Effects of 5-aza-2'-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease.

Fetal hemoglobin (HbF) decreases polymerization of sickle hemoglobin (HbS) and improves outcomes in sickle cell disease (SSD). Therefore, a therapeutic goal in SSD is pharmacologic reactivation of HbF. Silencing of the gamma-globin (HbF) gene is associated with DNA methylation. The cytosine analog 5-aza-2'-deoxycytidine (decitabine) hypomethylates DNA by inhibiting DNA methyltransferase. We examined if subcutaneous decitabine could increase HbF levels and improve SSD pathophysiology without cytotoxicity. Eight symptomatic SSD patients resistant or intolerant of standard treatment with hydroxyurea received decitabine 0.2 mg/kg subcutaneously 1 to 3 times per week in 2 cycles of 6-week duration. Treatment decreased neutrophils and increased mean HbF (6.5% to 20.4%, P <.0001) and mean total hemoglobin (76 to 96 g/L [7.6 to 9.6 g/dL], P <.001). Features of vaso-occlusive crisis pathophysiology such as red cell adhesion, endothelial damage, and coagulation pathway activity significantly improved. gamma-Globin gene promoter methylation decreased, and platelets and the proportion of megakaryocytes and erythroid cells in the marrow increased without a decrease in marrow cellularity, consistent with a DNA hypomethylating, noncytotoxic mechanism of action. Weekly subcutaneous decitabine produces cumulative increases in HbF and total hemoglobin through a noncytotoxic mechanism of action. Chronic dosing and sustained increases in hemoglobin F and total hemoglobin levels may be possible. Further studies in SSD and thalassemia are indicated.

Maintenance of elevated fetal hemoglobin levels by decitabine during dose interval treatment of sickle cell anemia.

We have previously demonstrated that 5-aza-2'-deoxycytidine (decitabine) augments fetal hemoglobin (HbF) levels in patients with sickle cell anemia (SS) who did not respond to hydroxyurea (HU). The present study was designed to determine the effect of repeated decitabine dosing on HbF levels and hematologic toxicity over a 9-month treatment period. Seven patients (5 HU nonresponders) were entered. One patient had alpha-thalassemia sickle cell anemia. Decitabine was administered by intravenous infusion at a starting dose of 0.3 mg/kg per day, 5 days a week for 2 weeks, followed by a 4-week observation period. If the absolute neutrophil count dropped below 1000, the dose was reduced by 0.05 mg/kg per day in the next cycle. A drug dose was obtained for each patient, and it resulted in an elevated HbF without neutropenia (absolute neutrophil count nadir greater than 1500) or evidence of cumulative toxicity. Average HbF and average maximal HbF levels attained during the last 20 weeks of treatment for the 6 SS patients increased to 13.93% +/- 2.75% and 18.35% +/- 4.46%, respectively, from a pretreatment mean of 3.12% +/- 2.75%. Mean and mean maximal hemoglobin (Hb) levels increased from 7.23 +/- 2.35 g/dL to 8.81 +/- 0.42 g/dL and 9.73 +/- 0.53 g/dL, respectively. Individual maximal F-cell number observed during the trial was 69% +/- 10.12%. The absence of cumulative toxicity may allow shorter intervals between drug treatments, which may lead to higher hemoglobin and HbF levels after several treatment cycles and, therefore, to greater clinical improvement.

A natural history study of adolescents and young adults with sickle cell disease as they transfer to adult care: a need for case management services.

Life expectancy for adolescents with SCD now extends well into adulthood. As a result, adolescents transfer to adult care. Little empirical evidence exists to show how transfer occurs and how well the current practices now work. The aim of this study was to obtain a database on the experience of adolescents/young adults with SCD that transfer to adult care. We assessed their treatment compliance, independence, and whether they receive uninterrupted care. Data were obtained through patient and provider interviews and patient record reviews. Results indicate patients leave pediatric care without adequate transfer preparation and readiness to transfer is not the major consideration in the decision to transfer, follow-up often ceases once the patients leave pediatric care, and patients who maintain follow-up appointments are more efficient in managing their illness (self-efficacy). The model for a structured transitioning process is provided with recommendations for nurse case managers to maintain follow-up.

Evaluation and Management of Sickle Cell Disease in the Emergency Department (An 18-year Experience): 1974--1992.

Painful episodes are the most frequent complaints of patients with sickle cell disease. The Emergency Department (ED) has provided management for acute events using the usual triage format for emergencies. A prospective study evaluated the role of the ED in the care of adults with sickle cell disease (SCD). The protocol, thus, addressed issues of acute events related to SCD and provided better care for patients with SCD in the ED. Approximately 37% of ED visits were for painful events. An inciting cause was identified in 35% of painful events and 75% of these required admission to the hospital. A 15-year follow-up prospectively showed similar results and that uncomplicated pain crisis can be treated with ED protocols. Outpatient clinics and urgent centers could reduce these visits. Absolute indications for admission include sepsis, fever >102 degreeF, white cell counts >20 000, worsening anemia, hypoxemia, acute chest syndrome and new CNS events. Patient database in the ED must be revised annually to avoid extensive workup in the ED and a complete history/physical examination, and a CBC could be sufficient for triage in an uncomplicated pain crisis. An acceptable protocol for care should be available at all EDs and a registry and information system for SCD will discourage overutilization of investigational tests and visits to multiple EDs.