Hematopoietic Stem Cell Transplantation in High Risk Patients With Fanconi Anemia

Phase 2

Completed

Conditions: Fanconi Anemia

Interventions: Biological: anti-thymocyte globulin
Biological: filgrastim
Drug: busulfan
Drug: cyclophosphamide
Drug: fludarabine phosphate
Drug: methylprednisolone
Biological: Hematopoietic stem cell transplantation

Registration Number: NCT00258427

Lead Sponsor: Masonic Cancer Center, University of Minnesota

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 14

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Marrow Isolex	anti-thymocyte globulin	Bone marrow processed using Isolex300i
Marrow Isolex	filgrastim	Bone marrow processed using Isolex300i
USB arm	Hematopoietic stem cell transplantation	No processing
Marrow Clinimacs	filgrastim	Bone marrow processed using CliniMACS system
Marrow Clinimacs	Hematopoietic stem cell transplantation	Bone marrow processed using CliniMACS system
Sibling without CliniMacs	anti-thymocyte globulin	Sibling donor without the use of CliniMACS system
Marrow Isolex	methylprednisolone	Bone marrow processed using Isolex300i
Marrow Clinimacs	anti-thymocyte globulin	Bone marrow processed using CliniMACS system
USB arm	anti-thymocyte globulin	No processing
USB arm	filgrastim	No processing
Marrow Isolex	Hematopoietic stem cell transplantation	Bone marrow processed using Isolex300i
Sibling without CliniMacs	filgrastim	Sibling donor without the use of CliniMACS system
Marrow Clinimacs	busulfan	Bone marrow processed using CliniMACS system
Sibling without CliniMacs	fludarabine phosphate	Sibling donor without the use of CliniMACS system
Sibling without CliniMacs	cyclophosphamide	Sibling donor without the use of CliniMACS system
Sibling without CliniMacs	Hematopoietic stem cell transplantation	Sibling donor without the use of CliniMACS system
Marrow Isolex	cyclophosphamide	Bone marrow processed using Isolex300i
Marrow Isolex	busulfan	Bone marrow processed using Isolex300i
Marrow Isolex	fludarabine phosphate	Bone marrow processed using Isolex300i
USB arm	busulfan	No processing
USB arm	fludarabine phosphate	No processing
USB arm	cyclophosphamide	No processing
USB arm	methylprednisolone	No processing
Marrow Clinimacs	cyclophosphamide	Bone marrow processed using CliniMACS system
Marrow Clinimacs	fludarabine phosphate	Bone marrow processed using CliniMACS system
Sibling without CliniMacs	busulfan	Sibling donor without the use of CliniMACS system
Sibling without CliniMacs	methylprednisolone	Sibling donor without the use of CliniMACS system
Marrow Clinimacs	methylprednisolone	Bone marrow processed using CliniMACS system

Primary Outcome Measures

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

Secondary Outcome Measures

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