Fludarabine Phosphate, Low-Dose Total-Body Irradiation, and Peripheral Blood Stem Cell Transplant Followed By Donor Lymphocyte Infusion in Treating Older Patients With Chronic Myeloid Leukemia

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT00003145
First received: November 1, 1999
Last updated: December 2, 2013
Last verified: December 2013
  Purpose

This clinical trial studies fludarabine phosphate, low-dose total-body irradiation, and peripheral blood stem cell transplant followed by donor lymphocyte infusion in treating older patients with chronic myeloid leukemia. Giving chemotherapy and total-body irradiation before a donor bone marrow transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem 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 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.


Condition Intervention Phase
Accelerated Phase Chronic Myelogenous Leukemia
Childhood Chronic Myelogenous Leukemia
Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Chronic Phase Chronic Myelogenous Leukemia
Relapsing Chronic Myelogenous Leukemia
Drug: fludarabine phosphate
Radiation: total-body irradiation
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Procedure: peripheral blood stem cell transplantation
Drug: cyclosporine
Drug: mycophenolate mofetil
Biological: therapeutic allogeneic lymphocytes
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Induction Of Mixed Hematopoietic Chimerism Using Fludarabine, Low Dose TBI , PBSC Infusion And Post-Transplant Immunosuppression With Cyclosporine And Mycophenolate Mofetil to be Followed by Donor Lymphocyte Infusion In Patients With Chronic Myeloid Leukemia in Chronic and Accelerated Phases: A Multi-Center Study.

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • Safety of establishing mixed chimerism using this non-lethal conditioning regimen, in terms of development of GVHD, myelosuppression, infections, and treatment-related mortality [ Time Frame: Within the first 65 days ] [ Designated as safety issue: Yes ]
    All unexpected toxicities will be summarized and reported.

  • Proportion of patients who successfully establish mixed chimerism (evidence of donor engraftment) and the proportion who convert to full donor chimeras among those who were mixed [ Time Frame: Day 28 ] [ Designated as safety issue: No ]
    Estimated and corresponding confidence intervals presented. Mixed chimerism is detection of donor T cells (CD3+) and granulocytes (CD33+), as proportion of total T cell and granulocyte population of > 5% and < 95% in peripheral blood. Full donor chimerism is > 95% donor CD3+ T cells. Increasing donor chimerism is absolute increase of 20% of CD3+ T cells over chimerism evaluation of previous month. Decreasing donor chimerism is absolute decrease of 20% of CD3+ T cell chimerism over previous month. Low donor chimerism is < 40% CD3+ T cells after HSCT.

  • Proportion of patients who successfully establish mixed chimerism (evidence of donor engraftment) and the proportion who convert to full donor chimeras among those who were mixed [ Time Frame: Day 56 ] [ Designated as safety issue: No ]
    Estimated and corresponding confidence intervals presented. Mixed chimerism is detection of donor T cells (CD3+) and granulocytes (CD33+), as proportion of total T cell and granulocyte population of > 5% and < 95% in peripheral blood. Full donor chimerism is > 95% donor CD3+ T cells. Increasing donor chimerism is absolute increase of 20% of CD3+ T cells over chimerism evaluation of previous month. Decreasing donor chimerism is absolute decrease of 20% of CD3+ T cell chimerism over previous month. Low donor chimerism is < 40% CD3+ T cells after HSCT.


Secondary Outcome Measures:
  • Proportion of patients experiencing a complete antileukemic response [ Time Frame: At 12 weeks after the final DLI ] [ Designated as safety issue: No ]
    Reported in a descriptive manner and confidence intervals will be presented for all estimates.

  • Proportion of patients experiencing GVHD [ Time Frame: Until day 90 after the last DLI ] [ Designated as safety issue: Yes ]
    Reported in a descriptive manner and confidence intervals will be presented for all estimates.

  • Proportion of patients experiencing non-relapse mortality [ Time Frame: Within 65 days of transplant ] [ Designated as safety issue: Yes ]
    Reported in a descriptive manner and confidence intervals will be presented for all estimates.

