Treatment of Refractory Diamond-Blackfan Anemia With Eltrombopag

• INCLUSION CRITERIA:

In order to be participate in this study, individuals must meet all of the following criteria:

• Diamond-Blackfan anemia defined as anemia presenting on or before the third year of life with reticulocytopenia and greatly reduced or absent bone marrow erythroid precursors, supported by, but not requiring either:
• familial history
• gene mutation testing demonstrating a known disease-causing mutation or a mutation of disease-associated gene in combination with clinical characteristics of DBA
• Patients with late-onset DBA (diagnosed after the third year of life) may also be included if gene mutation testing confirms a disease -causing mutation as above.
• Clinically-significant anemia as defined as either:
• hemoglobin less than 9.0 g/dL
• red cell transfusion of at least 2 units PRBC for adults or 30 cc/kg for children (whichever is less) in the eight weeks prior to study enrollment
• Relapsed and/or steroid-refractory or intolerant of systemic corticosteroids
• Age greater than or equal to 2 years
• Weight greater than or equal to 12 kilograms
• Residence within the United States of America or territories, or able to reside within the US or its territories while on drug during trial participation

EXCLUSION CRITERIA

Individuals meeting any of the following criteria will not be eligible for participation in this study. However, having met exclusion criteria in the past does not preclude study participation if the criteria are no longer met, unless otherwise specified (i.e. patients with modifiable factors such as laboratory abnormalities or acute health problems may be re-screened). For laboratory assessments, this requires no less than two weeks from the previous exclusionary finding. The intervals for health problems that must elapse prior to re-screening are specified below.

• Platelet count > 400,000 / microliter
• Stage 4 or greater kidney disease as defined by creatinine > 2.5 mg/ dL or GFR 2.0 mg/ dL, including congenital abnormalities in the bilirubin level
• SGOT (AST) or SGPT (ALT) > 5 times the upper limit of normal
• Treatment with androgens (danazol or oxymetholone) or corticosteroids less than 4 weeks prior to initiating eltrombopag.

--Physiologic steroid replacement for adrenal insufficiency or other similar conditions is not exclusive of trial participation

• Treatment with any medications that may interfere with the metabolism of eltrombopag (e.g., CYP1A2 and CYP2C8 modulators) or whose own altered metabolism by eltrombopag cannot be adjusted for
• Hypersensitivity to eltrombopag or its components
• Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient s ability to tolerate protocol therapy, or that death within 7-10 days is likely
• Life expectancy of less than 3 months for any cause
• Subjects with known liver cirrhosis in severity that would preclude tolerability of eltrombopag as evidenced by albumin 450msec using Fridericia correction on the screening EKG, other clinically significant cardio-vascular disease (e.g. uncontrolled hypertension, history of labile hypertension), history of known structural abnormalities (e.g. cardiomyopathy).
• Known active or uncontrolled infections not adequately responding to appropriate therapy.

--HIV infection is not exclusive of trial participation if the infection is effectively controlled with medications not known to interfere with eltrombopag metabolism or be metabolized by pathways known to be altered by eltrombopag. HIV RNA viral load must be undetectable at the time of enrollment, and CD4 cell count must be greater than or equal to 200/microliter. Patients must remain on antiretroviral therapy throughout study participation and must be periodically monitored for suppression of viral load and CD4 cell count. If drug-drug interactions between antiretroviral medications and eltrombopag are suspected, these must be addressed by a q