Low-Dose Total-Body Irradiation and Fludarabine Phosphate Followed by Unrelated Donor Stem Cell Transplant in Treating Patients With Fanconi Anemia

Low-Dose Total Body Irradiation and Fludarabine Followed By Unrelated Donor Stem Cell Transplantation for Patients With Fanconi Anemia - A Multicenter Trial

Based on success in other diseases, the Fred Hutchinson Cancer Research Center (FHCRC) has developed a transplant procedure for Fanconi anemia (FA), which does not completely destroy the patient's remaining bone marrow. It should also be less harmful (toxic). Researchers wish to test whether this approach can overcome the graft failure often seen when bone marrow or peripheral blood stem cells from an unrelated donor are used. Researchers also will look at whether the procedure is less toxic than a conventional bone marrow transplant (BMT).

Study Overview

• Status: Completed
• Conditions: Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Fanconi Anemia; Adult Acute Myeloid Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
• Intervention / Treatment: Drug: fludarabine phosphate; Radiation: total-body irradiation; Procedure: allogeneic bone marrow transplantation; Drug: cyclosporine; Drug: mycophenolate mofetil; Procedure: allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation

Detailed Description

PRIMARY OBJECTIVES:

I. To determine whether donor chimerism can be achieved in patients with Fanconi anemia receiving marrow or peripheral blood stem cell (PBSC) grafts from unrelated donors following low dose total body irradiation (TBI), fludarabine (fludarabine phosphate), mycophenolate mofetil, and cyclosporine.

II. To determine the lowest dose of TBI necessary to achieve donor chimerism in at least 80% of patients.

III. To determine the incidence of severe regimen-related toxicity.

SECONDARY OBJECTIVES:

I. To determine the survival of Fanconi anemia patients transplanted with unrelated donor marrow or PBSC grafts after conditioning with a non-myeloablative regimen.

II. To determine the incidence and severity of graft-vs-host disease (GVHD) incurred with unrelated bone marrow or PBSC grafts transplant patients with Fanconi anemia.

III. To determine if mixed chimerism results in amelioration of symptoms associated with bone marrow failure in patients with Fanconi anemia.

OUTLINE:

NON-MYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -4 to -2, cyclosporine IV every 8-12 hours on days -3 to 0, and undergo low-dose TBI on day 0.

TRANSPLANTATION: Patients undergo allogeneic bone marrow or PBSC transplantation on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) or IV every 8-12 hours on days 1-100 with taper to day 177, and mycophenolate mofetil PO or IV every 8 hours on days 0-40 with taper to day 96.

After completion of study treatment, patients are followed up at 6 months and annually thereafter.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Robert H. Lurie Comprehensive Cancer Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute/University of Utah
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Any patient with marrow failure and increased chromosome fragility as determined in the diepoxybutane (DEB) or mitomycin C test
• Any patient with Fanconi anemia (FA) with marrow failure meeting the following criteria:
• Granulocyte count < 0.2 x 10^9/L
• Platelet count < 20 x 10^9/L
• Hemoglobin < 8 g/dl
• Corrected reticulocyte count <1%
• Any patient with FA as determined by DEB fragility, who has life-threatening marrow failure involving a single hematopoietic lineage
• Any patient with FA and pre-existing cytogenetic abnormality including hematopoietic malignancy (myelodysplastic syndromes [MDS] or acute myeloid leukemia [AML]) in remission
• DONOR: Unrelated Donors who are prospectively: Matched for human lymphocyte antigen (HLA)-DRB1 and DQB1 alleles (must be defined by high resolution typing); only a single allele disparity will be allowed for HLA -A, B, or C as defined by high resolution typing
• DONOR: HLA typing will be performed at the highest level of resolution available at the time of transplant

Exclusion Criteria:

