Sickle Cell Disease Clinical Trial
Official title:
Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation for Children With Non-Malignant Diseases Who Have Been Multiply Transfused: a Pilot Study
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.
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.
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