Reduced Intensity Conditioning (RIC) Regimen for Patients With Non-malignant Disorders

The purpose of this study is to see if we can engraft (grow) donor cells and cure the underlying disease by using Reduced Intensity Conditioning (RIC) before receiving the donor blood or marrow cells. RIC involves giving medicines that suppress the immune system before giving the donor stem cells. It does not completely eliminate blood making cells in bone marrow. This is in contrast to standard myeloablative conditioning that would completely "wipe out" bone marrow with high doses of chemotherapy and radiation. The possible benefits of a reduced intensity conditioning regimen are fewer short-term toxicities of lungs, liver and heart, and less long-term side effects. The hospital stay is usually shorter than after conditioning that completely destroys the bone marrow, and blood counts may recover more quickly. In general, the benefits of undertaking this transplant include possible cure of primary disease.

Allogeneic hematopoietic stem cell transplant (HSCT) is curative for many non-malignant diseases, including immunodeficiencies and hemoglobinopathies. Standard myeloablative therapy to establish complete donor chimerism usually includes busulfan, cyclophosphamide +/- thymoglobulin. This approach may result in full donor engraftment with complete immune reconstitution. However, this approach has been associated with a poor outcome in patients with significant organ dysfunction, and is associated with significant organ morbidities including veno-occlusive disease. Late complications include gonadal failure and secondary malignancies.

Recently, reduced intensity conditioning (RIC) regimens have been used for both adult patients with leukemias and pediatric patients with non-malignant diseases. These regimens are better tolerated, resulting in less transplant related morbidity and mortality. Stable mixed chimerism, while insufficient for eradication of leukemias, may be sufficient to cure patients with non-malignant diseases.

There are two conditioning regimens in this protocol for children >6 months. They differ by the timing and dosing of Alemtuzumab (Campath). The "distal" Campath regimen proposed is identical to the regimen proposed by the Clinical Trials Network for patients with sickle cell disease with unrelated donors and has been used successfully in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX). The "proximal" Campath regimen protocol is used extensively in the UK for immune deficiencies, and is currently in use internationally for hemophagocytic lymphohistiocytosis (HLH) and Langerhans cell histiocytosis (LCH). Autologous reconstitution (graft loss) may be increased with RIC, but life-threatening aplasia from graft failure is rare.

The conditioning regimen for children with immunodeficiencies <6 months omits melphalan, and substitutes two days of busulfan. This regimen is successfully used in the United Kingdom (UK), and has been successful in a 3 month old infant at the Children's Hospital of Philadelphia (CHOP) who engrafted with a haploidentical donor.

• Non Malignant Diseases
• Immunodeficiencies
• Hemoglobinopathies

Inclusion Criteria:

1. Age >6 months- 25 years
2. IPEX syndrome
3. Sickle cell disease
4. Thalassemia major
5. Bone marrow failure, including Kostmann's, amegakaryocytic thrombocytopenia, Blackfan-Diamond syndrome
6. Hemophagocytic lymphohistiocytosis other macrophage activation syndromes, severe Langerhans histiocytosis
7. Severe combined immune deficiency, adenosine deaminase deficiency, common variable immunodeficiency
8. Wiskott-Aldrich syndrome
9. Age <6 months with immunodeficiencies: Eligible for "mini" busulfan, fludarabine, alemtuzumab

10. Organ criteria:

    • Cardiac: Echocardiogram shortening fraction >27%
    • Pulmonary: for those with pulmonary function tests: DLCO >40%
    • Renal: Serum creatinine <1.5 x upper limit of normal for age
    • Hepatic:; ALT and AST <5 x upper limit of normal
11. Infection: No active infections

Exclusion criteria

1. Uncontrolled bacterial, fungal or viral infections
2. Bare lymphocyte syndrome (MHC class II deficiency)