Fludarabine Phosphate and Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia That Has Responded to Treatment With Imatinib Mesylate, Dasatinib, or Nilotinib

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT00036738
First received: May 13, 2002
Last updated: July 22, 2014
Last verified: July 2014
  Purpose

This phase II trial is studying how well fludarabine phosphate and total-body irradiation followed by donor peripheral blood stem cell transplant work in treating patients with acute lymphoblastic leukemia or chronic myelogenous leukemia that has responded to previous treatment with imatinib mesylate, dasatinib, or nilotinib. Giving low doses of chemotherapy, such as fludarabine phosphate, and total-body irradiation (TBI) before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system and help destroy any remaining cancer cells (graft-versus-tumor effect). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving mycophenolate mofetil and cyclosporine after the transplant may stop this from happening.


Condition Intervention Phase
Adult Acute Lymphoblastic Leukemia in Remission
Blastic Phase Chronic Myelogenous Leukemia
Childhood Acute Lymphoblastic Leukemia in Remission
Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Chronic Phase Chronic Myelogenous Leukemia
Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia
Philadelphia Chromosome Positive Childhood Precursor Acute Lymphoblastic Leukemia
Recurrent Adult Acute Lymphoblastic Leukemia
Recurrent Childhood Acute Lymphoblastic Leukemia
Relapsing Chronic Myelogenous Leukemia
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Drug: imatinib mesylate
Drug: dasatinib
Drug: nilotinib
Radiation: total-body irradiation
Drug: cyclosporine
Drug: mycophenolate mofetil
Drug: fludarabine phosphate
Procedure: peripheral blood stem cell transplantation
Biological: therapeutic allogeneic lymphocytes
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Allogeneic Nonmyeloablative Hematopoietic Stem Cell Transplant for Patients With BCR-ABL Tyrosine Kinase Inhibitor Responsive Ph+ Acute Leukemia - a Multi-Center Trial

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Rate of relapse [ Time Frame: Assessed up to 5 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • TRM [ Time Frame: At day 100 ] [ Designated as safety issue: No ]
  • TRM [ Time Frame: At 1 year ] [ Designated as safety issue: No ]
  • Safety of DLI in patients with mixed or full donor chimerism as preemptive therapy to eliminate minimal residual disease [ Time Frame: Assessed up to 5 years ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: Assessed up to 5 years ] [ Designated as safety issue: No ]
  • Leukemia-free survival [ Time Frame: Assessed up to 5 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 30
Study Start Date: July 2001
Estimated Primary Completion Date: October 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (allogeneic nonmyeloablative HSCT)
See Detailed Description
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Undergo nonmyeloablative allogeneic PBSC transplantation
Drug: imatinib mesylate
Given PO
Other Names:
  • CGP 57148
  • Gleevec
  • Glivec
Drug: dasatinib
Given PO
Other Names:
  • BMS-354825
  • Sprycel
Drug: nilotinib
Given PO
Other Names:
  • AMN 107
  • Tasigna
Radiation: total-body irradiation
Undergo TBI
Other Name: TBI
Drug: cyclosporine
Given IV or PO
Other Names:
  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
Drug: mycophenolate mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Procedure: peripheral blood stem cell transplantation
Undergo allogeneic PBSC transplantation
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
Biological: therapeutic allogeneic lymphocytes
Given IV
Other Name: ALLOLYMPH

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine whether the rate of leukemia relapse can be decreased for patients with chronic myelogenous leukemia in blast crisis (CML-BC) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) responsive to imatinib mesylate (or either dasatinib or nilotinib for patients who have imatinib-resistant disease or who are intolerant of imatinib) followed by nonmyeloablative hematopoietic stem cell transplantation (HSCT) compared to historical controls given high-dose conventional allogeneic HSCT or chemotherapy.

II. To determine whether the rate of transplantation-related mortality (TRM) can be decreased for patients with CML-BC and Ph+ ALL responsive to imatinib mesylate (or dasatinib or nilotinib) followed by nonmyeloablative HSCT compared to historical controls given high-dose conventional allogeneic HSCT or chemotherapy.

SECONDARY OBJECTIVES:

I. To evaluate whether donor lymphocyte infusion (DLI) can be safely used in patients with mixed or full donor chimerism as preemptive therapy to eliminate minimal residual disease.

OUTLINE:

INDUCTION THERAPY: Patients continue to receive imatinib mesylate orally (PO), dasatinib PO, or nilotinib PO once or twice daily until day -2 and resume on day 14 or when blood counts recover after peripheral blood stem cell (PBSC) transplantation.

NONMYELOABLATIVE CONDITIONING: Patients receive fludarabine intravenously (IV) on days -4 to -2; and undergo TBI on day 0.

TRANSPLANTATION: Patients undergo allogeneic PBSC transplantation on day 0.

GRAFT-VERSUS-HOST-DISEASE (GVHD) PROPHYLAXIS: Patients receive mycophenolate mofetil (MMF) PO every 12 hours on days 0-27 (related donor recipients) or every 8 hours on days 0-96 with taper on day 40 (unrelated donor recipients). Patients also receive cyclosporine IV or PO every 12 hours on days -3 to 56, followed by taper on days 57-180 (related donor recipients) or on days -3 to 100, followed by taper on days 101-177 (unrelated donor recipients).

