Optimizing Haploidentical Aplastic Anemia Transplantation (BMT CTN 1502)
Condition: Severe Aplastic Anemia
MeSH terms: Anemia; Anemia, Aplastic
Intervention: Antithymocyte Globulin (ATG); Fludarabine; Cyclophosphamide; Total Body Irradiation (TBI); Haplo HSCT; Tacrolimus; Mycophenolate mofetil (MMF); G-CSF
Intervention description: Administration of ATG will be 0.5 mg/kg IV on Day -9 over 6 hours and 2 mg/kg IV on Days -8 and -7 over 4 hours.; Fludarabine dose will be 30 mg/m^2 IV daily for 5 days from Day -6 to Day -2.; Cyclophosphamide dose will be 14.5 mg/kg IV daily for 2 days (Day -6 to Day -5) prior to transplantation and 50 mg/kg IV daily for 2 days (Day +3 to Day +4) after transplantation.; TBI is to be delivered in a single dose of 200 cGy on Day -1.; Eligible patients without a fully matched related or unrelated donor available will undergo haploidentical bone marrow transplant.; Tacrolimus should be started on Day +5 and administered to maintain a level of 10-15 ng/mL.; MMF dose will be 15 mg/kg PO three times a day (TID) up to 1 gm TID (or IV equivalent) starting on Day +5.; G-CSF will be given IV or SQ starting on Day +5 at 5 mcg/kg/day until ANC is > 1500 for 3 days.
Intervention MeSH terms: Mycophenolic Acid; Cyclophosphamide; Fludarabine; Tacrolimus; Thymoglobulin; Antilymphocyte Serum
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Haploidentical Bone Marrow; Hematopoietic Stem Cell Transplant (HSCT); Severe Aplastic Anemia (SAA); Antithymocyte Globulin (ATG)

Summary:

      This study is a prospective, multicenter phase II study with patients receiving
      haploidentical transplantation for Severe Aplastic Anemia (SAA). The primary objective is to
      assess overall survival (OS) at 1 year post-hematopoietic stem cell transplantation (HSCT).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patient is < 75 years of age at time of enrollment.

          2. Confirmed diagnosis of SAA, either from initial diagnosis or follow-up assessments,
             defined as:

               1. Bone marrow cellularity < 25% or marrow cellularity < 50% but with < 30% residual
                  hematopoietic cells.

               2. Two out of three of the following (in peripheral blood): Neutrophils < 0.5
                  x10^9/L, Platelets < 20 x10^9/L, or Reticulocyte count < 20 x10^9/L (<60 x 10^9/L
                  using an automated analysis)

          3. No suitable fully matched related sibling donor (6/6 match for human leukocyte antigen
             (HLA)-A and B at intermediate or high resolution and DRB1 at high resolution using
             DNA-based typing) available.

          4. Failed at least one trial of immunosuppressive therapy (IST) by being refractory or
             having relapsed. IST could have included ATG based regimens, calcineurin inhibitors
             and/or other higher dose therapy directed at the treatment of primary SAA.

          5. Available relative of the patient who is a haploidentical match, including biological
             parents, siblings or half siblings, children, uncles/aunts, first cousins, etc.
             Eligible haploidentical donors will have 2-4 mismatches if HLA-A, -B, -C, and -DRB1
             typing is used; 2-5 mismatches if HLA-A, -B, -C, -DRB1, and -DQB1 typing is used; and
             2-6 mismatches if HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 typing is used. A
             unidirectional mismatch in either the graft versus host or host versus graft direction
             is considered a mismatch. The donor and recipient must demonstrate that they are a
             full haplotype match by being identical at a minimum of one allele (at high resolution
             DNA-based typing) at the following genetic loci: HLA-A, -B, -C, and DRB1 if 8 allele
             typing is used; HLA-A, -B, -C, -DRB1, and -DQB1 if 10 allele typing is used; and
             HLA-A, -B, -C, -DRB1-, DQB1, and -DPB1 is 12 allele typing is used by the local
             center. See Section 2.4 for additional information.

