Hematopoietic Stem Cell Transplantation in High Risk Patients With Fanconi Anemia

Hematopoietic Stem Cell Transplantation in High Risk Patients With Fanconi Anemia MT2002-02

RATIONALE: A bone marrow or umbilical cord blood transplant may be able to replace blood-forming cells that were destroyed by chemotherapy. Giving combination chemotherapy before a donor stem cell transplant may make the transplant more likely to work. This may be an effective treatment for patients with high risk Fanconi's anemia.

PURPOSE: This clinical trial is studying how well combination chemotherapy works in treating high risk patients who are undergoing a donor stem cell transplant for Fanconi's anemia.

Study Overview

• Status: Completed
• Conditions: Fanconi Anemia
• Intervention / Treatment: Biological: anti-thymocyte globulin; Biological: filgrastim; Drug: busulfan; Drug: cyclophosphamide; Drug: fludarabine phosphate; Drug: methylprednisolone; Biological: Hematopoietic stem cell transplantation

Detailed Description

OBJECTIVES:

Primary

• Determine whether the incidence of neutrophil engraftment is acceptable in high-risk patients with Fanconi's anemia treated with busulfan, cyclophosphamide, fludarabine, and antithymocyte globulin followed by allogeneic hematopoietic stem cell transplantation.

Secondary

• Determine the tolerability of mycophenolate mofetil in these patients.
• Determine the incidence of acute and chronic graft-vs-host disease in patients treated with this regimen.
• Determine the incidence of major infections in patients with a history of major infections treated with this regimen.
• Determine the incidence of relapse in patients with refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia treated with this regimen
• Determine the probability of 1-year survival of patients treated with this regimen.

OUTLINE: Patients are stratified according to donor/recipient HLA type (identical vs other).

• Cytoreductive combination chemotherapy: Patients receive busulfan intravenously (IV) over 2 hours twice daily on days -7 and -6 and cyclophosphamide IV over 2 hours and fludarabine IV over 30 minutes once daily on days -5 to -2.
• Graft failure prophylaxis: Patients receive methylprednisolone IV twice daily on days -5 to 30 and anti-thymocyte globulin IV over 4-6 hours twice daily on days -5 to -1.
• Graft-vs-host disease prophylaxis: Patients receive cyclosporine IV over 2 hours twice daily on days -3 to 100 (if patient has a matched sibling donor) or days -3 to 180 (if patient has another donor type). Patients also receive mycophenolate mofetil orally or IV twice daily on days -3 to 45.
• Allogeneic hematopoietic stem cell transplantation (HSCT): Patients undergo allogeneic HSCT (using bone marrow or umbilical cord blood) on day 0. Patients receive filgrastim (G-CSF) subcutaneously beginning on day 1 and continuing until blood counts recover.

After completion of study treatment, patients are followed periodically for 3 years.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2

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: No older than 44 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must be <45 years of age with a diagnosis of Fanconi anemia with:

  • Biallelic BRCA2 mutations, or
  • Aplastic anemia, or advanced myelodysplastic syndrome (MDS) (MDS with ≥5% blasts), or acute leukemia who are ineligible for total body irradiation. Aplastic anemia is defined as having at least one of the following (with or without cytogenetic abnormalities): platelet count <20 * 10^9, - absolute neutrophil count (ANC) <5 * 10^8/L, - Hgb <8 g/dL
• Patients must have an HLA-A, B, DRB1 identical or 1 antigen mismatched related or unrelated BM donor or have an HLA-A, B, DRB1 identical, 1 antigen or 2 antigen mismatched related or unrelated umbilical cord blood (UCB) donor. Patients and donors will be typed for HLA-A and B using serological level typing and for DRB1 using high resolution molecular typing.

• Adequate major organ function including:

  • Cardiac: ejection fraction >45%
  • Hepatic: no clinical evidence of hepatic failure (e.g. coagulopathy, ascites, no cirrhosis)
  • Karnofsky performance status >70% or Lansky >50%
• Women of child bearing potential must be using adequate birth control and have a negative pregnancy test.

Exclusion Criteria:

• Active CNS leukemia at time of HSCT.
• Active uncontrolled infection within one week of hematopoietic stem cell transplant (HSCT).
• Pregnant or lactating female.

Donor Inclusion Criteria:

• Donor must be in good health based on review of systems and results of physical examination.
• Donor must have a normal hemoglobin, white count, platelet count and partial thromboplastin time (PTT), and a negative diepoxybutane (DEB) test.
• HIV-NAT negative, HTLV-1, HTLV-2 negative, Hepatitis B and C negative.
• Female donors of childbearing potential must have a negative pregnancy test.
• Unrelated donors must agree to peripheral blood stem cell (PBSC) donation

Donor Exclusion Criteria:

• Donor is a lactating female.