DONOR LYMPHOCYTE INFUSION: Patients with persistent disease and no GVHD after stopping GVHD prophylaxis receive donor lymphocyte infusion IV over 30 minutes once every 28 days for 3 doses.

Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed up periodically for 2 years and then annually thereafter for 5 years.

  Eligibility

Ages Eligible for Study:   up to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients =< 12 years of age must be approved by Fred Hutchinson Cancer Research Center (FHCRC) principal investigator (PI) in advance
  • Patients with a history of Ph+ ALL or CML-BC who, after receiving imatinib mesylate, (or either dasatinib or nilotinib) have < 15% blasts on morphologic marrow evaluation; patients with no detectable Ph+ ALL by morphologic or molecular assays (complete remission) will be accepted
  • An appropriately human leukocyte antigen (HLA) matched related or unrelated donor must be prospectively identified who will be available to donate filgrastim (G-CSF) mobilized stem cells
  • RELATED DONOR:

    • Related donor who is HLA genotypically identical at least at one haplotype and may be genotypically or phenotypically identical at the allele level at HLA-A, -B, -C, -DRB1, and -DQB1;
    • Donor must consent to G-CSR administration and leukapheresis;
    • Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian)
  • HLA-MATCHED UNRELATED DONOR:

    • FHCRC matching allowed will be grades 1.0 to 2.1; unrelated donors who are prospectively matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing; only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing
    • A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion; donors are excluded when preexisting immunoreactivity is identified that would jeopardize donor hematopoietic cell engraftment; this determination is based on the standard practice of the individual institution; the recommended procedure for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain a panel reactive antibody (PRA) screens to class I and class II antigens for all patients before HCT; if the PRA shows >10% activity, then flow cytometric or B and T cell cytotoxic cross matches should be obtained; the donor should be excluded if any of the cytotoxic cross match assays are positive; for those patients with an HLA class I allele mismatch, flow cytometric or B and T cell cytotoxic cross matches should be obtained regardless of the PRA results
    • Patient and donor pairs homozygous at a mismatched allele in the graft rejection vector are considered a two-allele mismatch, i.e., the patient is A*0101 and the donor is A*0102, and this type of mismatch is not allowed
    • Only G-CSF mobilized PBSC only will be permitted as a HSC source on this protocol

Exclusion Criteria:

  • Central nervous system (CNS) involvement with leukemia refractory to intrathecal chemotherapy; prior to HSCT (all patients must receive a diagnostic lumbar puncture (LP) with intrathecal (IT) chemotherapy as per standard practice)
  • Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
  • Patients with active non-hematologic malignancies (except non-melanoma skin cancers); this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
  • Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a > 20% risk of disease recurrence; this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
  • Females who are pregnant or breastfeeding
  • Patients who are human immunodeficiency virus (HIV)-positive
  • Patients with poorly controlled hypertension despite multiple antihypertensives
  • Adults: Karnofsky score < 60
  • Pediatrics: Lansky play-performance score < 40
  • Patients with cardiac ejection fraction < 35% (or, if unable to obtain ejection fraction, shortening fraction of < 26%); ejection fraction is required if age > 50 years or there is a history of anthracycline exposure or history of cardiac disease; patients with a shortening fraction < 26% may be enrolled if approved by a cardiologist
  • Diffusing capacity of the lungs for carbon monoxide (DLCO) < 30%
  • Total lung capacity (TLC) < 30%
  • Forced expiratory volume in one second (FEV1) < 30% and/or receiving supplementary continuous oxygen; the FHCRC PI of the study must approve enrollment of all patients with pulmonary nodules
  • Patients with clinical or laboratory evidence of liver disease would be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, or symptomatic biliary disease
  • Creatinine levels more than 2.2 X's the upper limit of normal (ULN) at the laboratory where the analysis was performed
  • Patients with active bacterial or fungal infections unresponsive to medical therapy
  • For patients receiving dasatinib or nilotinib, baseline corrected QT interval (QTc) (Fridericia's method) prolongation greater than 500 msec
  • RELATED DONORS:

    • Identical twin
    • Infection with HIV
    • Inability to achieve adequate venous access
    • Known allergy to G-CSF
    • Current serious system illness
    • Bone marrow (BM) donors
  • HLA-MATCHED UNRELATED DONORS:

    • BM donors
    • Donors who are HIV-positive and/or, medical conditions that would result in increased risk for G-CSF mobilization and harvest of PBSC
  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: NCT00036738

Locations
United States, Colorado
Presbyterian - Saint Lukes Medical Center - Health One
Denver, Colorado, United States, 80218
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
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: George Georges Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided by Fred Hutchinson Cancer Research Center

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT00036738     History of Changes
Other Study ID Numbers: 1581.00, NCI-2010-00131, 1581.00, P30CA015704, P01CA078902
Study First Received: May 13, 2002
Last Updated: July 22, 2014
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Blast Crisis
Leukemia
Leukemia, Lymphoid
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid, Chronic-Phase
Philadelphia Chromosome
Abnormal Karyotype
Neoplasms by Histologic Type
Neoplasms
Cell Transformation, Neoplastic
Carcinogenesis
Neoplastic Processes
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Pathologic Processes
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Translocation, Genetic
Chromosome Aberrations
Cyclosporins
Cyclosporine
Mycophenolate mofetil
Mycophenolic Acid
Imatinib
Dasatinib

ClinicalTrials.gov processed this record on August 28, 2014