Treosulfan and Fludarabine Before Donor Stem Cell Transplant in Treating Patients With Nonmalignant Inherited Disorders

• Non-relapse mortality [ Time Frame: Up to 1 year following transplant ] [ Designated as safety issue: No ]
• Incidence of grade II-IV acute GVHD [ Time Frame: Within the first year following transplant ] [ Designated as safety issue: No ]
• Incidence of chronic GVHD [ Time Frame: Within the two years (on average) following transplant ] [ Designated as safety issue: No ]
• Donor chimerism [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  Peripheral blood chimerism for CD3, CD33, CD19, and CD56 will be evaluated.
• Disease response following HCT [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
• Immune reconstitution following HCT [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  Measured using samples of peripheral blood, and bone marrow aspirate.
• Incidence of infections [ Time Frame: Within the first year following transplant ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: Within the two years following transplant ] [ Designated as safety issue: No ]

• Incidence of non-relapse mortality at 200 days and at 1 year after transplant [ Designated as safety issue: No ]
• Incidence of grade II-IV acute graft-versus-host disease (GVHD) [ Designated as safety issue: No ]
• Incidence of chronic GVHD [ Designated as safety issue: No ]
• Donor chimerism at 28 days and at 100 days after transplant [ Designated as safety issue: No ]
• Disease response [ Designated as safety issue: No ]
• Immune reconstitution [ Designated as safety issue: No ]
• Incidence of infections [ Designated as safety issue: No ]
• Overall survival [ Designated as safety issue: No ]

The purpose of this phase II clinical trial is to see if the combination of two chemotherapy drugs, treosulfan and fludarabine with or without low dose radiation, just prior to stem cell transplantation is safe and effective in patients with nonmalignant (noncancerous) diseases. Hematopoietic cell transplantation has been shown to be curative for many patients with nonmalignant (noncancerous) diseases such as primary immunodeficiency disorders, bone marrow failure syndromes, hemoglobinopathies, and inborn errors of metabolism (metabolic disorders). Powerful chemotherapy drugs and/or radiation are often used to condition the patient before infusion of the new healthy donor cells. The purpose of the conditioning therapy is to destroy the patient's abnormal bone marrow which doesn't work properly in order to make way for the new healthy donor cells which functions normally. Although effective in curing the patient's disease, many hematopoietic cell transplantation regimens use intensive chemotherapy and/or radiation which can be quite toxic, have significant side effects, and can potentially be life-threatening. Investigators at the Fred Hutchinson Cancer Research Center in collaboration with Oregon Health & Sciences University, Vanderbilt University, and Medical College of Wisconsin are investigating whether a new conditioning regimen that uses less intensive drugs (treosulfan and fludarabine) with or without low dose radiation results in engraftment of the new donor cells without increased toxicities in patients with nonmalignant (noncancerous) diseases

PRIMARY OBJECTIVES:

I. To evaluate within the limits of a phase II study, the preliminary efficacy, as defined by engraftment, of a regimen consisting of treosulfan and fludarabine followed by allogeneic hematopoietic cell transplantation (HCT) in patients with nonmalignant inherited disorders.

SECONDARY OBJECTIVES:

I. To evaluate the incidence of non-relapse mortality 200 days and 1 year post-HCT.

II. To evaluate the incidence of grade II-IV acute graft-versus-host disease (GVHD).

III. To evaluate the incidence of chronic GVHD as defined as those patients requiring systemic immunosuppression.

IV. To evaluate donor chimerism on days +28 and +100.

V. To assess disease response following HCT.

VI. To evaluate immune reconstitution following HCT.

VII. To evaluate the incidence of infections.

VIII. To evaluate overall survival.

OUTLINE:

CONDITIONING REGIMEN: Patients receive treosulfan intravenously (IV) over 2 hours on days -6 to -4 and fludarabine IV over 1 hour on days -6 to -2. Patients receive anti-thymocyte globulin IV over 4-6 hours on days -4 to -2. Patients undergoing umbilical cord blood transplantation will also receive low dose total-body irradiation on day -1.

TRANSPLANTATION: Patients will receive either bone marrow, peripheral blood stem cells (PBSC), or umbilical cord blood from the donor on day 0. The use of either bone marrow, PBSC, or umbilical cord blood will depend on the donor status.

IMMUNOSUPPRESSION: Patients will receive a combination of immunosuppressive medications to try and prevent graft-versus-host disease. If patients undergo bone marrow or PBSC transplantation, tacrolimus and methotrexate will be used. If patients undergo cord blood transplantation, cyclosporine and mycophenolate mofetil will be used. In general, patients will receive immunosuppression until at least 180 days after transplantation; however they could be on immunosuppression longer if they develop graft versus host disease.

After completion of study treatment, patients are followed up periodically for 5 years.

