Hydroxyurea and Erythropoietin to Treat Sickle Cell Anemia
Hydroxyurea and Erythropoietin to Treat Sickle Cell Anemia
This study will examine the use of hydroxyurea and erythropoietin for treating sickle cell
 disease in patients who also have kidney disease or pulmonary hypertension (high blood
 pressure in the lungs). Hydroxyurea increases production of fetal hemoglobin in the red blood
 cells of patients with sickle cell disease, reducing the amount of sickle cells that cause
 pain and other complications requiring hospitalizations. However, hydroxyurea treatment has
 limitations: patients with sickle cell disease who have developed kidney disease may not be
 able to get the full benefit of the medicine, and hydroxyurea alone may not be able to treat
 life-threatening complications such as pulmonary hypertension or stroke. This study will
 determine which of two dosing schedules of hydroxyurea and erythropoietin is more effective
 for treating patients with sickle cell disease who also have kidney disease or pulmonary
 hypertension, and will examine whether the two drugs can lower blood pressure in the lungs.

 Patients 18 years of age and older with sickle cell anemia and kidney disease or pulmonary
 hypertension, or both, may be eligible for this study. Candidates are screened with a medical
 history, physical examination, blood tests, a 6-minute walk test (test to see how far the
 subject can walk in 6 minutes), and echocardiogram (ultrasound of the heart to measure blood
 pressure in the lungs).

 Participants undergo the following tests and procedures:

 Stabilization Phase: Patients take 2 hydroxyurea tablets a day until their fetal hemoglobin
 levels stabilize, usually over 2 to 4 months. They have blood tests every 2 weeks to monitor
 hemoglobin and fetal hemoglobin levels. At some time during this period, they undergo a test
 to measure kidney function, in which they are injected with an iodine-containing dye and wear
 a small pump for 1 day that injects a small amount of dye under the skin over 24 hours. They
 come to the clinic for 2 or 3 blood tests collected over 4 hours.

 Sequence I (Standard): When the fetal hemoglobin levels have been stable for 2 months,
 patients have a repeat echocardiogram and 6-minute walk test. Erythropoietin is then added to
 the hydroxyurea regimen. It is given 3 days a week, as an injection under the skin, along
 with iron supplements. Patients have blood tests and blood pressure measurements every week
 or every other week. Patients with pulmonary hypertension have another echocardiogram and
 6-minute walk test once the hemoglobin level is stable.

 Sequence II (Cycled): When hemoglobin levels have stabilized with hydroxyurea once a day and
 erythropoietin 3 times a week, the hydroxyurea is adjusted so that the amount taken in 7 days
 is "cycled" over 4 days, and the erythropoietin is cycled over 3 days, with the dose
 increased twice, every 3 to 4 weeks. Blood pressure and hemoglobin are monitored once or
 twice a month. Patients with pulmonary hypertension have another echocardiogram and 6-minute
 walk test once the hemoglobin level is stable.

 Patients who develop complications while taking the drugs have their treatment regimens
 adjusted as needed.
Sickle cell disease (SCD) is a genetic disease that afflicts over eighty thousand Americans,
 4 to 5,000 newborns per year in the US, and 100s of thousands of children and adults
 world-wide. This disease arises from a single amino acid mutation of the beta globin chain of
 hemoglobin, which results in abnormal polymerization of deoxygenated hemoglobin. The
 deceptively simple biologic origin for SCD belies the debilitating chronic multi-faceted
 clinical syndrome with which it is associated; SCD is characterized by lifelong hemolysis,
 chronic anemia, recurrent painful vaso-occlusive crises (VOC), hepatic, renal,
 musculo-skeletal, and central nervous system complications, and a shortened life-expectancy.
 Our group has found an up to 33% incidence of pulmonary hypertension in adult patients with
 SCD who were screened and followed prospectively; with two-year follow-up, this pulmonary
 hypertension is associated with a 10-fold increased mortality rate.

