Rituximab to Treat Moderate Aplastic Anemia, Pure Red Cell Aplasia, or Diamond Blackfan Anemia

This study will test whether the immune-suppressing drug rituximab can increase blood counts
and reduce the need for transfusions in patients with moderate aplastic anemia, pure red cell
aplasia, or Diamond Blackfan anemia. These are rare and serious blood disorders in which the
immune system turns against bone marrow cells, causing the bone marrow to stop producing red
blood cells in patients with pure red cell aplasia and Diamond Blackfan anemia, and red blood
cells, white blood cells and platelets in patients with aplastic anemia. Rituximab is a
laboratory-made monoclonal antibody that recognizes and destroys white blood cells called
lymphocytes that are responsible for destroying bone marrow cells in these diseases. The drug
is currently approved by the Food and Drug Administration for treating patients with B-cell
non-Hodgkin lymphoma, a disease of white blood cells.

Participants receive four doses of rituximab, once a week for 4 weeks through a needle in an
arm vein. The infusion rate depends on how well the patient tolerates the drug. The first
infusion usually takes 4 to 6 hours and the rest take 3 to 4 hours. The first and fourth
infusions are given at NIH; the second and third may be given at NIH or by a patient's
referring doctor. Patients who respond to rituximab but then relapse may receive one
additional course of four doses. Patients may continue with transfusions and their current
medications, including growth factors (e.g., Epogen and Neupogen) while on study, but may
have to stop taking immunosuppressive drugs, such as prednisone or cyclosporine. Patients who
must start another immunosuppressive medication are taken off rituximab and followed for
safety with clinic visits one week and then once a month for 6 months after the first dose of
rituximab.

Patients have a blood test once a week while receiving rituximab to evaluate blood counts.
After treatment is completed, patients are evaluated once a month until 6 months, then once a
year until 3 years to monitor the response to treatment and any drug side effects. Patients
are evaluated at NIH for the 3- and 6-month visits and the annual visits. They may be seen at
NIH or by their referring doctors for the 1-, 2-, 4- and 5-month visits. A blood test is done
at every visit, and a bone marrow aspiration and biopsy are done at the 3-month visit (and
when clinically needed to evaluate the effect of rituximab on bone marrow cells).

- INCLUSION CRITERIA:

Diagnosis of acquired moderate aplastic anemia defined as aplastic anemia (hypocellular
bone marrow) and no evidence for an underlying disease process and depression of at least
two out of three blood counts below these values:

- Absolute neutrophil count (ANC) equal to or less than l200/mm(3)

- platelet count equal to or less than 70,000/mm(3)

- anemia with hemoglobin equal to or less than 8.5 g/dl or absolute reticulocyte count
equal to or less than 60,000/mm(3) in transfusion-dependent patients but not
fulfilling the criteria for severe disease defined by bone marrow cellularity less
than 30% (excluding lymphocytes) and depression of at least two of the three
peripheral counts:

- ANC equal to or less than 500/ul

- platelet count equal to or less than 20,000/ul

- reticulocyte count less than 60,000/ul

Or

Diagnosis of pure red cell aplasia or Diamond Blackfan anemia requiring red blood cell
(RBC) transfusions

Pure red cell aplasia is defined by

- anemia,

- reticulocytopenia (reticulocyte count equal to or less than 50,000/ mm(3))

- and absent or decreased marrow erythroid precursors

Diamond Blackfan anemia is defined by

- anemia,

- reticulocytopenia (reticulocyte count equal to or less than 50,000/ mm(3))

- and absent or decreased marrow erythroid precursors diagnosed at an early age

Because this population is prone to dry bone marrow aspirates, subjects from whom
sufficient bone marrow cannot be collected for the evaluation of cellularity will not be
excluded provided they meet all other inclusion criteria based on peripheral blood counts.

Pure Red cell Aplasia and Diamond Blackfan patients must be age greater than or equal to 2
years old and weight greater than 12 kg; Moderate Aplastic anemia patients must be age
greater than or equal to 18.

Refractory to at least 1 course of immunosuppressive therapy or relapsed disease after
prior immunosuppressive therapy (PRCA/DBA patients only).

Patients or their parent(s)/responsible guardian(s) must be able to comprehend and be
willing to sign an informed consent.

EXCLUSION CRITERIA:

Current diagnosis of Fanconi's anemia or other congenital bone marrow failure syndromes
except for DBA

History of a cytogenetic abnormality indicating myelodysplasia (MDS)

Active infection not adequately responding to appropriate therapy

HIV positivity

Positive anti- hepatitis B core antibody (antiHBc) or HBsAG

History of clinically significant arrhythmia

Known anaphylaxis or immunoglobulin E (IgE) mediated hypersensitivity to murine proteins or
to any component of this product.

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 the next month is likely

Potential subjects with cancer who are on active chemotherapeutic treatment or who take
drugs with hematological effects will not be eligible.

History of recent or ongoing B19 parvovirus infection

Psychiatric, affective, or other disorder that may compromise the ability to give informed
consent or to cooperate in a research study.

Pregnancy or lactation or unwillingness to take contraceptives

Participation in any other investigational drug trial or exposure to other investigational
agents (other than hematopoietic growth factors) within 30 days of study entry. Use of low
dose immunosuppressive agents may continue at the PIs discretion provided that the patient
has been taking this drug for at least 3 months.