Conditions: Thalassemia Sickle Cell Disease Glanzmann Thrombasthenia Wiskott-Aldrich Syndrome Chronic-granulomatous Disease Severe Congenital Neutropenia Leukocyte Adhesion Deficiency Schwachman-Diamond Syndrome Diamond-Blackfan Anemia Fanconi Anemia Dyskeratosis-congenita Chediak-Higashi Syndrome Severe Aplastic Anemia
Keywords: bone marrow transplant sickle cell disease thalassemia Glanzmann thrombasthenia Wiskott-Aldrich syndrome chronic-granulomatous disease severe congenital neutropenia leukocyte adhesion deficiency Schwachman-Diamond syndrome Diamond-Blackfan anemia Fanconi anemia dyskeratosis-congenita Chediak-Higashi syndrome severe aplastic anemia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
Allogeneic blood and marrow transplantation remains the only viable cure for children who suffer from many serious non-malignant hematological diseases. Transplantation, however, carries a high risk of fatal complications. Much of the risk stems from the use of high dose radiation and chemotherapy for conditioning, the treatment administered just prior to transplant that eliminates the patients' marrow and immune system, effectively preventing rejection of the donors' cells. Attempts to make blood and marrow transplantation safer for children with non-malignant diseases by using lower doses of radiation and chemotherapy have largely failed because of a high rate of graft rejection.

In many such cases, it is likely that the graft is rejected because the recipient is sensitized to proteins on donor cells, including bone marrow cells, by blood transfusions. The formation of memory immune cells is a hallmark of sensitization, and these memory cells are relatively insensitive to chemotherapy and radiation. Alefacept, a drug used to treat psoriasis, on the other hand, selectively depletes these cells. The investigators are conducting a pilot study to begin to determine whether incorporating alefacept into a low dose conditioning regimen can effectively mitigate sensitization and, thereby, prevent rejection of allogeneic blood and marrow transplants for multiply transfused children with non-malignant hematological diseases.

Detailed description:
There are a large number of serious non-malignant diseases of childhood, most of them congenital and rare, which can be corrected by HSCT. These diseases are all characterized by deficiencies, either in number or in function, of marrow derived cells. These diseases usually affect immune or blood cells and frequently involve transfusion therapy with erythrocytes, platelets or granulocytes. Examples of such diseases include sickle cell disease, thalassemia major, Glanzmann thrombasthenia, Wiskott-Aldrich syndrome, chronic-granulomatous disease, severe congenital neutropenia, leukocyte adhesion deficiency, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, Fanconi anemia, dyskeratosis-congenita, Chediak-Higashi syndrome, and severe aplastic anemia.

Allogeneic blood HSCT, whether performed for a malignant or a non-malignant condition, relies on the use of a pre-transplant conditioning regimen. Traditionally, very high doses of chemotherapy or total body irradiation have been utilized as conditioning. The use of intensive conditioning, which, practically speaking eliminates the host marrow and immune system, however, can produce serious and sometimes fatal infections and injuries to vital organs, such as the liver and lung. In children, the use of intensive conditioning can also produce serious late effects, including hypogonadism, stunted growth, impaired cognitive development and secondary malignancies.

Over the past decade, there has been a move to minimize the risk for such complications by reducing the intensity of conditioning regimens. Added impetus for reducing conditioning intensity arose from the observation in transplantation for thalassemia and sickle cell disease that sustained mixed chimerism, that is partial donor engraftment, is usually sufficient to cure non-malignant diseases. This observation suggested that sustained engraftment could be achieved without "ablation" or elimination of the host marrow. Pre-clinical studies demonstrated in small and large animals that sustained mixed chimerism can be achieved with preparative regimens consisting of TBI doses as low as 100-300 cGy (by comparison, standard intensity regimens typically employ 1000 cGy or more in combination with chemotherapy).

This approach was first translated in a clinical trial involving 45 adults with hematological malignancies who were not candidates for standard conditioning because of older age or serious co-morbidities. Using a single 200 cGy dose of TBI, sustained engraftment was achieved in 80% of cases and, remarkably, transplant related mortality was only 6.7% in this frail group of patients at 14 months. It is also notable that these transplants were performed primarily in the outpatient setting-the median length of hospitalization was 1 day. Low-dose TBI based conditioning has also been safely and effectively utilized for infants and children with severe combine immune deficiency and other severe immune deficiencies, undergoing related and unrelated donor transplantation. This clinical experience strongly suggests that if an effective low-dose TBI conditioning regimen can be developed for children with non-malignant diseases it could transform BMT from a costly, highly morbid, and sometimes life-taking procedure to a relatively inexpensive, safe and well-tolerated one.

Thousands and thousands of children around the world suffer from sickle cell disease and thalassemia major. There is a myriad of other less common serious non-malignant hematological diseases, which have even more devastating effects, for which HSCT remains the only viable cure. Low-dose TBI based conditioning represents a minimally toxic approach to transplantation for these children-a way to overcome alloimmunization, however, is needed to make this approach more effective. Alefacept, the only currently FDA approved agent that specifically targets memory T cells, the investigators believe, holds the key to making low-dose TBI based conditioning more effective and could, thereby, dramatically alter the field of transplantation for non-malignant diseases. sustained donor engraftment needs to be developed.

Arms:
arm 1: Pediatric subjects with non-malignant diseases (NMD) will receive pre-conditioning with alefacept 0.5 mg/kg/dose i.v. with the first dose split on days -40 and -39 and the remaining doses given on days -33, -26, -19, and -12 (e.g. weekly for 5 doses).

Interventions: intervention 1: Alefacept
Intervention descriptions: intervention 1: 0.25 mg/kg IV on day -40 and day -39 0.5 mg/kg IV on days -33, -26, -19 and -12 Alefacept was diluted in sterile water (2 ml total volume) and administered via i.v. push followed by a normal saline flush per package insert.

Protocol document: