Cytoxan, Fludara, and Antithymocyte Globulin Conditioning Followed By Stem Cell Transplant in Treating Fanconi Anemia

University of Minnesota (UMN)

Status and phase: Completed; Phase 2; Phase 1

Conditions: Fanconi Anemia

Treatments: Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Mycophenolate Mofetil; Drug: Cyclosporine; Drug: Filgrastim; Procedure: Hematopoietic Stem Cell Transplantation; Biological: Anti-Thymocyte Globulin; Drug: Methylprednisolone

Study type: Interventional

Funder types: Other

Identifiers

NCT00630253

MT2000-09

0001M34441 (Other Identifier)

Details and patient eligibility

About

RATIONALE: Giving chemotherapy, such as cyclophosphamide and fludarabine, before a donor stem cell transplant helps to remove the patient's cells to allow for the transplant cells to take and grow. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient, they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells can make an immune response against the body's normal cells. Giving antithymocyte globulin and removing the T cells from the donor cells before transplant and giving cyclosporine before and after transplant may stop this from happening.

PURPOSE: This phase I/II trial is studying the side effects of cyclophosphamide, fludarabine, and antithymocyte globulin followed by donor stem cell transplant and to see how well it works in treating patients with Fanconi anemia.

Full description

OBJECTIVES:

Primary

• To determine the probability of engraftment in patients with Fanconi anemia treated with cyclophosphamide, fludarabine phosphate, and antithymocyte globulin followed by HLA-genotypically identical sibling donor hematopoietic stem cell transplantation that is T-cell depleted.

Secondary

• To evaluate the incidence of acute graft-versus-host disease (GVHD) and chronic GVHD in patients treated with this regimen.
• To evaluate the incidence of regimen-related toxicity in these patients.
• To evaluate the 1-year survival of patients treated with this regimen.
• To evaluate the incidence of late secondary malignancies (e.g., squamous cell carcinoma of the head and neck or cervix) in patients treated with this regimen.

OUTLINE:

• Preparative cytoreductive therapy: Patients receive cyclophosphamide IV over 2 hours on days -6 to -3 and fludarabine phosphate IV over 30 minutes and anti-thymocyte globulin IV over 4-6 hours on days -6 to -2.
• T-cell depleted donor hematopoietic stem cell transplantation: Patients undergo T-cell depleted donor bone marrow or umbilical cord blood stem cell transplantation on day 0. Patients also receive filgrastim (G-CSF) IV beginning on day 1 and continuing until blood counts recover.
• Graft-versus-host disease prophylaxis: Patients receive cyclosporine IV over 2 hours or orally every 8-12 hours beginning on day -3 and continuing until day 100, followed by a taper. Patients will receive Mycophenolate Mofetil (MMF) therapy beginning on day -3 through day +30 or for 7 days after engraftment, whichever day is later, if no acute GVHD. Engraftment is defined as 1st day of 3 consecutive days of absolute neutrophil count [ANC] > 0.5 x 10^9/L.

After completion of study therapy, patients are followed periodically.

Enrollment: 31 patients

Sex: All

Ages: Under 59 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Patients must be <60 years of age with a diagnosis of Fanconi Anemia (FA).

• Patients must have an HLA-A, B, DRB1 identical sibling 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 moderately severe aplastic anemia (AA), early myelodysplastic syndrome (MDS) with no excess blasts with or without chromosomal abnormalities.

  • In patients <18 years of age, moderately severe aplastic anemia is defined as having at least one of the following:

    • platelet count <40 x 10^9/L
    • absolute neutrophil count (ANC) <10 x 10^8/L
    • Hgb <9 g/dL

  • In patients 18-60 years of age, moderately severe aplastic anemia is defined as having at least one of the following:

    • platelet count <20 x 10^9/L
    • absolute neutrophil count ANC <5 x 10^8/L
    • Hgb <8 g/dL

  • Early myelodysplastic syndrome, with multilineage dysplasia with < 5% blasts, with or without chromosomal anomalies.

• Adequate major organ function including:

  • Cardiac: ejection fraction >45%
  • Hepatic: no clinical evidence of hepatic failure (e.g. coagulopathy, ascites)
  • Karnofsky performance status >70% or Lansky >50%

• Women of child bearing age must be using adequate birth control and have a negative pregnancy test.

Exclusion criteria

• Active bacterial infection within one week of hematopoietic cell transplant (HCT)
• Active fungal infection at time of HCT.
• Late MDS with greater than 5% blasts in bone marrow.
• Acute myelogenous leukemia (AML) or history of AML
• Malignant solid tumor (e.g. squamous cell carcinoma of the head/neck/cervix) within 2 years of HCT.
• Pregnant or lactating female.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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31 participants in 3 patient groups

Marrow Isolex

Experimental group

Description:

bone marrow processed using Isolex 300i (for patients enrolled through April 2010)

Treatment:

Drug: Methylprednisolone

Biological: Anti-Thymocyte Globulin

Drug: Filgrastim

Procedure: Hematopoietic Stem Cell Transplantation

Drug: Cyclosporine

Drug: Mycophenolate Mofetil

Drug: Cyclophosphamide

Drug: Fludarabine

UCB

Experimental group

Description:

No processing Notes: sibling donor UCB is used as the stem cell source and co-enroll for unlicensed UCB registry

Treatment:

Drug: Methylprednisolone

Biological: Anti-Thymocyte Globulin

Drug: Filgrastim

Procedure: Hematopoietic Stem Cell Transplantation

Drug: Cyclosporine

Drug: Mycophenolate Mofetil

Drug: Cyclophosphamide

Drug: Fludarabine

Marrow Clinimax

Experimental group

Description:

bone marrow processed using CliniMACS (for patients enrolled beginning with the August 2010 protocol version)

Treatment:

Drug: Methylprednisolone

Biological: Anti-Thymocyte Globulin

Drug: Filgrastim

Procedure: Hematopoietic Stem Cell Transplantation

Drug: Cyclosporine

Drug: Mycophenolate Mofetil

Drug: Cyclophosphamide

Drug: Fludarabine