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

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Marrow Isolex; Bone marrow processed using Isolex300i	Biological: anti-thymocyte globulin; Given 15 mg/kg/day intravenously every 12 hours on Days -5 through -1.; Other Names: ATG; Biological: filgrastim; given 5 mcg/kg/day intravenously on Day 1 (continue until absolute neutrophil count (ANC) ≥2.5 x 10^9/L); Other Names: G-CSF; Drug: busulfan; Busulfan 0.8 mg/kg intravenously (IV) every 12 hours on Days -7 and -6 (1.0 mg/kg IV if <4 years old); Other Names: Busulfex; Drug: cyclophosphamide; 10 mg/kg intravenously (IV) on Days -5 through -2.; Other Names: Cytoxan; Drug: fludarabine phosphate; 35 mg/m^2 intravenously (IV) on Days -5 through -2.; Other Names: Fludara; Drug: methylprednisolone; 1 mg/kg intravenously (IV) every 12 hours on Days -5 through -1.; Other Names: Medrol; Biological: Hematopoietic stem cell transplantation; Infused on Day 0 - Donor bone marrow or umbilical cord blood will be collected in the usual sterile manner using established parameters determined by the National Marrow Donor Program.; Other Names: HSCT
Experimental: USB arm; No processing	Biological: anti-thymocyte globulin; Given 15 mg/kg/day intravenously every 12 hours on Days -5 through -1.; Other Names: ATG; Biological: filgrastim; given 5 mcg/kg/day intravenously on Day 1 (continue until absolute neutrophil count (ANC) ≥2.5 x 10^9/L); Other Names: G-CSF; Drug: busulfan; Busulfan 0.8 mg/kg intravenously (IV) every 12 hours on Days -7 and -6 (1.0 mg/kg IV if <4 years old); Other Names: Busulfex; Drug: cyclophosphamide; 10 mg/kg intravenously (IV) on Days -5 through -2.; Other Names: Cytoxan; Drug: fludarabine phosphate; 35 mg/m^2 intravenously (IV) on Days -5 through -2.; Other Names: Fludara; Drug: methylprednisolone; 1 mg/kg intravenously (IV) every 12 hours on Days -5 through -1.; Other Names: Medrol; Biological: Hematopoietic stem cell transplantation; Infused on Day 0 - Donor bone marrow or umbilical cord blood will be collected in the usual sterile manner using established parameters determined by the National Marrow Donor Program.; Other Names: HSCT
Experimental: Marrow Clinimacs; Bone marrow processed using CliniMACS system	Biological: anti-thymocyte globulin; Given 15 mg/kg/day intravenously every 12 hours on Days -5 through -1.; Other Names: ATG; Biological: filgrastim; given 5 mcg/kg/day intravenously on Day 1 (continue until absolute neutrophil count (ANC) ≥2.5 x 10^9/L); Other Names: G-CSF; Drug: busulfan; Busulfan 0.8 mg/kg intravenously (IV) every 12 hours on Days -7 and -6 (1.0 mg/kg IV if <4 years old); Other Names: Busulfex; Drug: cyclophosphamide; 10 mg/kg intravenously (IV) on Days -5 through -2.; Other Names: Cytoxan; Drug: fludarabine phosphate; 35 mg/m^2 intravenously (IV) on Days -5 through -2.; Other Names: Fludara; Drug: methylprednisolone; 1 mg/kg intravenously (IV) every 12 hours on Days -5 through -1.; Other Names: Medrol; Biological: Hematopoietic stem cell transplantation; Infused on Day 0 - Donor bone marrow or umbilical cord blood will be collected in the usual sterile manner using established parameters determined by the National Marrow Donor Program.; Other Names: HSCT
Experimental: Sibling without CliniMacs; Sibling donor without the use of CliniMACS system	Biological: anti-thymocyte globulin; Given 15 mg/kg/day intravenously every 12 hours on Days -5 through -1.; Other Names: ATG; Biological: filgrastim; given 5 mcg/kg/day intravenously on Day 1 (continue until absolute neutrophil count (ANC) ≥2.5 x 10^9/L); Other Names: G-CSF; Drug: busulfan; Busulfan 0.8 mg/kg intravenously (IV) every 12 hours on Days -7 and -6 (1.0 mg/kg IV if <4 years old); Other Names: Busulfex; Drug: cyclophosphamide; 10 mg/kg intravenously (IV) on Days -5 through -2.; Other Names: Cytoxan; Drug: fludarabine phosphate; 35 mg/m^2 intravenously (IV) on Days -5 through -2.; Other Names: Fludara; Drug: methylprednisolone; 1 mg/kg intravenously (IV) every 12 hours on Days -5 through -1.; Other Names: Medrol; Biological: Hematopoietic stem cell transplantation; Infused on Day 0 - Donor bone marrow or umbilical cord blood will be collected in the usual sterile manner using established parameters determined by the National Marrow Donor Program.; Other Names: HSCT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing Graft Failure	Graft failure is defined as absolute neutrophil count( ANC ) <5 x 10^8/L by day 30.	Day 30

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing Chronic Graft-Versus-Host Disease	Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cellsinto a foreign host.	Day 42
Number of Participants Experiencing Chronic Graft-Versus-Host Disease	Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cellsinto a foreign host.	1 year
Number of Participants Experiencing Acute Graft-Versus-Host Disease	Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.	1 year
Number of Participants Experiencing Acute Graft-Versus-Host Disease	Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.	Day 42
Number of Participants Experiencing Relapse	Patients with leukemia will have this done by BM biopsy and additional special studies such as cytogenetics or flow cytometry as appropriate.	1 Year
Number of Participants Experiencing Overall Survival	Overall Survival - Number of patients alive at 1 year post transplant	1 Year
Number of Participants Experiencing Major Infections	Number of participants experiencing Major Infections by the end of treatment	Day 1 through 1 year post-transplant

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2002
• Primary Completion (Actual): October 10, 2020
• Study Completion (Actual): October 10, 2020

Study Registration Dates

• First Submitted: November 22, 2005
• First Submitted That Met QC Criteria: November 22, 2005
• First Posted (Estimate): November 24, 2005

Study Record Updates

• Last Update Posted (Actual): December 2, 2021
• Last Update Submitted That Met QC Criteria: November 4, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Fanconi anemia
• 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; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuroprotective Agents; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Methylprednisolone; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Busulfan; Antilymphocyte Serum
• Other Study ID Numbers: 2002LS014; MT2002-02 (Other Identifier: Blood and Marrow Transplantation Program); 0202M18741 (Other Identifier: IRB, University of Minnesota)