Hydroxyurea and Erythropoietin to Treat Sickle Cell Anemia

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 .