• Procedure: umbilical cord blood transplantation
  Single or double unit umbilical cord blood transplant, infused IV
  Other Names:

  • cord blood transplantation
  • transplantation, umbilical cord blood
  • UCB transplantation
• Procedure: peripheral blood stem cell transplantation
  Infused IV
  Other Names:

  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
• Procedure: allogeneic bone marrow transplantation
  Infused IV
  Other Names:

  • bone marrow therapy, allogeneic
  • bone marrow therapy, allogenic
  • transplantation, allogeneic bone marrow
  • transplantation, allogenic bone marrow
• Drug: fludarabine phosphate
  Given IV
  Other Names:

  • 2-F-ara-AMP
  • Beneflur
  • Fludara
• Drug: treosulfan
  Given IV
  Other Names:

  • dihydroxybusulfan
  • Ovastat
  • tresulfon
• Radiation: total-body irradiation
  Undergo total body irradiation
  Other Name: TBI
• Drug: tacrolimus
  Given IV or PO
  Other Names:

  • FK 506
  • Prograf
• Drug: methotrexate
  Given IV
  Other Names:

  • amethopterin
  • Folex
  • methylaminopterin
  • Mexate
  • MTX
• Drug: cyclosporine
  Given IV or PO
  Other Names:

  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
• Drug: mycophenolate mofetil
  Given IV or PO
  Other Names:

  • Cellcept
  • MMF
• Genetic: DNA analysis
  Correlative studies
• Other: laboratory biomarker analysis
  Correlative studies
• Genetic: cytogenetic analysis
  Correlative studies
• Biological: anti-thymocyte globulin
  Given IV
  Other Names:

  • ATG
  • ATGAM
  • lymphocyte immune globulin
  • Thymoglobulin

• Experimental: Group I (PBSCT and BMT)
  See Detailed Description. Patients undergoing bone marrow or PBSC transplantation receive tacrolimus IV continuously or PO twice daily on days -1 to 50 followed by a taper until day 180 in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
  Interventions:

  • Procedure: peripheral blood stem cell transplantation
  • Procedure: allogeneic bone marrow transplantation
  • Drug: fludarabine phosphate
  • Drug: treosulfan
  • Drug: tacrolimus
  • Drug: methotrexate
  • Genetic: DNA analysis
  • Other: laboratory biomarker analysis
  • Genetic: cytogenetic analysis
  • Biological: anti-thymocyte globulin
• Experimental: Group II (UBCT)
  See Detailed Description. Patients undergoing UCB transplantation receive cyclosporine IV over 1 hour every 8-12 hours on days -3 to 100 followed by a taper until day 180 in the absence of GVHD. Patients also receive mycophenolate mofetil IV or PO every 8 hours on days 0 to 40 followed by a taper until day 96 in the absence of GVHD.
  Interventions:

  • Procedure: umbilical cord blood transplantation
  • Drug: fludarabine phosphate
  • Drug: treosulfan
  • Radiation: total-body irradiation
  • Drug: cyclosporine
  • Drug: mycophenolate mofetil
  • Genetic: DNA analysis
  • Other: laboratory biomarker analysis
  • Genetic: cytogenetic analysis
  • Biological: anti-thymocyte globulin

Inclusion Criteria:

• Patients with a nonmalignant disease treatable by allogeneic HCT
• Patients with a known nonmalignant disease that is not clearly defined will need to be discussed with the protocol principal investigator (PI) (Dr. Lauri Burroughs) and potentially the nonmalignant board to determine if they are eligible for HCT on this study
• DONOR: Human leukocyte antigens (HLA)-identical related donors or unrelated donors matched for HLA-A, B, C, DRB1, and DQB1 or mismatched for a single allele at HLA-A, B, C, DRB1 or a single DQB1 antigen or allele mismatch by high resolution deoxyribonucleic acid (DNA) typing
• DONOR: Bone marrow is the preferred cell source; PBSC are allowed if donor refuses or is unable to give marrow
• DONOR, Umbilical Cord Blood: Unit selection is based on the cryopreserved total nucleated cell (TNC) dose and matching at HLA-A, B antigen level and DRB1 allele level typing. While HLA-C antigen/allele level typing is not considered in the matching criteria, if available, may be used to optimize unit selection.
• DONOR, Umbilical Cord Blood: The patient and the cord blood unit(s) must be matched for at least 4 of 6 loci as defined above.
• DONOR, Umbilical Cord Blood: Selection of two UCB units is allowed to provide sufficient cell dose

Exclusion Criteria:

• Patients with idiopathic aplastic anemia and Fanconi anemia; (patients with aplastic anemia associated with paroxysmal nocturnal hemoglobinuria [PNH] or inherited marrow failure syndromes, except Fanconi anemia, will be allowed)
• Patients with impaired cardiac function as evidenced by ejection fraction < 35% (or, if unable to obtain ejection fraction, shortening fraction of < 26%) or cardiac insufficiency requiring treatment or symptomatic coronary artery disease; patients with a shortening fraction < 26% may be enrolled if approved by a cardiologist
• Patients with impaired pulmonary function as evidenced by diffusion capacity of the lung for carbon monoxide (DLCO) < 50% of predicted (or, if unable to perform pulmonary function tests, then oxygen [O2] saturation < 92% on room air)
• Patients with impaired renal function as evidenced by creatinine-clearance < 50% for age, weight, height or serum creatinine > 2X upper normal limit or dialysis-dependent
• Patients with evidence of synthetic dysfunction or severe cirrhosis requiring deferral of conditioning as recommended by a gastroenterology specialist
• Patients with an active infectious disease requiring deferral of conditioning; as recommended by an infectious disease specialist
• Patients who are seropositive for human immunodeficiency virus (HIV)
• Females who are pregnant or breast-feeding
• Patients with a known hypersensitivity to treosulfan and/or fludarabine
• Receiving another experimental drug within 4 weeks of initiation of conditioning (day -6)
• DONOR: Deemed unable to undergo marrow harvesting or PBSC mobilization and leukapheresis
• DONOR: HIV-positive
• DONOR: With active infectious hepatitis
• DONOR: Females with a positive pregnancy test

• National Heart, Lung, and Blood Institute (NHLBI)
• National Cancer Institute (NCI)
• medac GmbH