Thalassemia Clinical Trial
Official title:
Protocol for Related Donor Hematopoietic Stem Cell Transplantation (HSCT) for Treatment of Symptomatic Genetic Lymphohematological Diseases
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).
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.
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Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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