Partially Matched Stem Cell Transplantation for Patients With Refractory Severe Aplastic Anemia or Refractory Cytopenias

Hematopoietic Stem Cell Transplantation (HSCT) From Partially Matched Family Donors for Patients With Refractory Severe Aplastic Anemia or Refractory Cytopenias: A Pilot Study

Due to an overall and disease free survival of 85% to 100%, allogeneic blood or bone marrow stem cell transplantation using an HLA matched sibling donor is the therapy of choice for patients with severe aplastic anemia (SAA). Unfortunately, only about 25% of patients have such a donor. For patients with SAA lacking a matched sibling donor, immunosuppressive therapy is the current treatment of choice. Approximately 70% of these patients have a complete or partial response to immunosuppressive therapy, achieving transfusion independence and/or growth factor independence.

For the approximately 30% of patients who do not respond to immunosuppressive therapy or experience recurrence, alternative donor (matched unrelated, partially matched family member) transplantation is a treatment option. However, graft rejection and graft-versus-host-disease (GVHD) are significant barriers to success, decreasing event-free survival to 30% to 50%.

This study offers stem cell transplantation using a partially matched family member (haploidentical) donor to those patients with no available HLA-matched sibling or matched unrelated donor. In an attempt to reduce GVHD and regimen-related toxicity while maintaining adequate engraftment, we plan to infuse a highly purified stem cell graft. The Miltenyi Biotec CliniMACS CD3 depletion system will be used to derive a defined allogeneic graft highly enriched for CD34+ hematopoietic cells and depleted of CD3+ T-lymphocytes from G-CSF mobilized, donor-derived peripheral blood stem cells.

Patients 21 years of age and younger with refractory cytopenias are also eligible for this protocol as there are no other potentially curative therapies currently available for these conditions.

The primary objective of this study is to evaluate the safety of transplantation using a haploidentical donor product engineered to targeted cell counts using the investigational CliniMACS device for patients with refractory severe aplastic anemia (SAA) or refractory cytopenias. The treatment plan would be considered unsafe if we can find this type of procedure is associated with a significantly higher treatment failure rate. Treatment failure is defined as any occurrence of the following events, overall grade III-IV acute GVHD, graft failure or death due to any cause within 100 days after transplant.

Secondary objectives for this protocol include the following:

• To observe the degree of hematopoietic chimerism in T-cells during the first year posttransplant.
• To observe the relative proportions of donor/host T-regulatory cells during the first year posttransplant.
• To monitor rates of acute and chronic GVHD during the first year posttransplant.

Inclusion Criteria:

• One of the following diagnoses:
• Refractory severe aplastic anemia
• Refractory Kostmann syndrome
• Refractory Diamond-Blackfan anemia
• Refractory amegakaryocytic thrombocytopenia
• Absence of a suitable HLA-matched sibling donor and absence of a 10/10 allele matched unrelated donor.
• Life expectancy of greater than six weeks as per the judgment of the principal investigator.
• Karnofsky or Lansky Performance Status score of greater than or equal to 70%.
• Creatinine clearance is greater than or equal to 40 cc/min/1.73 m2.
• FVC greater than or equal to 40% of predicted or pulse oximetry greater than or equal to 92% on room air.
• Does not have a known allergy to murine products.

Exclusion criteria:

• Ejection fraction or shortening fraction below the lower limit of normal for age.
• Lactating (female patient).
• Pregnant or lactating
• Diagnosis of Fanconi Anemia.
• Positive HLA crossmatch with donor