• Evidence for hematopoietic malignancy in relapse
• Heart or lung disease that would prevent compliance with conditioning and GvHD regimen or would severely limit the probability of survival
• Human immunodeficiency virus (HIV) seropositive patients
• Females who are pregnant or breastfeeding, or unwilling to use contraceptive techniques during and for the 12 months following treatment
• DONOR: Donors who by DEB testing are found to have FA
• DONOR: Donors who test positive in the lymphocytotoxic crossmatch assay
• DONOR: Donors who are HIV positive
• DONOR: Donors who for other medical or psychological reasons are not suitable as donors

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Treatment (allogeneic bone marrow or PBSC transplantation); NON-MYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -4 to -2, cyclosporine IV every 8-12 hours on days -3 to 0, and undergo low-dose TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic bone marrow or PBSC transplantation on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO or IV every 8-12 hours on days 1-100 with taper to day 177, and mycophenolate mofetil PO or IV every 8 hours on days 0-40 with taper to day 96.

Drug: fludarabine phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; Radiation: total-body irradiation; Undergo TBI; Other Names: TBI; Procedure: allogeneic bone marrow transplantation; Undergo allogeneic bone marrow transplantation; Other Names: bone marrow therapy, allogeneic; bone marrow therapy, allogenic; transplantation, allogeneic bone marrow; transplantation, allogenic bone marrow; Drug: cyclosporine; Given IV or PO; Other Names: ciclosporin; cyclosporin; cyclosporin A; CYSP; Sandimmune; Drug: mycophenolate mofetil; Given PO or IV; Other Names: Cellcept; MMF; Procedure: allogeneic hematopoietic stem cell transplantation; Undergo allogeneic PBSC transplantation; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Engraftment, defined as donor chimerism (mixed or complete)	Mixed chimerism is defined as presence of 5-95%, complete chimerism as > 95% donor derived cells in the peripheral blood. Patient data will be summarized using standard statistical methods.	Day 28
Engraftment, defined as donor chimerism (mixed or complete)	Mixed chimerism is defined as presence of 5-95%, complete chimerism as > 95% donor derived cells in the peripheral blood. Patient data will be summarized using standard statistical methods.	Day 56
Engraftment, defined as donor chimerism (mixed or complete)	Mixed chimerism is defined as presence of 5-95%, complete chimerism as > 95% donor derived cells in the peripheral blood. Patient data will be summarized using standard statistical methods.	Day 84
Engraftment, defined as donor chimerism (mixed or complete)	Mixed chimerism is defined as presence of 5-95%, complete chimerism as > 95% donor derived cells in the peripheral blood. Patient data will be summarized using standard statistical methods.	Day 180
Regimen toxicity assessed using the Bearman scale	Patient data will be summarized using standard statistical methods.	Up to day 100
Acute GvHD defined using the Seattle criteria	For the evaluation of GvHD, time of onset, severity, and treatment will be recorded. Patient data will be summarized using standard statistical methods.	Day 84

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Hans-Peter Kiem, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start: January 1, 2000
• Primary Completion (ACTUAL): September 1, 2007

Study Registration Dates

• First Submitted: October 6, 2004
• First Submitted That Met QC Criteria: October 7, 2004
• First Posted (ESTIMATE): October 8, 2004

Study Record Updates

• Last Update Posted (ACTUAL): February 20, 2017
• Last Update Submitted That Met QC Criteria: February 16, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Neoplasms by Histologic Type; Neoplasms; Kidney Diseases; Urologic Diseases; Disease; Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; DNA Repair-Deficiency Disorders; Precancerous Conditions; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Renal Tubular Transport, Inborn Errors; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Anemia; Fanconi Syndrome; Fanconi Anemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Fludarabine; Fludarabine phosphate; Mycophenolic Acid; Cyclosporine; Cyclosporins
• Other Study ID Numbers: 1444.00 (OTHER: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium); P30CA015704 (U.S. NIH Grant/Contract); NCI-2012-00593 (REGISTRY: CTRP (Clinical Trial Reporting Program))