  • Incidence of myelosuppression after initial PBSC infusion [ Time Frame: Until 2 months post-transplant ] [ Designated as safety issue: Yes ]
    Defined as absolute neutrophil count [ANC] < 500 for > 2 days, platelets < 20,000 for > 2 days.

  • Incidence of aplasia after DLI [ Time Frame: Until 2 months post-transplant ] [ Designated as safety issue: Yes ]
  • Incidence of grades 2-4 acute GVHD after DLI [ Time Frame: Until day 90 after the last DLI ] [ Designated as safety issue: Yes ]
  • Incidence of grades 2-4 acute GVHD after PBSC infusion [ Time Frame: Until day 90 after the last DLI ] [ Designated as safety issue: Yes ]
  • Incidence of grades chronic extensive GVHD after DLI [ Time Frame: At 1 year ] [ Designated as safety issue: Yes ]
  • Dose of CD3+ cells required to convert mixed to full lymphoid chimeras [ Time Frame: Day 56 ] [ Designated as safety issue: No ]

Estimated Enrollment: 20
Study Start Date: August 1997
Primary Completion Date: March 2005 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (chemotherapy, TBI, PBSCT, DLI)

CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo low-dose TBI on day 0.

TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID or IV BID or TID on days -3 to 56 with taper to day 77 or 180, and mycophenolate mofetil PO or IV BID on days 0-27.

DLI: At least 2 weeks after completion of immunosuppression, patients with > 5% donor CD3+ T cells and no evidence of GVHD receive donor lymphocytes IV over 30 minutes. Patients may receive up to 3 DLIs at increasing cell doses in the absence of GVHD.

Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Radiation: total-body irradiation
Undergo TBI
Other Name: TBI
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Undergo allogeneic PBSCT
Procedure: peripheral blood stem cell transplantation
Undergo allogeneic PBSCT
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
Drug: cyclosporine
Given PO or IV
Other Names:
  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
Drug: mycophenolate mofetil
Given PO or IV
Other Names:
  • Cellcept
  • MMF
Biological: therapeutic allogeneic lymphocytes
Given IV
Other Name: ALLOLYMPH
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine if mixed hematopoietic chimerism can be safely established using a non-myeloablative conditioning regimen in patients > 65 years of age with chronic myeloid leukemia (CML) in chronic or accelerated phase who have human leukocyte antigen (HLA) identical related donors.

II. To determine if mixed chimerism, established with non-myeloablative conditioning regimens, can be converted to full donor hematopoietic chimerism by infusions of donor lymphocytes (DLI), and thereby produce an immunologic cure of the malignancy.

OUTLINE:

CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 and undergo low-dose total-body irradiation (TBI) on day 0.

TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation (PBSCT) on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) twice daily (BID) or IV BID or thrice daily (TID) on days -3 to 56 with taper to day 77 or 180, and mycophenolate mofetil PO or IV BID on days 0-27.

DLI: At least 2 weeks after completion of immunosuppression, patients with > 5% donor cluster of differentiation (CD)3+ T cells and no evidence of graft-versus-host disease (GVHD) receive donor lymphocytes IV over 30 minutes. Patients may receive up to 3 DLIs at increasing cell doses in the absence of GVHD.

After completion of study treatment, patients are followed up periodically for 5 years.

  Eligibility

Ages Eligible for Study:   up to 74 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with Philadelphia chromosome positive (Ph+) CML in first and second chronic and first accelerated phases
  • Patients =< 65 years old who are at high risk of regimen related toxicity through pre-existing chronic disease affecting liver, lungs, and/or heart, or others who wish to be treated on this protocol, will be considered on a case-by-case basis; transplants should be approved for these inclusion criteria by both the participating institutions' patient review committees such as the Patient Care Conference (PCC) at the Fred Hutchinson Cancer Research Center (FHCRC) and by the principal investigators at the collaborating centers; patients =< 65 years of age who have received previous high-dose transplantation do not require patient review committee approvals; all children < 12 years must be discussed with the FHCRC principal investigator (PI) (Brenda Sandmaier, MD 206-667-4961) prior to registration
  • HLA genotypically identical related donor willing to undergo leukapheresis initially for collection of peripheral blood stem cell (PBSC) and subsequently for collection of peripheral blood mononuclear cell (PBMC)
  • Patients treated with alpha interferon must have discontinued drug at least 1 month prior to transplant
  • DONOR: HLA genotypically identical family member (excluding identical twins)
  • DONOR: Donor must consent to filgrastim (G-CSF) administration and leukapheresis
  • DONOR: Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian)

