Related Hematopoietic Stem Cell Transplantation (HSCT) for Genetic Diseases of Blood Cells

Brief Title

Related Hematopoietic Stem Cell Transplantation (HSCT) for Genetic Diseases of Blood Cells

Official Title

Protocol for Related Donor Hematopoietic Stem Cell Transplantation (HSCT) for Treatment of Symptomatic Genetic Lymphohematological Diseases

Brief 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).

Detailed Description

      The present study is to evaluate de-escalation of the cyclophosphamide (CY) dose in an
      innovative conditioning regimen with fludarabine and alemtuzumab as additional agents to
      achieve immunoablation, in combination with Busulfan (BU) to achieve myeloablation.
      Replacement of at least part of the cyclophosphamide dose by fludarabine in the conditioning
      regimen would be expected to maintain immunosuppression (and, therefore, engraftment) while
      reducing transplant-related complications (mucositis, hepatotoxicity, cardiotoxicity,
      pulmonary toxicity, hemorrhagic cystitis, mucositis, and possibly GVHD), thereby improving
      disease-free survival rates. Similarly, the potential benefits of alemtuzumab in the proposed
      conditioning regimen are increased rates of hematopoietic engraftment with less toxicity than
      that observed with cyclophosphamide, ultimately resulting in improved immune function and
      enhanced quality of life (12,13). A fludarabine/alemtuzumab-based, less intensive
      conditioning regimen with adequate immunosuppressive activity could conceivably allow more
      successful engraftment of stem cells from related donors in patients with genetic
      lymphohematological diseases, as well as lower rates of transplant-related mortality.

      Regimen-related toxicity is also believed to be a major contributing factor to GVHD (14).
      Therefore, conditioning regimens that cause less tissue injury may also lead to reduced GVHD.
      In the present study, the use of alemtuzumab in the conditioning regimen may be an added
      benefit, as this antibody causes T-cell depletion, thus, the risk of GVHD may also be reduced
      (15). The overall goal of the study is to improve the therapeutic index of HSCT by decreasing
      and, if possible, eliminating cyclophosphamide as a component of the pre-transplant
      conditioning for patients with genetic diseases of lymphohematopoiesis. The investigation
      will explore the risks and benefits of the proposed novel-conditioning regimen using a
      decreased dose of cyclophosphamide and additional immunosuppression with fludarabine and
      alemtuzumab to prevent graft rejection and recurrence of disease. The investigators will
      evaluate this regimen's impact on conditioning-related morbidity and mortality, and measure
      the success of the transplant procedure by engraftment and disease-free survival. If this
      regimen is able to successfully permit engraftment and reduce regimen-related toxicity, the
      next phase of treatment will test a further dose de-escalation for cyclophosphamide. It is
      anticipated that there will be four dose levels of cyclophosphamide in the overall study: 1)
      105 mg/kg; 2) 70 mg/kg; 3) 35 mg/kg; and then finally, 4) 0 mg/kg. This study design was
      chosen to minimize study risks possibly associated with substitution of fludarabine and
      alemtuzumab for CY as immunoablation. The present protocol represents Level 1 in the study
      design; an amended protocol will be prepared prior to further de-escalation of the
      cyclophosphamide dose.

Study Phase

Phase 2

Study Type


Primary Outcome

Number of Participants With Neutrophil Engraftment (=/>500 Cells/uL) and Platelet Engraftment (>20K Cell/uL) at 30 Days

Secondary Outcome

 Number of Participants Who Developed Graft-Versus-Host-Disease (GVHD) as Determined by the Glucksberg Scale


Stem Cell Transplantation


Cyclophosphamide Dose Level 1

Study Arms / Comparison Groups

 Cyclophosphamide Dose Level 1
Description:  Cyclophosphamide given by Intravenous (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.
Drug to be given in combination of Busulfan, Campath and Fludarabine


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

February 2007

Completion Date

February 2014

Primary Completion Date

September 2013

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.




3 Months - N/A

Accepts Healthy Volunteers



Neena Kapoor, M.D., , 

Administrative Informations



Organization ID


Responsible Party

Principal Investigator

Study Sponsor

Children's Hospital Los Angeles


 Lucile Packard Children's Hospital

Study Sponsor

Neena Kapoor, M.D., Principal Investigator, Children's Hospital Los Angeles

Verification Date

January 2017