Stem Cell Transplantation for Fanconi Anemia

A Study of Thymic Shielding in Recipients of Total Body Irradiation, Cyclophosphamide, and Fludarabine Followed by Alternate Donor Hematopoietic Stem Cell Transplantation in Patients With Fanconi Anemia

The purpose of this study is to determine whether thymic shielding during total body irradiation can be given and whether it will reduce the risk of infections in Fanconi Anemia patients undergoing alternate donor (not a matched sibling) stem cell transplants.

Study Overview

• Status: Terminated
• Conditions: Fanconi Anemia
• Intervention / Treatment: Procedure: Hematopoietic Stem Cell Transplant; Procedure: Thymic Shielding During Radiation; Procedure: Total Body Irradiation; Drug: Cyclophosphamide, Fludarabine

Detailed Description

All subjects will be given the same treatment regimen of total body irradiation (TBI), Fludarabine, Cyclophosphamide, and anti-thymocyte globulin (ATG), followed by an alternate donor stem cell transplant. Since this treatment regimen has been given before, without thymic shielding, we will compare the outcomes of these patients with the historical data from subjects who did not receive thymic shielding.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Masonic Cancer Center, University of Minnesota

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must be less than (<) 18 years of age with a diagnosis of Fanconi anemia.
• Patients must have an HLA-A, B, DRB1 identical unrelated donor or less than or equal to (≤)1 antigen mismatched related (non-HLA-matched sibling) or <1 antigen mismatched unrelated UCB donor. Patients and donors will be typed for HLA-A and B using serological or molecular techniques and for DRB1 using high resolution molecular typing.

• Patients with FA must have aplastic anemia (AA), myelodysplastic syndrome without excess blasts, or high risk genotype as defined below.

  • Aplastic anemia is defined as having at least one of the following when not receiving growth factors or transfusions
  • Platelet count <20 x 10^9/L
  • ANC <5 x 10^8/L
  • Hgb <8 g/dL
  • Myelodysplastic syndrome with multilineage dysplasia with or without chromosomal anomalies
  • High risk genotype (e.g. IVS-4 or exon 14 FANCC mutations, or BRCA1 or 2 mutations)

• Adequate major organ function including

  • Cardiac: ejection fraction greater than (>)45%
  • Hepatic: bilirubin, AST/ALT, ALP <2 x normal
  • Karnofsky performance status >70% or Lansky performance status >50%
• Women of child-bearing age must be using adequate birth control and have a negative pregnancy test

Exclusion Criteria:

• Available HLA-genotypically identical related donor
• History of gram negative sepsis or systemic fungal infection (proven or suspected based on radiographic studies)
• Refractory anemia with excess blasts, or leukemia
• Active central nervous system (CNS) leukemia at time of hematopoietic cell transplant (HCT)
• History of squamous cell carcinoma of the head/neck/cervix within 2 years of HCT
• Pregnant or lactating female
• Prior radiation therapy preventing use of total body irradiation (TBI) 450 centigray (cGy)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: HSCT Patients; Patients who received total body irradiation (450 cGy [centigray]) with thymic shielding prior to chemotherapy regimen and Hematopoietic Stem Cell Transplant (HSCT)

Procedure: Hematopoietic Stem Cell Transplant; Bone marrow failure may be treated by giving patients stem cells that come from someone else. This is called a stem-cell transplant. As part of the transplant process, patients receive high doses of chemotherapy and/or radiation to treat their underlying disease. As one of its effects, this treatment also kills the healthy stem cells that are already in the marrow. The transplant provides new stem cells for the patient from a healthy donor; that replace the bone marrow and allow the blood counts to recover.; Other Names: Bone Marrow Transplant; Procedure: Thymic Shielding During Radiation; protecting the thymus during total body radiation (450 cGy administered); Other Names: TBI; Procedure: Total Body Irradiation; Six days before the stem cells are given (day -6), subjects will receive total body irradiation with thymic shielding. Thymic shielding is done by placing a piece of lead on the chest during the irradiation treatment so that the irradiation beams do not go to the thymus.; Other Names: Radiation Therapy, Therapuetic Radiation; Drug: Cyclophosphamide, Fludarabine; Day -5 through Day -2, subjects will receive a chemotherapy regimen of Fludarabine, Cyclophosphamide via central line; Other Names: Cytoxan, Fludara

