Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation

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 forreducing 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, we 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.