TBI Dose De-escalation for Fanconi Anemia

• Incidence of grade ≥3 regimen related toxicity . [ Time Frame: at day 100 ] [ Designated as safety issue: Yes ]
• Incidence of secondary graft failure at 100 days. [ Time Frame: 100 days ] [ Designated as safety issue: No ]
• Incidence of acute graft-versus-host disease (GVHD) [ Time Frame: at 100 days. ] [ Designated as safety issue: No ]
• Incidence of chronic GVHD . [ Time Frame: at one year ] [ Designated as safety issue: No ]
• Probability of survival . [ Time Frame: at one year ] [ Designated as safety issue: No ]
• Incidence of infections . [ Time Frame: at 100 days, 6 months and one year ] [ Designated as safety issue: No ]
• Immune reconstitution . [ Time Frame: at 100 days, 6 month and one year ] [ Designated as safety issue: No ]

• Incidence of grade ≥3 regimen related toxicity at day 100.
• Incidence of secondary graft failure at 100 days.
• Incidence of acute graft-versus-host disease (GVHD) at 100 days.
• Incidence of chronic GVHD at one year.
• Probability of survival at one year.
• Incidence of infections at 100 days, 6 months and one year.
• Immune reconstitution at 100 days, 6 month and one year.

This is a single arm, total body irradiation (TBI) trial. All patients will be prescribed TBI 300 cGy with the goal of evaluating secondary endpoints.

Study Treatment: Patients will receive voriconazole (antifungal therapy) by mouth beginning 1 month prior to conditioning therapy, if possible. 1) The subject is to receive total body irradiation (300 cGy) with thymic shielding; it will be given six days before the stem cells are given (day -6). 2) Day -5 through Day -2, subjects will receive a chemotherapy regimen of Fludarabine, Cyclophosphamide, anti-thymocyte globulin (ATG), and Methylprednisone via central line (i.e. Hickman or Broviac). On day -1, subjects will receive ATG and Methylprednisone. 3) Starting Day -3, patients will receive CSA therapy beginning on day -3 with a taper commencing on day +180 and also mycophenolate mofetil (MMF) through day +30 or for 7 days after engraftment, whichever day is later, if no acute graft-versus-host disease (GVHD). 4) If the subject is receiving bone marrow or "peripheral" stem cells (cells collected from the donor's arm via a cell separator), on the day of transplantation, the stem cells taken from the donor will be put into a machine which will separate the lymphocytes (the cells that cause graft-versus-host disease [GVHD]) from the stem cells. If the subject is receiving an umbilical cord blood, the lymphocytes will not be removed because the risk of GVHD is not as high. Otherwise all patients will receive the same treatment. The stem cells are given as an infusion into the subject's existing catheter over 1-2 hours on day 0.5. On the day after transplant (day +1) subjects will be given G-CSF to stimulate the growth of the transplanted cells. 6. While receiving treatment and until the subject's blood counts recover he/she will have daily blood tests, and several bone marrow biopsies and aspirates. After recovery, subjects will be seen once a month for a health assessment and blood tests until at least 3 months after the cells have been infused. Additional blood tests or assessments may be done as medically indicated.

• Drug: Cyclophosphamide
  Day -5 through Day -2, subjects will receive chemotherapy of Cyclophosphamide via central line (i.e. Hickman or Broviac),10 mg/kg intravenously (IV)
  Other Name: cytoxan
• Drug: Fludarabine
  Day -5 through Day -2 prior to transplant; subjects will receive chemotherapy of Fludarabine via central line (i.e. Hickman or Broviac),35 mg/m^2 intravenous (IV)
  Other Name: fludara
• Drug: anti-thymocyte globulin (ATG)
  Day -5 through Day -1, subjects will receive ATG via central line (i.e. Hickman or Broviac), 30 mg/kg/day IV
  Other Name: Thymoglobulin
• Procedure: Total Body Irradiation
  total body irradiation (300 cGy) with thymic shielding will be given six days before the stem cells are given (day -6). 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 Name: Radiation Therapy, Therapeutic radiation
• Procedure: Bone Marrow Transplantation
  A target of 5 * 10^6/kg and a minimum of 4 * 10^6 CD34+ cell/kg recipient weight will be collected by apheresis and used for transplant. In most cases this dose will be recovered in a single apheresis; however, a second or rarely third apheresis performed on the following days may be required to achieve the minimum dose.
  Other Name: Stem Cell transplantation
• Drug: Mycophenolate Mofetil
  Patients will receive MMF therapy beginning on day -3 through day +30 or for 7 days after engraftment, whichever day is later, if no acute graft-versus-host disease (GVHD). Engraftment is defined as 1st day of 3 consecutive days of absolute neutrophil count [ANC] > 0.5 * 10^9/L. MMF will be given at a dose of 15 mg/kg/dose every 8 hours by mouth(to a maximum dose of 1 gram).
  Other Name: MMF
• Drug: Methylprednisolone
  Methylprednisolone (MP) 2 mg/kg/day intravenously every 24 hours will be given from day -5 until day -1 as a premedication for antithymocyte globulin (ATG). Equine ATG 30 mg/kg/day will be administered after MP on days -5, -4, -3, -2 and -1 preceding transplant.
  Other Name: Medrol

Inclusion Criteria:

Meeting the definition of standard risk or high risk Fanconi anemia as defined in the next two sections:

• Standard risk patients must be <18 years of age with a diagnosis of Fanconi anemia with 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 * 10^9/L
    • ANC <5 * 10^8/L
    • Hemoglobin <8 g/dL
  • Myelodysplastic syndrome (MDS) 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)

• High risk patients must have one or more of the following high risk features:

  • Advanced MDS (≥ 5% blast) or acute leukemia
  • History at any time of systemic fungal or gram negative infection
  • Severe renal disease with a creatinine clearance <40 mL/min
  • Age > 18 years
• Very high risk patients must have Advanced MDS (≥ 5% blast) or acute leukemia after initial hematopoietic stem cell transplant (HSCT)
• Patients must have an appropriate source of stem cells. Patients and donors will be typed for HLA-A, B, C and DRB1 using high resolution molecular typing.

• Adequate major organ function including:

  • Cardiac: ejection fraction >45%
  • Hepatic: bilirubin, AST or ALT, ALP <5 x normal
  • Karnofsky performance status >70% or Lansky >50 (if < 16 years of age)
• Women of child-bearing age must be using adequate birth control and have a negative pregnancy test.
• Written consent.

Exclusion Criteria:

• Available HLA-genotypically identical related donor in standard risk patients.
• Active central nervous system (CNS) leukemia at time of study enrollment.
• History of squamous cell carcinoma of the head/neck/cervix within previous 2 years.
• Prior radiation therapy that prevents further total body irradiation (TBI).