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients Who Exhibited Hematopoietic Recovery and Engraftment	Calculated from Day 1 of hematopoietic cell transplant to Day 42 post-transplant. Hematopoietic recovery and engraftment is defined as the first of three consecutive days the patient's absolute neutrophil count is greater than or equal to 0.5X10^9/Liter.	Day 42 after hematopoietic cell transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients Who Exhibited Secondary Graft Failure	Calculated from Day 1 of hematopoietic cell transplant to Day 100 after transplant. A complication after Bone Marrow Transplant in which the transplanted stem cells do not grow in the recipient's bone marrow and thus do not produce new blood cells.	Day 100 after hematopoietic cell transplant
Number of Patients With Acute Graft Versus-Host Disease (aGVHD)	Calculated from Day 1 of hematopoietic cell transplant to Day 100 after transplant. GVHD is a common complication of allogeneic bone marrow transplantation in which functional immune cells in the transplanted marrow recognize the recipient as "foreign" and mount an immunologic attack.	Day 100 after hematopoietic cell transplant
Number of Patients With Chronic Graft Versus-Host Disease (GVHD)	Calculated from Day 1 of hematopoietic cell transplant to 1 year after transplant. GVHD is a common complication of allogeneic bone marrow transplantation in which functional immune cells in the transplanted marrow recognize the recipient as "foreign" and mount an immunologic attack.	1 year after hematopoietic cell transplant
Number of Patients Who Exhibited Regimen-related Toxicity (RRT)	Calculated from Day 1 of hematopoietic cell transplant to 1 year after transplant. Regimen-related toxicity involves harmful effects in an organism through exposure to the treatment given.	1 year after hematopoietic cell transplant
Immune Reconstitution - Mean Value (1 Year)	Calculated mean value of patient CD4 values collected at intervals from Day 30 through 1 year post-transplant.	1 year post-transplant.
Immune Reconstitution - Mean Value (2 Years)	Calculated mean value of patient CD4 values collected at intervals from Day 30 through 2 years post-transplant.	at 2 years after transplant
Number of Patients Alive at 1 Year	Calculated from Day 1 of hematopoietic cell transplant to 1 year post-transplant.	1 year after transplant
Number of Patients Alive at 2 Years	Calculated from Day 1 of hematopoietic cell transplant to 2 years post-transplant.	2 years after transplant

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota
• Investigators: Principal Investigator: Margaret MacMillan, MD, Masonic Cancer Center, University of Minnesota

Publications and helpful links

General Publications

• MacMillan ML, DeFor TE, Young JA, Dusenbery KE, Blazar BR, Slungaard A, Zierhut H, Weisdorf DJ, Wagner JE. Alternative donor hematopoietic cell transplantation for Fanconi anemia. Blood. 2015 Jun 11;125(24):3798-804. doi: 10.1182/blood-2015-02-626002. Epub 2015 Mar 30.

Study record dates

Study Major Dates

• Study Start: March 1, 2004
• Primary Completion (Actual): December 1, 2008
• Study Completion (Actual): December 1, 2008

Study Registration Dates

• First Submitted: September 9, 2005
• First Submitted That Met QC Criteria: September 9, 2005
• First Posted (Estimate): September 14, 2005

Study Record Updates

• Last Update Posted (Actual): August 26, 2019
• Last Update Submitted That Met QC Criteria: August 21, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Chemotherapy; Stem Cell Transplant; Total Body Irradiation; Thymic Shielding
• Additional Relevant MeSH Terms: Metabolic Diseases; Kidney Diseases; Urologic Diseases; Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; DNA Repair-Deficiency Disorders; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Renal Tubular Transport, Inborn Errors; Anemia; Fanconi Syndrome; Fanconi Anemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine
• Other Study ID Numbers: 0312M54991; MT2003-18 (Other Identifier: Blood and Marrow Transplantation Program)