Decitabine for High-Risk Sickle Cell Disease

Neutropenia, Sickle Cell Disease

Neutropenia, Hemaglobin, Coagulation Disorders, Thrombocytosis, Red Blood Cells, Sickle Cell Disease

Background: * In sickle cell disease (SCD), the proteins in the red blood cells that carry oxygen do not behave normally. In parts of the body where there are low levels of oxygen or where oxygen is used more, the sickle hemoglobin proteins may change shape and stick together. This causes the red cells to clump, which reduces blood flow. This leads to even lower oxygen levels and causes damage and/or pain. * One way to stop the red blood cells from sticking together is to increase the levels of fetal (baby or good ) hemoglobin. The good hemoglobin then takes the place of the sickle hemoglobin. * Hydroxyurea is the only approved drug for SCD. But hydroxyurea works in only about two-thirds of people with SCD. Even in those cases it sometimes stops working over time. * Researchers are interested in testing decitabine. The drug may help to increase fetal hemoglobin levels. But it has not yet been approved to treat SCD. Objectives: \- To test the safety and effectiveness of decitabine in increasing fetal hemoglobin levels and improving the symptoms of sickle cell disease. Eligibility: \- People at least 18 years of age who have sickle cell disease that has not improved after at least 6 months of hydroxyurea therapy. Those who cannot take hydroxyurea because of side effects may also participate. Design: * Participants will be screened with a physical exam and medical history. They will also have blood and urine tests, a lung function test, and other tests as required. * Participants will receive decitabine injections up to twice a week for 1 year. Depending on the response to treatments, the dose will remain the same or be reduced to once a week. * Participants will be monitored with frequent blood tests and other studies as directed by the study doctors. * After the study is completed, participants will go back to their usual sickle cell care. If decitabine has improved a participant's SCD, treatment may be continued under regular health coverage insurance if this can be arranged.

Overview: Elevated fetal hemoglobin (HbF), whether pharmacologically induced or congenital, has a favorable impact on the morbidity and mortality of SCD. The agent currently used to elevate HbF, hydroxyurea (HU), has limited efficacy. There are mechanistic reasons to believe that the DNA methyltransferase inhibitor 5-aza-2 -deoxycytidine (decitabine) can more potently increase HbF. This has been demonstrated in vivo in animals and small phase 1/2 studies of decitabine in SCD subjects. Decitabine at low, non-cytotoxic doses was very well tolerated and very efficacious at increasing HbF and total hemoglobin (Hb) in subjects who did not respond to, or were intolerant of, HU. In addition to HbF levels, major improvements were noted in a range of surrogate clinical endpoints measuring red blood cell (RBC) adhesion, endothelial damage, and coagulation pathway activity. Also, substantial clinical improvement was seen in severely ill patients treated off-label. The primary objective herein is to provide evidence and guidance for a phase III study by demonstrating the dose and schedule of decitabine that when given over a 12 month period, produces sustained elevations in HbF without significant toxicity. Secondary objectives examine patient reported outcome measurements (PROMIS), crisis frequency, and laboratory indices that measure different domains of sickle cell pathophysiology and DNA methylation. These secondary and scientific measurements will be correlated with each other and examined over time to understand mechanisms of disease and the mechanism of action of the study drug. Intervention: Decitabine starting dose of 0.2 mg/kg (range, 0.05-0.3 mg/kg) 1-2x/wk x 48 weeks Hypotheses: In SCD subjects at risk of early death, non-cytotoxic DNMT1 depletion using a metronomic (frequent but intermittent) regimen of the nucleoside analogue decitabine directly antagonizes a mechanism of gamma-globin repression, and produces sustained, clinically significant HbF elevations. Primary Objective: To measure, in high-risk SCD subjects, the effect of chronic metronomic subcutaneous (SQ) decitabine administration on HbF levels. These aims are achieved through the conduct of an extended, open-label, phase 2 study in subjects who remain at high risk of early mortality and morbidity despite HU therapy. Secondary Objectives: To measure, in high-risk SCD subjects, the effect of chronic metronomic SQ decitabine administration on clinical and laboratory indices of safety, patient reported outcome measures (PROMIS), frequency of crises, SCD pathophysiologic activity (hemolysis, coagulation, platelet activation and inflammation), and molecular effects of study drug. Criteria for Evaluation: Primary Endpoint: the percentage change in HbF level from baseline to the average percent over the final 3 months of the study period (48 weeks). Secondary Endpoints: clinical and laboratory assessment of safety, patient reported outcomes (PROMIS), frequency of crises, quantity of F cells and F cell subsets, measurements of hemolysis, coagulation, platelet activation, inflammation, endothelial damage, pulmonary arterial pressure, DNMT levels, global and beta-globin locus specific DNA methylation. Study Design: This is an extended, single arm, open-label, phase II clinical trial. Study Population: Adults with symptomatic SCD who are at high risk of early mortality despite greater than or equal to 6 months of HU therapy. Specifically, they still have: HbF \<5 percent, OR 3 or more pain episodes per year requiring parenteral narcotics, OR 1 or more acute chest syndrome episodes, OR hemoglobin \<9 g/dL and absolute reticulocyte count (ARC) less than or equal to 250,000/mm(3). Subjects who meet the above criteria for high risk but are unwilling or unable to tolerate HU are also eligible. Clinical and Laboratory Evaluations: Pre-treatment and every 2 weeks: CBC, chem 20 including LDH, and retic count Pre-treatment and every 4 weeks: interim medical history & physical exam, HbF%, and pregnancy test Pre-treatment and every 12 weeks: urinanalysis, percent F-cells & percent F-reticulocytes, biomarkers, scientific correlative studies of DNA methylation Pre-treatment, 24 and 48 weeks: PROMIS, PFT, 6 minute walk, endo-PAT Pre-treatment and 48 weeks: erythropoietin level Follow-ups every 3-4 months between 52-54 weeks and 93-96 weeks: interim medical history & physical exam, CBC, reticulocyte count, HbF percent, chem 20 (including LDH), and pregnancy test Sample Size: 40 subjects Data Analyses: The effect of decitabine on HbF levels over time will be explored using a general linear mixed model from which the average percent change from baseline to the average HbF level on the final 3 months of treatment will be estimated along with a 95 percent confidence interval. AE and other safety measurements will be summarized by age group, dose, and dose frequency at the time of AE onset. No interim analyses will be performed in this study. Human Subjects: There is a risk of neutropenia, thrombocytosis, and teratogenicity. Patients must take precautions to use contraception and avoid pregnancy during treatment.

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