CHORI Staff Directory
CHORI Intranet

 
The Search Is On
Hydroxyurea and Red Blood Cells in Thalassemia

"Children's has been a major center for sickle cell disease and thalassemia for over 25 years, caring for patients and pro-viding prenatal diagnosis and preven-tative methods as well as a lot of basic, clinical and translational research."

In a new study published in the December issue of the American Journal of Hematology, CHORI scientists Sylvia T. Singer, MD, Frans A. Kuypers, PhD and Elliot Vichinksy, MD and their colleagues in the Center for Sickle Cell Disease and Thalassemia report on the effects of hydroxyurea treatment on red blood cell (RBC) “well being” in non-transfusion dependant thalassemia patients.

“Hydroxyurea, or at least the way we’ve been using hydroxyurea, does not seem to result in clinically significant enough outcomes or cellular changes in RBC,” says Dr. Singer, whose study was the first to assess the affects of hydroxyurea treatment in this population on a cellular rather than clinical level in attempts to better explain hydroxyurea's somewhat disappointing clinical results. The studies were performed in Dr. Kuypers Red Cell Laboratory at CHORI.

Thalassemia is a genetic disease that affects the hemoglobin in the red blood cells. The different mutations result in a variable effect on the stability of the RBC and diverse levels of clinical severity. The most severely effected are those individuals with mutations which result in absence of betaglobin chains who will be dependent upon blood transfusions for survival the entirety of their lives.

"It used to be considered a life-threatening disease, but with current medical advances, there is now enough knowledge on how to treat the disease, how often to transfuse, and how best to chelate the exccesive iron that accumulates and treat complications. The overall quality of life and life expectancy has improved dramatically," says Dr. Singer. "It's now a manageable chronic illness."

This shift from a life threatening disease to a manageable chronic illness is due in no small part to the research that CHORI's Center for Sickle Cell Disease and Thalassmia has pioneered in the last two decades or more.

In the latest American Journal of Hematology publication, Dr. Singer and her colleagues tackled the affects hydroxyurea treatment at the cellular level.

"Hydroxyurea is actually a type of chemotherapy drug that works on the DNA of the cell. In a very low dose, however, it's been found to increase the synthesis of fetal hemoglobin (HbF), which is a good hemoglobin," Dr. Singer explains.
"It creates more balance within the globin chains in the RBC of subjects affected with beta thalassemia and ameliorates some of the problems associated with thalassemia, such as reducing anemia and RBC break-down, or hemolysis."
In spite of how hydroxyurea theoretically appears to function, however, previous clinical studies of hydroxyurea treatment in thalassemia patients had had somewhat disappointing results, showing much less clinical benefit than researchers had hoped. Drs. Singer, Kuypers, Vichinsky and their colleagues wanted to push the boundaries even further, by assessing what actually happens to the RBC when HbF is increased in patients with thalassemia.

"We wanted to see how clinical results correlated with changes in the red blood cell by measuring the size and volume of the cell, as well as its flexibility, as red blood cells in thalassemia are very stiff and rigid," explains Dr. Singer.

In fact, the study confirmed the lackluster clinical results of using hydroxyurea.

"We found only some cellular advantage that corresponded with clinical outcomes, mostly in patients who had their spleen removed. There wasn't a dramatic differentiation between red cell abnormalities before and during the experimental treatment." Dr. Singer says.
Nevertheless, the study provides critical clues in the search for better thalassemia treatment. First, it confirms that hydroxyurea is not likely to emerge as a treatment drug of choice in patients with a more severe type of thalassemia. Still, the study also suggests that while hydroxyurea isn't the best agent, increasing HbF is still an optimal approach, as some improvement in the red blood cell abnormalities was observed. In addition, the red cell changes while patients are taking an experimental drug can help in future testing of effectiveness of new drugs in clinical trials.

"It does show that we are trending in the right direction," says Dr. Singer.

"Although no one has found that magic pill yet, trying to increase HbF with different types of medications absolutely is a trend in the right direction."

Back

© 2005 Children's Hospital Oakland Research Institute
5700 Martin Luther King Jr Way • Oakland, California 94609
Phone 510-450-7600 • Fax 510-450-7910
Site MapDisclaimerCHORI Intranet