          6. Patient and/or legal guardian must sign informed consent for HSCT.

          7. The haplo donor and/or legal guardian must be able to sign informed consent documents.

          8. The potential haplo donor must be willing and able to donate bone marrow.

          9. The weight of the haplo donor must be ≥ 20 kg.

         10. Adequate organ function defined as:

               1. Cardiac: Left ventricular ejection fraction (LVEF) at rest ≥ 40%. For patients
                  aged < 13 years, shortening fraction (SF) ≥ 26% by echocardiogram or Multi Gated
                  Acquisition Scan (MUGA) may be substituted for LVEF.

               2. Hepatic: Total bilirubin < 3.0 x the upper limit of normal (ULN) for age
                  (patients who have been diagnosed with Gilbert's Disease are allowed to exceed
                  this limit) and alanine aminotransferase (ALT) and aspartate aminotransferase
                  (AST) < 5.0 x ULN for age.

               3. Renal: For patients > 13.0 years of age at the time of enrollment: estimated
                  creatinine clearance > 50 mL/minute (using the Cockcroft-Gault formula and actual
                  body weight). For patients < 13.0 years of age at enrollment: Glomerular
                  Filtration Rate (GFR) estimated by the updated Schwartz formula ≥ 90 mL/min/1.73
                  m2. If the estimated GFR is < 90 mL/min/1.73 m^2, then renal function must be
                  measured by 24-hour creatinine clearance or nuclear GFR, and must be > 50
                  mL/min/1.73 m^2.

               4. Pulmonary: For patients > 13.0 years of age: Diffusing capacity of the lung for
                  carbon monoxide (DLCO) (corrected/adjusted for hemoglobin) > 40% and forced
                  expiratory volume in one second (FEV1) > 50% predicted (without administration of
                  bronchodilator) and forced vital capacity (FVC) > 50% predicted. For patients <
                  13.0 years of age unable to perform pulmonary function tests (PFT) due to age or
                  developmental ability: (1) no evidence of dyspnea at rest and (2) no need for
                  supplemental oxygen and (3) O2 saturation > 92% on room air at sea level (with
                  lower levels allowed at higher elevations per established center standard of care
                  (e.g., Utah, 4,200 feet above sea level, does not give supplemental oxygen unless
                  below 90%)).

         11. Karnofsky or Lansky performance status ≥ 60%.

         12. Females and males of childbearing potential must agree to practice 2 effective methods
             of contraception at the same time or agree to abstinence.

        Exclusion Criteria:

          1. Inherited bone marrow failure syndromes such as Fanconi anemia must be ruled out
             according to center standard.

          2. Clonal cytogenetic abnormalities consistent with pre-myelodysplastic syndrome
             (pre-MDS) or MDS on marrow examination (e.g. Monosomy 7).

          3. Presence of anti-donor HLA antibodies (positive anti-donor HLA antibody is defined as
             a positive cross-match test of any titer by complement-dependent cytotoxicity or flow
             cytometric testing or the presence of anti-donor HLA antibody to the high expression
             loci HLA-A, B, C, DRB1, or DPB1 with mean fluorescence intensity (MFI) > 1000 by solid
             phase immunoassay).

          4. Prior allogeneic stem cell transplant.

          5. Prior solid organ transplant.

          6. Known life-threatening reaction (i.e., anaphylaxis) to Thymoglobulin® that would
             prohibit use for the patient as this study requires use of the Thymoglobulin®
             preparation of ATG.

          7. Uncontrolled bacterial, viral, or fungal infection at the time of enrollment.
             Uncontrolled is defined as currently taking medication and with progression or no
             clinical improvement on adequate medical treatment.

          8. Seropositive for the human immunodeficiency virus (HIV).

          9. Active Hepatitis B or C determined by a detectable viral load of HBV or HCV.

         10. Female patients who are pregnant (per institutional practice) or breast-feeding.

         11. Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma
             in situ. Cancer treated with curative intent > 5 years previously will be allowed.
             Cancer treated with curative intent ≤ 5 years previously will not be allowed unless
             approved by the Protocol Chairs and/or Protocol Officer.

         12. Alemtuzumab or ATG within 2 weeks of enrollment.