Decitabine for High-Risk Sickle Cell Disease

• INCLUSION CRITERIA:

Subjects who meet all of the following criteria are eligible for enrollment into the study:

• Age 18 years or older.
• Written, informed consent provided by the subject before study entry.
• Confirmed SCD (SS, S-beta (0)-thalassemia, or SC on hemoglobin electrophoresis),
• Symptomatic SCD while on 6 months of HU OR symptomatic SCD and intolerant of HU (unable or unwilling to tolerate HU due to hematological or other toxicities). Symptomatic SCD is defined as having one of following:
• 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 degree g/dL and ARC less than or equal to 250,000/mm(3),
• Subject is in his/her steady state and not amidst any acute complication due to SCD.
• Willing to use 2 forms of contraception. Some acceptable combinations include male partner using condoms and female partner using oral contraceptives, male partner using condoms and female partner who had bilateral oophorectomy, male partner who had a vasectomy and female partner using injectable contraceptives (e.g. Depo Provera).

EXCLUSION CRITERIA

Since the protocol targets an at risk population, and the tolerability and potential benefits of this approach have been suggested in off-label treatment of seriously ill SCD patients, the exclusion criteria are not overly stringent and are primarily directed at avoiding teratogenic risks.

Subjects who meet any of the following criteria are disqualified from enrollment in the study:

• Inability to give informed consent.
• Experienced severe sepsis or septic shock within the previous 12 weeks.
• Last HU or erythropoietin dose obtained within the previous 4 weeks. Renal replacement doses of erythropoietin is allowed as decitabine would not be expected to exert a red cell and/or HbF response when there is no endogenous erythropoietin production.
• Participant is on chronic transfusion therapy (e.g., for history of TIA or stroke) and medically contraindicated to discontinue transfusions.
• Currently pregnant or breast-feeding.
• Sexually active female of childbearing potential (all females except those who are menopausal [appropriate age and no period for more than 12 months] or have had a hysterectomy and/or bilateral oophorectomy) who is unwilling to use at least 2 acceptable methods of contraception as determined by the investigators. The use of a condom by a male partner would be considered one acceptable method of contraception.
• Sexually active male whose partner is of child-bearing potential and who is unwilling to use at least 2 acceptable methods of contraception as determined by the investigators during treatment and for 8 weeks after the last dose of decitabine.
• Moribund or any concurrent disease (e.g., hepatic, renal, cardiac, metabolic) of such severity that death within 24 weeks is likely.
• Other experimental or investigational drug therapy in the past 28 days.
• Inability to bring ANC above 2 x 10(9) cells/L or platelet count less than 1,000 x 10(9) cells/L.

For female participants: Not having heterosexual sexual contact starting 4 weeks before beginning to take decitabine and continuing until 4 weeks after the last dose of decitabine OR using TWO methods of birth control. One birth control method must be highly effective, such as an Intrauterine Device (IUD), birth control pills, Depo-Provera (medroxyprogesterone acetate) injections, or tying of the fallopian tubes. The other additional effective method of birth control can be use of a diaphragm or a condom by the male partner. Birth control should begin at the screening visit and continue until 4 weeks after the last dose of decitabine. These steps must be taken even if the patient has a history of infertility, unless the patient has had a hysterectomy or has not had periods for at least 24 months.

For male participants: during decitabine treatment and 8 weeks after last dose of drug, a condom