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NCT00281983 · CITED IN SOURCE DOCUMENTS

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

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE1, PHASE2
Status at capture
COMPLETED
Registry last update
2017-07-24

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.

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What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

No posted result sections were captured. Registered plans do not establish that a treatment works.

Who could take part
eligibility Criteria
DISEASE CHARACTERISTICS: * 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 PATIENT CHARACTERISTICS: * 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 PRIOR CONCURRENT THERAPY: * Not specified
healthy Volunteers
false
maximum Age
65 Years
minimum Age
18 Years
sex
ALL
std Ages
  1. ADULT
  2. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    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)
    intervention Names
    1. Biological: alemtuzumab
    2. Biological: anti-thymocyte globulin
    3. Biological: filgrastim
    4. Biological: rituximab
    5. Biological: therapeutic allogeneic lymphocytes
    6. Drug: busulfan
    7. Drug: cyclophosphamide
    8. Drug: cyclosporine
    9. Drug: fludarabine phosphate
    10. Drug: methotrexate
    11. Drug: mycophenolate mofetil
    12. Procedure: peripheral blood stem cell transplantation
    label
    Allogeneic stem cell transplantation
    type
    EXPERIMENTAL
interventions
  1. arm Group Labels
    1. Allogeneic stem cell transplantation
    name
    alemtuzumab
    type
    BIOLOGICAL
  2. arm Group Labels
    1. Allogeneic stem cell transplantation
    name
    anti-thymocyte globulin
    type
    BIOLOGICAL
  3. arm Group Labels
    1. Allogeneic stem cell transplantation
    name
    filgrastim
    type
    BIOLOGICAL
  4. arm Group Labels
    1. Allogeneic stem cell transplantation
    name
    rituximab
    type
    BIOLOGICAL
  5. arm Group Labels
    1. Allogeneic stem cell transplantation
    name
    therapeutic allogeneic lymphocytes
    type
    BIOLOGICAL
  6. arm Group Labels
    1. Allogeneic stem cell transplantation
    name
    busulfan
    type
    DRUG
  7. arm Group Labels
    1. Allogeneic stem cell transplantation
    name
    cyclophosphamide
    type
    DRUG
  8. arm Group Labels
    1. Allogeneic stem cell transplantation
    name
    cyclosporine
    type
    DRUG
  9. arm Group Labels
    1. Allogeneic stem cell transplantation
    name
    fludarabine phosphate
    type
    DRUG
  10. arm Group Labels
    1. Allogeneic stem cell transplantation
    name
    methotrexate
    type
    DRUG
  11. arm Group Labels
    1. Allogeneic stem cell transplantation
    name
    mycophenolate mofetil
    type
    DRUG
  12. arm Group Labels
    1. Allogeneic stem cell transplantation
    name
    peripheral blood stem cell transplantation
    type
    PROCEDURE
Study design
allocation
NA
intervention Model
SINGLE_GROUP
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
100
type
ACTUAL
Registered outcome plans (not posted results)
primary Outcomes
  1. measure
    Feasibility as measured by the proportion of eligible patients completing the transplant procedure successfully
  2. measure
    Safety as measured by a treatment-related mortality of < 25% at 2 years following transplant
secondary Outcomes
  1. measure
    Clinical remission rate by NIH criteria at 12 months following transplant
  2. measure
    Minimal residual disease negativity rate as measured by high-resolution flow or CDR PCR at 12 months following transplant
  3. measure
    Chimerism as measured by STR-PCR at 12 months following transplant
  4. measure
    Event-free and overall survival at 5 years following transplant
Full study description
brief Summary
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.
detailed Description
OBJECTIVES: Primary * 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). Secondary * 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.
Source references
references
  1. citation
    Dreger P, Dohner H, Ritgen M, Bottcher S, Busch R, Dietrich S, Bunjes D, Cohen S, Schubert J, Hegenbart U, Beelen D, Zeis M, Stadler M, Hasenkamp J, Uharek L, Scheid C, Humpe A, Zenz T, Winkler D, Hallek M, Kneba M, Schmitz N, Stilgenbauer S; German CLL Study Group. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood. 2010 Oct 7;116(14):2438-47. doi: 10.1182/blood-2010-03-275420. Epub 2010 Jul 1.
    pmid
    20595516
    type
    RESULT
  2. citation
    Ritgen M, Bottcher S, Stilgenbauer S, Bunjes D, Schubert J, Cohen S, Humpe A, Hallek M, Kneba M, Schmitz N, Dohner H, Dreger P; German CLL Study Group. Quantitative MRD monitoring identifies distinct GVL response patterns after allogeneic stem cell transplantation for chronic lymphocytic leukemia: results from the GCLLSG CLL3X trial. Leukemia. 2008 Jul;22(7):1377-86. doi: 10.1038/leu.2008.96. Epub 2008 Apr 17.
    pmid
    18418404
    type
    RESULT
  3. citation
    Dreger P, Schnaiter A, Zenz T, Bottcher S, Rossi M, Paschka P, Buhler A, Dietrich S, Busch R, Ritgen M, Bunjes D, Zeis M, Stadler M, Uharek L, Scheid C, Hegenbart U, Hallek M, Kneba M, Schmitz N, Dohner H, Stilgenbauer S. TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG CLL3X trial. Blood. 2013 Apr 18;121(16):3284-8. doi: 10.1182/blood-2012-11-469627. Epub 2013 Feb 22.
    pmid
    23435461
    type
    RESULT
  4. citation
    Scheffold A, Jebaraj BMC, Jaramillo S, Tausch E, Steinbrecher D, Hahn M, Bottcher S, Ritgen M, Bunjes D, Zeis M, Stadler M, Uharek L, Scheid C, Hegenbart U, Hallek M, Kneba M, Schmitz N, Dohner H, Dreger P, Stilgenbauer S. Impact of telomere length on the outcome of allogeneic stem cell transplantation for poor-risk chronic lymphocytic leukaemia: results from the GCLLSG CLL3X trial. Br J Haematol. 2017 Oct;179(2):342-346. doi: 10.1111/bjh.14219. Epub 2016 Jul 8. No abstract available.
    pmid
    27391907
    type
    RESULT
  5. citation
    Kramer I, Stilgenbauer S, Dietrich S, Bottcher S, Zeis M, Stadler M, Bittenbring J, Uharek L, Scheid C, Hegenbart U, Ho A, Hallek M, Kneba M, Schmitz N, Dohner H, Dreger P. Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial. Blood. 2017 Sep 21;130(12):1477-1480. doi: 10.1182/blood-2017-04-775841. Epub 2017 Jul 17. No abstract available.
    pmid
    28716861
    type
    RESULT
Source notices and limitations
    Discovery and provenance
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        survival plateau for allogeneic SCT suggests an additional graft-versus-leukemia effect.[<a href="#cit/section_6.30">30</a>] A series (<a href="/clinicaltrials/NCT00281983">NCT00281983</a>) of 90 patients with relapsed or refractory CLL who underwent allogeneic SCT reported a 6-year OS rate of 58% and a 6-year EFS rate of 38%, wh
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        eau for allogeneic SCT suggests an additional graft-versus-leukemia effect.[<a href="#cit/section_6.30">30</a>] A series (<a href="/clinicaltrials/NCT00281983">NCT00281983</a>) of 90 patients with relapsed or refractory CLL who underwent allogeneic SCT reported a 6-year OS rate of 58% and a 6-year EFS rate of 38%, which included
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      source update dates
      1. context
        Updated: April 25, 2025
        datetime
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        display
        April 25, 2025

    Preserved source evidence · Not medical advice