 Hydroxyurea has emerged as a useful therapy in sickle cell disease. It is a cell-cycle
 specific agent that blocks DNA synthesis by inhibiting ribonucleotide reductase, the enzyme
 that converts ribonucleotides to deoxyribonucleotides. Hydroxyurea has been shown to induce
 the production of fetal hemoglobin (HbF) in patients with sickle cell anemia, with associated
 diminished morbidity and, likely, mortality in these patients. Any HbF is good in SCD,
 although it is estimated that levels of 20 percent HbF are required to substantially reduce
 the sickling propensity of red cells and to modulate disease severity. The majority of
 patients with SCD respond to hydroxyurea with a more than two-fold increase in HbF levels; in
 some patients the percent of HbF exceeds 10 or 15 percent, but it is not uniformly
 distributed in all cells, i.e. has a hetero-cellular rather than a pan-cellular distribution.
 The mechanism through which hydroxyurea augments fetal Hgb is incompletely characterized. An
 additional benefit of hydroxyurea may be through effects on the nitric oxide (NO) system.
 Recently, members of our group found that hydroxyurea therapy is associated with the
 intravascular and intra-erythrocytic generation of NO, and that NO increases HbF expression
 via the guanylyl cyclase/cGMP dependent pathways.

 We have treated more than 30 patients chronically with hydroxyurea to determine hematological
 changes Iongitudinally, and have established the maximal HbF raising effect of hydroxyurea in
 these patients. We have found that the levels of HbF that are induced by hydroxyurea alone
 are insufficient, and insufficiently widely distributed, to ameliorate the life-threatening
 complications of pulmonary HTN and of on-going hemolysis in patients with sickle cell
 disease.

 Earlier studies had suggested that the addition of erythropoietin (Erythropoietin) therapy to
 chronic hydroxyurea therapy may induce fetal hemoglobin at higher, more widely distributed,
 levels. We plan to test this in patients with sickle cell disease who have chronic kidney
 disease, which, presumably, leaves them with a depressed Erythropoietin reserve and an
 inability to tolerate standard doses of F-inducing therapy with hydroxyurea, and in patients
 with pulmonary HTN, which carries an ominous prognosis in SCD. A secondary endpoint of this
 study will be to evaluate if hydroxyurea plus Erythropoietin therapy can improve
 cardiovascular aerobic capacity in general, and in particular minimize symptoms and morbidity
 in patients with both chronic kidney disease and pulmonary HTN.
-  INCLUSION CRITERIA:

 Patients with homozygous SCD or other sickling disorders (e.g., B(0) Thalassemia/Sickle)
 who are 18 years of age or greater will be eligible for treatment. Patients currently being
 followed on an NIH study or at Howard University on stable doses of hydroxyurea are also
 eligible. A total of 60 patients will be recruited to the study, with the recognition from
 our earlier studies of a failure-to-complete rate approaching 50%.

 Patients must have documented hemoglobin S-only or S-beta(0)-thalassemia.

 Patients must have relatively well preserved hepatic function (less than 3 X upper limits
 of normal ALT).

 Patients must be able to provide informed consent.

 Patients must have:

 -an eGFR of 15 to 60 ml/min per 1.73 m(2) BSA,

 or

 an eGFR of 61 - 90 ml/min per 1.73 m(2) BSA and greater than 16.9 mg of albumin/g
 creatinine (greater than 0.017 ratio g/g),

 and/or

 a trans-thoracic echocardiographic measurements of pulmonary artery pressure (PAP), as
 estimated by tricuspid regurgitant velocity, of greater than 2.5 m sec(-1) monthly at
 baseline times two.

 EXCLUSION CRITERIA:

 Patients who are doubly heterozygous for hemoglobin-S and fully or partially expressed
 hemoglobin-A or any other non-S beta-type globin chain, or hemoglobin A-only (non-sickle
 cell).

 Patients who are on a chronic transfusion program, defined as regular transfusions every
 2-8 weeks.

 Patients who are pregnant or breast-feeding.

 Patients who have a history of a documented cerebrovascular accident or venous thrombosis
 within one year of study entry.

 Patients with active proliferative retinopathy within 1 year of study entry

 Patients with eGFR less than or equal to 14 ml/min per 1.73 M(2) BSA.

 Patients with a total Hgb at entry that is 10.5 g/dl or greater

 Patients with a known allergy to Albumin or cell-derived products

 Patients with uncontrolled hypertension, defined as a systolic blood pressure greater than
 170 mmHg and diastolic blood pressure greater than 110 mm Hg that is sustained and
 unresponsive over 1 week to conventional anti-hypertensive therapy .