Related Hematopoietic Stem Cell Transplantation (HSCT) for Genetic Diseases of Blood Cells
Condition: Stem Cell Transplantation; Bone Marrow Transplantation; Peripheral Blood Stem Cell Transplantation; Allogeneic Transplantation; Genetic Diseases; Thalassemia; Pediatrics; Diamond-Blackfan Anemia; Combined Immune Deficiency; Wiskott-Aldrich Syndrome; Chronic Granulomatous Disease; X-linked Lymphoproliferative Disease; Metabolic Diseases
MeSH terms: Thalassemia; Granulomatous Disease, Chronic; Lymphoproliferative Disorders; Anemia, Diamond-Blackfan; Wiskott-Aldrich Syndrome; Genetic Diseases, Inborn; Metabolic Diseases; Immunologic Deficiency Syndromes
Intervention: Cyclophosphamide Dose Level 1; Cyclophosphamide Dose Level 2; Cyclophosphamide Dose Level 3; Cyclophosphamide Dose Level 4
Intervention description: given by IV at a total dose of 105 mg/kg, to be divided into three doses of one 35 mg/kg dose per day, for 3 days on the first level. After ten patients the de-escalation will begin if the stopping rule is not met.; Level 2 will be 70mg/kg in 2 divided given once a day for 2 days;; Level 3 will be 35mg/kg as a one-time dose.; Level 4 will be no cytoxan.
Intervention MeSH terms: Cyclophosphamide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 3 Months
Healthy volunteers: No
Keywords: Hematopoietic Stem Cell Transplantation Pediatrics,; stem cell transplantation; bone marrow transplantation; Peripheral Blood Stem Cell Transplantation; Allogeneic Transplantation; pediatrics; Combined Immune Deficiency; Chronic Granulomatous disease

Summary:

      Many genetic diseases of lymphohematopoietic cells (such as sickle cell anemia, thalassemia,
      Diamond-Blackfan anemia, Combined Immune Deficiency (CID), Wiskott-Aldrich syndrome, chronic
      granulomatous disease, X-linked lymphoproliferative disease, and metabolic diseases affecting
      hematopoiesis) are sublethal diseases caused by mutations that adversely affect the
      development or function of different types of blood cells. Although pathophysiologically
      diverse, these genetic diseases share a similar clinical course of significant progressive
      morbidity, overall poor quality of life, and ultimate death from complications of the disease
      or its palliative treatment. Supportive care for these diseases includes chronic transfusion,
      iron chelation, and surgery (splenectomy or cholecystectomy) for the hemoglobinopathies;
      prophylactic antibiotics, intravenous immunoglobulin, and immunomodulator therapies for the
      immune deficiencies; and enzyme replacement injections and dietary restriction for some of
      the metabolic diseases. The suboptimal results of such supportive care measures have led to
      efforts to implement more aggressive therapeutic interventions to cure these
      lymphohematopoietic diseases. The most logical strategies for cure of these diseases have
      been either replacement of the patient's own hematopoietic stem cells (HSC) with those
      derived from a normal donor allogeneic bone marrow transplant (BMT) or hematopoietic stem
      cell transplant (HSCT), or to genetically modify the patient's own stem cells to replace the
      defective gene (gene therapy).
    

Eligibility criteria:

        Inclusion Criteria:

          -  All patients with lethal or sublethal genetic lymphohematological disease (such as
             Hemaphagocytic lymphohistiocytosis (HLH) / Familial Erythrophagocytic
             Lymphohistiocytosis (FEL), Hurler's Syndrome, Hunter's Syndrome, Kostmann's Syndrome,
             Blackfan-Diamond Anemia, Chronic granulomatous Disease (CGD), Red Cell Aplasia, CID,
             Sickle Cell Anemia, Thalassemia, Adreno-leukodystrophy, metachromatic leukodystrophy,
             Wiskott-Aldrich Syndrome, X-Linked Lymphoproliferative Disease (XLD), Metabolic
             diseases affecting hematopoiesis, but not limited to), who are candidates for
             allogeneic transplantation for their disease and have a histocompatible sibling or
             related donor, ages 0 to 21 years, will be candidates for this study protocol. The
             suitable related donor is a 10/10 or 9/10 allele Human Leukocyte Antigen (HLA) match
             with the patient. All patients who have previously had serious life- threatening
             events due to disease process may be included in the study. Patients must have
             adequate physical function and vital organ function to tolerate transplant procedure,
             as measured by:

          -  Cardiac: Shortening fraction >26% or left ventricular ejection fraction at rest must
             be > 40%.

          -  Hepatic: Bilirubin, Alanine Aminotransferase (ALT) and Aspartate Aminotransferase
             (AST) < 3x upper limit of normal (as per local laboratory) for age (with the exception
             of isolated hyperbilirubinemia due to Gilbert's syndrome).

          -  Renal: Serum creatinine < 2x upper limit of normal for age or if serum creatinine
             elevated beyond normal range patient must have creatinine Clearance or Glomerular
             filtration rate (GFR) >50% lower limit of normal for age.

          -  Pulmonary: Forced expiratory volume (FEV)1, Forced Vital Capacity (FVC), and Diffusing
             Lung Capacity for Carbon Monoxide (DLCO) (corrected for Hgb) > 50% predicted. For
             patients where pulse oximetry is performed, O2 saturation > 92%

          -  Evaluation of iron status in patients who have received more than 12 red cell
             transfusions. Measurements of serum ferritin levels and MRI of the liver and heart
             tissue will evaluate the iron stores. If high iron load is identified in these organs
             further evaluation will be done to determine the suitability as transplant recipient.
             Should these studies indicate that chelation is necessary the following should apply:
             That the treating hematologist will provide the specific chelation type and timing.
             Evaluation of organ iron load will be part of the HSCT work-up and if high iron load
             is identified then the BMT team will work with the hematologist attending in
             developing a plan for the patient.

        Exclusion Criteria:

          -  Karnofsky performance status < 70%, or Lansky < 40% for patients < 16 years old.

          -  Uncontrolled bacterial, viral, or fungal infections (currently taking medication yet
             clinical symptoms progress).

          -  Seropositivity for the human immunodeficiency virus (HIV).

          -  Acute active hepatitis.

          -  Diagnosis of end-organ dysfunction that precludes the ability to tolerate the
             transplant procedure.

          -  Patients with a diagnosis of Fanconi Anemia are excluded.