Treosulfan and Fludarabine Phosphate Before Donor Stem Cell Transplant in Treating Patients With Nonmalignant Inherited Disorders
Condition: Non-Neoplastic Hematologic and Lymphocytic Disorder
MeSH terms: Hematologic Diseases
Intervention: Allogeneic Bone Marrow Transplantation; Anti-Thymocyte Globulin; Cyclosporine; Fludarabine Phosphate; Laboratory Biomarker Analysis; Methotrexate; Mycophenolate Mofetil; Peripheral Blood Stem Cell Transplantation; Tacrolimus; Total-Body Irradiation; Treosulfan; Umbilical Cord Blood Transplantation
Intervention description: Infused IV; Given IV; Given IV or PO; Given IV; Correlative studies; Given IV; Given IV or PO; Infused IV; Given IV or PO; Undergo total body irradiation; Given IV; Single or double unit umbilical cord blood transplant, infused IV
Intervention MeSH terms: Cyclosporine; Mycophenolic Acid; Methotrexate; Fludarabine phosphate; Fludarabine; Treosulfan; Busulfan; Tacrolimus; Cyclosporins; Thymoglobulin; Antilymphocyte Serum
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 98.0
Sex: All
Maximum age: 49 Years
Healthy volunteers: No
Keywords: nonmalignant diseases; nonmalignant inherited disorders; primary immunodeficiency diseases; primary immune deficiency disorders; chronic granulomatous; disease; IPEX syndrome; hemophagocytic lymphohistiocytosis; Wiskott Aldrich Syndrome; bone marrow failure syndromes; Shwachman Diamond Syndrome; Dyskeratosis Congenita; Diamond Blackfan Anemia; inborn errors of metabolism; metabolic diseases; hemoglobinopathies; sickle cell disease; thalassemia; reduced intensity transplantation; hematopoietic cell transplantation; bone marrow transplantation; umbilical cord blood transplantation

Summary:

      This phase II clinical trial studies how well treosulfan and fludarabine phosphate with or
      without low dose radiation before donor stem cell transplantation works in treating 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
      are investigating whether a new conditioning regimen that uses less intensive drugs
      (treosulfan and fludarabine phosphate) with or without low dose radiation results in new
      blood-forming cells (engraftment) of the new donor cells without increased toxicities in
      patients with nonmalignant (noncancerous) diseases.
    

Eligibility criteria:

        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: PBSC is the preferred cell source (when feasible) for fully matched donors;
             PBSC may also be used for a mismatched donor following discussion with the PI; bone
             marrow is allowed when PBSC is not feasible or as determined by the PI

          -  DONOR: HLA-matched sibling bone marrow in combination with HLA-matched sibling
             umbilical cord blood if the HLA-matched sibling umbilical cord blood was collected and
             stored; the HLA-matched sibling bone marrow and cord blood would be matched for HLA-A,
             B, C, DRB1, and DQB1

          -  DONOR: Unrelated 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: Unrelated 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: Unrelated Umbilical Cord Blood: Selection of two umbilical cord blood (UCB)
             units is allowed to provide sufficient cell dose

          -  DONOR: Unrelated Umbilical Cord Blood: The UCB unit with the least HLA disparity (with
             the patient) will be selected first (i.e., selection priority is 6/6 match > 5/6
             match> 4/6 match); additional UCB units then may be selected to achieve the required
             cell dose; if a second unit is required, this unit will be the unit that most closely
             HLA matches the patient and meets minimum size criteria outlined below of at least 1.5
             x 10^7 TNC/kg (i.e. a smaller more closely matched unit will be selected over a larger
             less well matched unit as long as minimum criteria are met)

          -  DONOR: Unrelated Umbilical Cord Blood: Each UCB unit MUST contain at least 1.5 x 10^7
             TNC per kilogram recipient weight

          -  DONOR: Unrelated Umbilical Cord Blood: The total cell dose of the combined units must
             be at least 3.0 x 10^7 TNC per kilogram recipient weight

        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 > 2 x 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 positive 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) unless approved by the PI

          -  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

          -  DONOR: HLA-matched sibling cord blood exclusions: Any cord blood units that have not
             passed donor screening for infectious disease markers as recommended by the National
             Marrow Donor Project (NMDP) will not be used unless a waiver is signed by the clinical
             attending allowing use of cord blood unit; cord blood units are presumed to be
             cytomegalovirus (CMV) negative regardless of serologic testing due to passive
             transmission of maternal CMV antibodies

          -  DONOR: Unrelated Umbilical Cord Blood: Any cord blood units with < 1.5 x 10^7 total
             nucleated cells per kilogram recipient weight

          -  DONOR: Unrelated Umbilical Cord Blood: Any cord blood units that have not passed donor
             screening for infectious disease markers as recommended by NMDP will not be used
             unless a waiver is signed by the clinical attending allowing use of cord blood unit;
             cord blood units are presumed to be CMV negative regardless of serologic testing due
             to passive transmission of maternal CMV antibodies