A Study of the Effect of Blood Stem Cell Transplant After Chemotherapy Alone in Patients With Fanconi Anemia
Condition: Fanconi Anemia; Myelodysplastic Syndrome (MDS); Acute Myelogenous Leukemia (AML)
MeSH terms: Preleukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Fanconi Syndrome; Anemia; Myelodysplastic Syndromes; Fanconi Anemia
Intervention: Busulfan; Fludarabine; Cyclophosphamide; Anti-Thymocyte Globulin (Rabbit); The CliniMACS device; G-CSF
Intervention description: A standard dose of busulfan, associated with excellent outcomes in our previous trial will be used for young patients with marrow aplasia (arm A).
A higher dose of busulfan will be used in younger patients with MDS and AML (arm B) to maximize disease control.
A lower dose of busulfan will be used in older patients (arm C) to minimize toxicity.; Arms A, B and C - Fludarabine will be given IV over 30 minutes daily for 4 days. The dose will be adjusted according to renal function according to Institutional guidelines.; Arms A, B and C - Cytoxan will be given as a 1-2 hour infusion for 4 days. The dose will be adjusted according to patients ideal body weight for obese patients.; Arms A, B and C - 4 doses will be given prior to transplant to promote engraftment; The source of stem cells for all patients will be peripheral blood stem cells (PBSC) induced and mobilized by treatment of the donor with G-CSF for 4-6 days. T-cell depletion will be uniformly performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device); All patients will also receive G-CSF post-transplant to foster engraftment.
Intervention MeSH terms: Cyclophosphamide; Busulfan; Fludarabine; Antilymphocyte Serum; Thymoglobulin; Lenograstim
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: A three-arm phase II treatment protocol designed to examine engraftment, toxicity, graft-versus-host disease, and disease-free survival following a novel cytoreductive regimen including busulfan, cyclophosphamide and fludarabine and ATG
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 1 Month
Healthy volunteers: No
Keywords: Blood Stem Cell Transplant; busulfan; cyclophosphamide; fludarabine; 17-498

Summary:

      The goal of this study is to see if the study therapy can decrease the chemotherapy-related
      side effects while maximizing the effectiveness of disease control. The physicians will also
      be studying the effect of removing T-cells from the donor"s stem cells before transplant.
      T-cells are a type of white blood cell that may help cause a serious side effect of
      transplant called Graft versus Host Disease (GVHD). The way it removes the T-cells from the
      donor stem cells is actually by selecting only the stem cells (called CD34 cells) by using a
      device called CliniMACS. This process is called CD34 selection. The CliniMACS® device is
      currently under the supervision of the FDA .
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have a diagnosis of Fanconi anemia (confirmed by mitomycin C or
             diepoxybutane [DEB] chromosomal breakage testing at a CLIA approved laboratory).

        Patients must have one of the following hematologic diagnoses:

        1. Severe Aplastic Anemia (SAA), with bone marrow cellularity of <25% OR Severe Isolated
        Single lineage Cytopenia

        AND at least one of the following features:

          1. Platelet count <20 x 10^9/L or platelet transfusion dependence*

          2. ANC <1000 x 10^9/L

          3. Hgb <8 gm/dl or red cell transfusion dependence*

        2. Myelodysplastic Syndrome (MDS) (Appendix 1: MDS Classification)

        MDS at any stage, based on either one of the following classifications:

          -  WHO Classification

          -  Refractory anemia and transfusion dependence*

          -  Any of other stages

          -  IPSS Classification

          -  Low risk (score 0) and transfusion dependence*

          -  Any other risk groups Score > 0.5 Note that patients with chromosome 1q cytogenetic
             abnormalities in the absence of morphologic dysplasia will not be considered to have
             MDS.

             3. Acute Myelogenous Leukemia Patients with acute leukemia are included in this trial
             untreated, in remission or with refractory or relapsed disease.

             * Transfusion dependence will be defined as greater than ONE transfusion of platelets
             or red blood cells in the last year prior to evaluation on protocol.

        Donor

        Donor choices will be determined by the investigators according to institutional criteria.
        Patients who will be enrolled on this protocol must have one of the following donor
        choices:

        HLA-compatible unrelated volunteer donors Patients who do not have a related HLA-matched
        donor but have an unrelated donor who is either matched at all A, B, C and DRB1 (8/8) loci
        or who is mismatched at no more than 2/8 loci (A, B, C or DRB1) (6/8) as tested by DNA
        analysis (high resolution), will be eligible for entry on this protocol.

        HLA-mismatched Related donors Patients who do not have a related or unrelated
        HLA-compatible donor must have a healthy family member who is at least HLA-haplotype
        identical to the recipient. First degree related donors must have a normal DEB test.

        The donor must be healthy and willing and able to receive a 4-6 day course of G-CSF and
        undergo 1-3 daily leukaphereses, as per institutional guidelines.

        Related and unrelated donors must be medically evaluated and fulfill the criteria for
        collection of PBSCs as per institutional guidelines.

        Patients and donors may be of either gender or any ethnic background. Patients must have a
        Karnofsky adult, or Lansky pediatric performance scale status ≥ 70%.

        Patients must have adequate physical function measured by :

          1. Cardiac: asymptomatic or if symptomatic then 1) LVEF at rest must be ≥ 50% and must
             improve with exercise or 2) Shortening Fraction ≥ 29%

          2. Hepatic: < 5 x ULN alanine transaminase (ALT) and < 2.0 mg/dl total serum bilirubin.

          3. Renal: serum creatinine ≤1.5 mg/dl or if serum creatinine is outside the normal range,
             then CrCl > 50 ml/min/1.73 m^2

          4. Pulmonary: asymptomatic or if symptomatic, DLCO > 50% of predicted (corrected for
             hemoglobin) Each patient must be willing to participate as a research subject and must
             sign an informed consent form. Parent or legal guardians of patients who are minors
             will sign the informed consent form. Assents will be obtained as per institutional
             guidelines.

        Female patients and donors must not be pregnant or breastfeeding at the time of signing
        consent. Women must be willing to undergo a pregnancy test prior to transplant and avoid
        becoming pregnant while on study. Positive pregnancy test results will be reported to the
        parent(s) or guardian of minor participants, as required per institutional guidelines.

        Exclusion Criteria:

        Active CNS leukemia Female patients who are pregnant (positive serum or urine HCG) or
        breast-feeding. Women of childbearing age must avoid becoming pregnant while on study.

        Active uncontrolled viral, bacterial or fungal infection Patient seropositive for HIV-I/II;
        HTLV -I/II