and low probability of successful autografting, defined by one of the following criteria:

      • Progressive disease with unfavorable cytogenetics (deletion or mutation of critical regions on chromosomes 11q and/or 17p [p53]; and/or unmutated status of the immunoglobulin V_H gene region; and/or usage of the V_H 3-21 gene), defined as 1 of the following:

        • Doubling of lymphocyte count or nodal involvement within 3 months or less
        • Progressive decline of platelet count and/or hemoglobin values defining Binet stage C disease (or to 50% or less of baseline values within 3 months) not due to immune mechanisms
        • Symptomatic splenomegaly
        • Discomfort or imminent complications due to large tumor masses
        • B symptoms
      • Refractory disease or early relapse (within 12 months) after treatment with a fludarabine-containing regimen
      • Relapsed after autologous stem cell transplant (SCT)
      • Insufficient stem cell harvest for intended autologous SCT
  • Presence of a clonal CDR III rearrangement detected by polymerase chain reaction
  • No Richter's syndrome
  • HLA-identical sibling or unrelated donor available


  • ECOG performance status ≤ 1
  • Creatinine clearance > 60 mL/min
  • SGOT, SGPT, and bilirubin < 2 times normal
  • Normal cardiac function determined by ECG and echocardiographic examination
  • Inspiratory vital capacity, FEV_1, and DLCO > 50% of predicted
  • No serious localized or systemic infections
  • No other concurrent malignant disease
  • No impaired organ function
  • No uncontrolled diabetes
  • No uncontrolled hypertension
  • Not pregnant or nursing
  • Fertile patients must use effective contraception
  • No HIV infection
  • No hepatitis B or C infection
  • No concurrent alcohol or drug abuse
  • No dementia or altered mental status that would preclude giving informed consent


  • Not specified
  Contacts and Locations
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Please refer to this study by its identifier: NCT00281983

Canada, Quebec
Maisonneuve-Rosemont Hospital
Montreal, Quebec, Canada, H1T 2M4
Charite - Universitaetsmedizin Berlin - Campus Benjamin Franklin
Berlin, Germany, 12200
Universitaetsklinikum Essen
Essen, Germany, 45122
Universitaetsklinikum Goettingen
Goettingen, Germany, 37075
Asklepios Klinik St. Georg
Hamburg, Germany, D-20099
Medizinische Hochschule Hannover
Hannover, Germany, 30625
Universitaets-Kinderklinik Heidelberg
Heidelberg, Germany, D-69120
Universitaetsklinikum des Saarlandes
Homburg, Germany, 66421
Clinic for Bone Marrow Transplantation and Hematology and Oncology
Idar-Oberstein, Germany, D-55743
University Hospital Schleswig-Holstein - Kiel Campus
Kiel, Germany, 24116
University Hospital of Leipzig
Leipzig, Germany, 04103
Klinikum der Universitaet Regensburg
Regensburg, Germany, 93053
Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm
Ulm, Germany, 89081
Sponsors and Collaborators
German CLL Study Group
Study Chair: Peter Dreger Universitaets-Kinderklinik Heidelberg
  More Information

Additional Information:
Publications: Identifier: NCT00281983     History of Changes
Other Study ID Numbers: CLL3X
Study First Received: January 24, 2006
Last Updated: February 23, 2017
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by German CLL Study Group:
B-cell chronic lymphocytic leukemia
refractory chronic lymphocytic leukemia
stage III chronic lymphocytic leukemia
stage IV chronic lymphocytic leukemia
Waldenström macroglobulinemia

Additional relevant MeSH terms:
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Waldenstrom Macroglobulinemia
Neoplasms by Histologic Type
Leukemia, B-Cell
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Fludarabine phosphate
Mycophenolic Acid
Antilymphocyte Serum processed this record on May 25, 2017