Exclusion Criteria:

  • Patients who are human immunodeficiency virus positive (HIV+)
  • GROUP 1: (PATIENTS AGED > 65 AND < 75 YEARS)
  • Patients unwilling to use contraceptive techniques during and for 12 months following treatment
  • Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with CML
  • Patients in an interferon induced complete or partial cytogenetic remission
  • Organ dysfunction:

    • Patients with renal failure are eligible, however patients with renal compromise (Serum creatinine greater than 2.0) will likely have further compromise in renal function and may require hemodialysis (which may be permanent) due to the need to maintain adequate serum cyclosporine levels
    • Cardiac ejection fraction < 40%; ejection fraction is required if the patient has a history of anthracyclines or history of cardiac disease
    • Diffusing capacity of the lung for carbon monoxide (DLCO) < 50% of predicted
    • Liver function tests including total bilirubin, serum glutamic pyruvate transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) > 2x the upper limit of normal unless proven to be due to the malignancy
    • Karnofsky score < 70
  • Patients with poorly controlled hypertension
  • GROUP 2 (PATIENTS AGED =< 65)
  • Patients who are HIV+
  • Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with CML
  • Females who are pregnant
  • Patients unwilling to use contraceptive techniques during and for 12 months following treatment
  • Patients in an interferon induced complete or partial cytogenetic remission
  • Organ dysfunction:

    • Patients with renal failure are eligible, however patients with renal compromise (Serum creatinine greater than 2.0) will likely have further compromise in renal function and may require hemodialysis (which may be permanent) due to the need to maintain adequate serum cyclosporine levels
    • Cardiac ejection fraction < 40% or a history of congestive heart failure; ejection fraction is required if the patient has a history of anthracyclines or history of cardiac disease
    • Severe defects in pulmonary function testing as defined by the pulmonary consultant (defects are currently categorized as mild, moderate and severe) or receiving supplementary continuous oxygen; DLCO < 50% of predicted
    • Liver function tests: total bilirubin > 2x the upper limit of normal, SGPT and SGOT 4x the upper limit of normal
    • Karnofsky score < 50
  • Patients with poorly controlled hypertension
  • DONOR: Age less than 12 years
  • DONOR: Pregnancy
  • DONOR: Infection with HIV
  • DONOR: Inability to achieve adequate venous access
  • DONOR: Known allergy to G-CSF
  • DONOR: Current serious systemic illness
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00003145

Locations
United States, California
City of Hope Medical Center
Duarte, California, United States, 91010
Stanford University Hospitals and Clinics
Stanford, California, United States, 94305
United States, Colorado
University of Colorado
Denver, Colorado, United States, 80217-3364
United States, Texas
Baylor University Medical Center
Dallas, Texas, United States, 75246
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
VA Puget Sound Health Care System
Seattle, Washington, United States, 98101
Germany
Universitaet Leipzig
Leipzig, Germany, D-04103
Italy
University of Torino
Torino, Italy, 10126
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: Brenda Sandmaier Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT00003145     History of Changes
Other Study ID Numbers: 1209.00, NCI-2012-00579, 1209.00, P30CA015704, P01CA078902, P01CA018029
Study First Received: November 1, 1999
Last Updated: December 2, 2013
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Accelerated Phase
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid, Chronic-Phase
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Cyclosporins
Cyclosporine
Mycophenolate mofetil
Mycophenolic Acid
Fludarabine phosphate
Vidarabine
Fludarabine
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Dermatologic Agents
Antirheumatic Agents
Antibiotics, Antineoplastic
Antineoplastic Agents

ClinicalTrials.gov processed this record on August 01, 2014