Sickle-Cell Disease

Description

Treatment

Research is ongoing toward identifying the biologic and chemical activities that promote or protect against the sickle-cell process. Currently, experimental treatments focus on the basic processes that cause the red blood cells to sickle in the first place. There are three basic modes of treatment:

• Stimulation of production of healthy fetal hemoglobin in order to inhibit the sickling process.
• Blocking dehydration in the cells.
• Transplantation of bone marrow or stem cells from healthy donors so that normal hemoglobin is produced rather than hemoglobin S.

Drugs that Stimulate Fetal Hemoglobin

Hemoglobin F (HbF, also called fetal hemoglobin) is the form of hemoglobin that exists in the fetus and small infants. Most HbF is later replaced by the hemoglobin that is present in the growing child and adult, although some HbF may persist. Fetal hemoglobin is able to block the sickling action of red blood cells so that infants with sickle-cell disease do not develop symptoms of the illness while they still have hemoglobin F. Adults who have sickle-cell disease but still retain high levels of hemoglobin F generally have mild disease.

Studies are now reporting that the severity of sickle-cell disease can be reduced by using drugs that stimulate production of HbF. Even increases as modest as 4% may have a significant benefits for these patients.

Hydroxyurea. Hydroxyurea (Droxia, Hydrea) destroys cells in the bone marrow, which results in an increase in special cells that can produce HbF. It is currently the only agent in general use to prevent acute sickle-cell crises. It appears to have a number of effects on sickle cell:

• Hydroxyurea reduces the intensity and frequency of sickle-cell crises by nearly 50%. (It does not have any effect on pain, however, once it starts.)
• Over time, the drug may improve spleen function, which aids in the immune process, particularly in children.
• Hydroxyurea increases water content in red blood cells.
• The drug reduces the number of neutrophils, the white blood cells that contribute to the process causing sickle cells to stick to the blood vessel walls. This effect may actually be more protective over time than its effect on increasing levels of hemoglobin F.

Hydroxyurea is now indicated in adults and adolescents with moderate to severe recurrent pain (occurring three or more times a year). The drug is proving to reduce sickling crises and pain, priapism, the number of transfusions, and life-threatening complications in this group. The benefits appear to be long lasting. For example, a 2002 study reported that after four years patients who had taken the drug for at least two years experienced 30% fewer hospitalizations and 58% fewer transfusions than before they took hydroxyurea. In a nine-year study, the agent also reduced mortality rates by about 40%. Hydroxyurea is not a cure-all. Not all patients respond to hydroxyurea, and the best candidates for the treatment are not yet clear. Small studies have reported no protection from damage in the spleen or bones and joints. Effects on stroke and complications in the eye or kidney are not yet known.

Hydroxyurea is still being investigated in young people. To date, the response to the drug in children and teenagers with sickle-cell disease is similar to the response in adults, and few severe adverse effects are being reported. Data is still limited, however, and there is still concern about long-term risks. Parents should consult expert physicians about clinical trials for children.

Side effects include gastrointestinal problems, headache, drowsiness, and skin and nail changes. In rare cases, there have been reports of hallucinations and seizures. Long-term use of hydroxyurea (three years) may induce leg ulcers in certain patients. There is some concern that it may also pose a slight long-term risk for cancers, such as leukemia, but long-term research is needed. At this time, it should not be used during pregnancy.

Cytidine Analogues.Cytidine analogues increase HbF production by affecting the genes that regulate it. Decitabine is one such agent that was developed to treat leukemia and other blood malignancies. Early studies are suggesting that it significantly increases HbF production, even in patients who have failed hydroxyurea. Only minor toxic side effects have been reported to date.

Butyrates.Butyrates are natural fatty acids, which are the end-products of fermented carbohydrates in the intestinal tract and they are also metabolized from fiber. One derivative, arginine butyrate, has been under investigation for some time in sickle cell for its role in stimulating production of HbF. Intermittent therapy using intravenous administration has achieved increased levels. In a promising 2002 study administering arginine butyrate improved ulcer healing by ten-fold. Because its actions are different from hydroxyurea, experts hope the two drugs may eventually be used in combination. However, arginine butyrate is difficult to administer, and experts are looking for different forms that might make it simpler to use.

Nitric Oxide and Arginine

Nitric oxide, a soluble gas, is a natural chemical in the body that relaxes smooth muscles and dilates blood vessels. Hemoglobin removes nitric oxide and because abnormal sickle cells release such hemoglobin, patients with the disease are deficient in nitric oxide, which may play an important role in blood vessels constriction and pain in sickle cell diseases. In adult patients, men may be more susceptible to this effect than women. Some studies indicate that inhaling nitric oxide may slow the disease process and improve symptoms in acute sickle-cell crises. It is difficult to administer, however. (Nitric oxide is not the same substance as nitrous oxide, the so-called laughing gas used in dentistry.)

