Sickle Cell Anemia - Clinical Trials

What was MSH?

What is a "painful crisis" in a patient with sickle cell anemia?

A painful crisis is a sudden attack of pain, which may be mild or extremely severe, often occurring in bones and joints in adults. For this study, which was limited to patients with moderately severe disease (at least 3 attacks/year), a crisis was a visit to a medical facility for pain not due to another disease, lasting at least 4 hours, and treated with injections of a narcotic pain-killer.

Why was an early "Clinical Alert" put out?

To get information from the study to doctors and patients as quickly as possible; to be sure that physicians and patients knew that the drug has to be used very carefully, if it is to be used safely; and to be sure that the drug is not used inappropriately (as for treatment of acute attacks, or without careful monitoring).

What were the most important findings in the study?

Sickle cell anemia patients treated with HU: had about half as many painful crises; had longer periods between crises; had fewer attacks of acute chest syndrome (a pneumonia-like problem); had to be hospitalized less often; had to be transfused less often; and had no significant bad effects from treatment.

Most HU treated patients did continue to have some crises, and all had to get their blood counts checked every 2-4 weeks. Taking capsules during an acute attack did not stop the attacks. HU works slowly, and a decrease in the frequency of crises was not seen until about 6-8 weeks after starting. Good effects of treatment only last while patients continue to take their capsules.

Is hydroxyurea a "cure" for sickle cell disease?

No, but it can help some patients. It can prevent attacks from occurring, but is of no help in actually treating a painful crisis once it has started.

Were there any deaths in the study?

Yes, but numbers in the HU and placebo groups did not differ significantly. No deaths were related to use of HU.

Is hydroxyurea ever dangerous?

It can be very dangerous if the patient and his/her blood count are not followed carefully. If, and only if, they are watched closely, it is not dangerous when prescribed by a physician experienced in the use of such treatments.

Are there any unclear/undefined risks?

This study did not address these problems directly, but there might be a risk to the baby if a pregnant woman took HU. Problems which developed in animals were seen at doses about 10 times as large as those we used. There also might possibly be a risk if a man were taking HU at the time of conception. In our study, treatment was stopped if any patient or his partner became pregnant during the study, and all babies were normal at birth. If there is a risk, and we aren't sure there is, we don't know if the risk would continue after one stopped taking the drug.

There might be a risk of leukemia or cancer from long-term therapy (greater than 5 years) at doses similar to those we used, but there are no data which support that possibility in patients with sickle cell anemia. No patients in our 2-year study developed cancer or leukemia. We acually began testing HU about 10 years ago, and the first 2 patients we treated are doing well, although they still do have crises. We do not know if the drug is safe in growing children.

Are there any unclear/undefined benefits?

Our study did not address these questions, but long-term treatment might prevent development of such long-term problems as kidney failure, problems with the hip and shoulder joints, and perhaps ankle ulcers. There was no evidence that HU helped these conditions once they had developed.

Must patients be evaluated before starting treatment?

Definitely. They must understand the possible benefits, the possible short and long-term risks, and what they must do if treatment is to be safe. Our study was carried out in adult patients with more than 3 crises per year; patients with less than 3 crises per year must understand that the MSH study results do not necessarily apply to them.

Are there any special things that patients must do?

They must take the drug regularly, every day, only as directed by their doctors, and they must not continue to take the drug without having their blood counts checked regularly.

How often must patients have blood tests?

At the beginning of treatment, about every 2 weeks. Later that interval can be lengthened, and some patients followed for 5 or more years need tests every other month.

How often must patients see a doctor?

At the beginning, every 2 weeks. Later, if the patient is feeling well, visits as well as blood counts can be less frequent, but they must be done regularly. The exact schedule will vary from patient to patient.

Will all patients with sickle cell anemia benefit from using hydroxyurea?

Probably not. We don't know for sure which patients are most likely to benefit, but the results we obtained came from severely affected patients, and we think that treatment with HU should probably be reserved for patients with frequent crises.

There are patients with other types of sickle cell disease--hemoglobin SC disease for example--who did not participate in the trial. Could hydroxyurea help such patients?

Since most patients with hemoglobin SC disease have fewer crises than the patients in our study, they probably would not think that the inconvenience of frequent blood counts, and the possible risks of treatment, were worth the possible gain. A few patients with Hb SC disease do have frequent crises, and they theoretically could benefit from treatment with hydroxyurea.

Can hydroxyurea save a patient's life?

No, in an acute situation, like a stroke or heart, lung or kidney failure. It cannot make such problems go away, any more than it can make an on-going painful crisis go away. By preventing future sickling, it might prolong patients' lives, but we have not used the drug long enough to know if that is really true.

Is the drug safe or effective in children?

We don't know; all of our patients were adults.

Is hydroxyurea a new drug?

No, it has been available for treating other diseases for many years.

What is the correct dose?

Our study was designed to test whether maximum tolerated doses were effective, but did not examine the question of whether lower doses might also work. Based on present knowledge, we recommend using maximum tolerated doses, with careful observation for beneficial effects at lower doses. Each patient's dose must be adjusted individually over the course of several months. In longterm use, doses are about 1-15 mg/lb/day taken by mouth as a single daily dose. We suggest starting with a single daily dose of no more than 7 mg/lb (15 mg/kg), which is usually two 500 mg capsules/day, and carefully working up or down to find a dose which produces maximum benefit with minimum depression of blood counts. At first, counts must be checked every 2 weeks. Other dosage regimens are being investigated, and might eventually be shown to be superior.

Is the drug readily available?

It is available in the United States, but has not been approved for use in sickle cell anemia by the FDA. Doctors can prescribe it for sickle cell patients, but patients must understand that it is still a very new drug for this disease. Because it is new, insurance companies may not be obligated to pay for it under certain prescription programs.

How much does it cost?

In pharmacies, the price of 100 capsules is $121-164; it can be purchased from AARP by mail for $117/100 capsules. Most patients take 2-3 capsules/day, which would cost about $100/month.

How does the drug work?

It may work by increasing the amount of fetal (baby) hemoglobin in red blood cells, but we aren't sure. We think it makes red cells less likely to sickle, or less likely to plug-up blood vessels, or both, but we aren't sure.

What led to the discovery?

Basic research in sickling and the way hemoglobin is made in the test tube, which led to experiments in animals, and then to early trials in patients. The first research on the subject began more than 30 years ago, but has accelerated greatly in the past 10 years or so.

Are there new developments on the horizon?

Several other drugs under investigation (erythropoietin, butyrate and related compounds) may work together with hydroxyurea to make it more effective, but those studies are still in progress. Bone marrow transplantation can really cure the disease, but the risks are high, and only a small number of young patients are good candidates for that form of experimental therapy. Some day gene therapy may provide a safe and effective cure, and that will be some years in the future.

WHAT anemia? cell sickle with patients for step next the is

If patients think they might be interested in hydroxyurea treatment, they should discuss it with their doctors. Consultation with a blood specialist (a hematologist) might be helpful in some situations. In every case, the patient must understand the risks of treatment, the need for frequent blood counts, the cost of the drug, and the fact that HU cannot treat crises once they have started.

Where can my doctor get more information?

By calling the Sickle Cell Disease Scientific Research Group (301-435-0055) to get the name of one of the clinics which participated in the study closest to you.