Arginine, a natural amino acid that is metabolized to nitric oxide, and other agents that convert to arginine, such as L-citrulline, are under investigation. A 2003 study indicated that arginine might improve pulmonary hypertension, a serious complication of sickle cell. Arginine may prove to be particularly useful in combination with hydroxyurea.

Drugs to Prevent Dehydration

Researchers are studying the mechanisms behind cell membrane damage, dehydration, and potassium loss in order to develop drugs that will inhibit these processes. Promising agents under investigation are those that specifically block the Gardos channel, which is an important route for potassium loss and dehydration. They include magnesium pidolate and clotrimazole and its derivatives.

Clotrimazole.Clotrimazole (a common ingredient in ointments, such as Lotrimin or Mycelex used to treat fungal skin infections) stops potassium from leaving and calcium from entering red blood cells, thereby preventing water loss in the cells. Early studies using an oral form of clotrimazole have been promising, but more research is needed.

Magnesium. Small studies have reported some benefits from the use of supplements containing magnesium pidolate to improve potassium and calcium interactions. A trial is currently underway.

Zinc. Zinc sulphate appears to help reduce red blood cell dehydration. Important studies are reporting that it helps prevent sickle cell crises and reduce pain and life-threatening complications.

Piracetam. Piracetam (Nootropil) prevents water loss, and important studies suggest that it may reduce sickle-cell crises and pain.It also may improve rehabilitation in people who have had strokes.

Bone Marrow or Stem Cell Transplantation

The only true cure for sickle-cell disease at this time is bone marrow or stem cell transplantation. The bone marrow nurtures stem cells, early cells that mature into red and white blood cells and platelets. By destroying the sickle-cell patient's diseased bone marrow and stem cells and transplanting healthy bone marrow from a genetically matched, or allogeneic, donor, normal hemoglobin may be produced. Trials using a few carefully selected patients have reported very successful results.

Candidates. Possible candidates for transplantation are patients with the following conditions:

• A history of stroke.
• Sickle pulmonary disease.
• Recurrent acute chest syndrome or vaso-occlusive crises.

Up to 80% to 85% of patients who receive transplants remain disease free. Unfortunately, only about 7% meet the criteria for transplantation, which include the following:

• They must be under age sixteen.
• They must have severe symptoms but no long-term organ or neurologic damage.
• They must have genetically matched siblings who will donate their marrow.

Complications. Bone marrow transplant carries its own dangers and limitations. About 10% of those treated die from the treatment. Some complications include the following:

• Transplanted cells which come from a donor (called allogeneic grafts) may attack the patient's own tissues, a potentially fatal condition called graft-versus-host disease (GVHD). Drugs that destroy bone marrow and suppress immunity must be administered before the procedure so that the body's immune system does not attack the transplanted tissue. Nonetheless, this does not always prevent the problem.
• Other very serious complications include bleeding, pneumonia, and severe infection.
• Those who live but are not cured face long-term problems caused by the drugs used in transplantation and by the disease itself.
• Even in those who are cured, long-term consequences may include a higher risk for cancer and infertility.

Investigative Approaches. Experts hope that better diagnostic techniques will identify at an early age more patients who are at high risk for developing serious sickle-cell disease and in whom the benefits of transplantation would outweigh the risks. Researchers are also investigating regimens that might be suitable for adult patients and less toxic regimens.

The use of umbilical cord blood and cells from placentas is showing promise for providing healthy stem cells to patients who do not have genetically matched donors for bone marrow transplant. Cord blood has certain advantages over stem cell transplantation, including the capacity to produce more cells quickly. Because immune factors in cord blood are immature, the risk and severity of graft-versus-host disease (GVHD) may be reduced.

Early trials are also reporting some success with a process called partial chimerism, in which a mixture of the patient's and a donor's bone marrow is used. The procedure has far fewer side effects because all the bone marrow is not destroyed. Although some sickle blood cells remain, small studies indicate that the patients are still free of the typical infections and pain of the disease.

Gene Therapy

Some researchers are focusing on therapies that transfer certain genes to bone marrow that might prevent the sickling process. Gene therapy has successfully cured sickle cell disease in mice. It is not know if such techniques are applicable to humans, and even if they are, effective gene therapy would be years away.