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's lymphoma, a disease of white blood cells.

Patients 2 years of age or older with pure red cell aplasia or Diamond Blackfan anemia and patients 18 years of age or older with moderate aplastic anemia who did not respond to previous immunosuppressive therapy or relapsed after treatment may be eligible for this study. Candidates are screened with a medical history and physical examination, blood tests, electrocardiogram, and bone marrow biopsy (withdrawal of a mall sample of bone marrow through a needle).

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).

Many bone marrow failure syndromes in humans result from an immune destruction of single or multiple hematopoietic cell lines. These diseases include aplastic anemia, pure red cell aplasia (PRCA) and Diamond-Blackfan anemia (DBA). Immunosuppression has significantly improved the survival of severe aplastic anemia (SAA) patients. However, the management of moderate aplastic anemia (MAA) remains controversial, given its better prognosis as well as the toxicity and inconvenience of long term immunosuppressants like antithymocyte globulin (ATG) and cyclosporine (CsA). Similarly PRCA and DBA frequently respond to steroids but prolonged or repetitive courses may be needed with significant long term toxicity. There are no studies describing the natural history of MAA in adults. Based on studies in children where 2/3 of patients progress to SAA, we have taken a proactive approach to study activity of milder and less toxic immunosuppressants. During the last several years we introduced daclizumab in the treatment of MAA with a response rate of 38%.

Rituximab (Rituxan(Registered Trademark)) is a chimeric murine/human monoclonal antibody, directed against CD20. CD20 is expressed on pre-B lymphocytes as well as on resting and activated mature B lymphocytes. Rituximab leads to rapid and sustained depletion of both normal and malignant B-cells. Its safety profile is well defined, as it has been given to more than 300,000 patients with non-Hodgkin's lymphoma. Rituximab (Rituxan(Registered Trademark)) has proven beneficial as a therapy for a variety of autoimmune diseases including autoimmune hemolytic anemia, immune thrombocytopenic purpura, PRCA, acquired factor VIII and factor IX inhibitors, chronic refractory graft-versus-host disease, rheumatoid arthritis and systemic lupus erythematosus.

To investigate whether rituximab (Rituxan(Registered Trademark)) has activity in patients with bone marrow failure syndromes, we propose this non-randomized, off label, Phase II study in MAA, PRCA, or DBA. Subjects will be treated with 375 mg/m2 of rituximab (Rituxan(Registered Trademark)), infused intravenously once every week for a total of 4 doses. Patients who respond and relapse may receive a second cycle of drug per PI discretion. Subjects with suboptimal response may receive a second cycle of drug at the 6 month time point.

Subjects will be evaluated for the efficacy and safety of this monoclonal antibody on their disease. Primary endpoints will be changes in peripheral blood counts (platelets, absolute neutrophil count, reticulocyte count, hemoglobin) and transfusion requirements at 6 months. Secondary endpoints include response at 3 months, durability of response, disease progression, survival and the response to a second course of therapy when indicated.

• Anemia, Aplastic
• Red-Cell Aplasia, Pure
• Anemia, Diamond-Blackfan

• Wang J, Wiley JM, Luddy R, Greenberg J, Feuerstein MA, Bussel JB. Chronic immune thrombocytopenic purpura in children: assessment of rituximab treatment. J Pediatr. 2005 Feb;146(2):217-21.
• Gottenberg JE, Guillevin L, Lambotte O, Combe B, Allanore Y, Cantagrel A, Larroche C, Soubrier M, Bouillet L, Dougados M, Fain O, Farge D, Kyndt X, Lortholary O, Masson C, Moura B, Remy P, Thomas T, Wendling D, Anaya JM, Sibilia J, Mariette X; Club Rheumatismes et Inflammation (CRI). Tolerance and short term efficacy of rituximab in 43 patients with systemic autoimmune diseases. Ann Rheum Dis. 2005 Jun;64(6):913-20. Epub 2004 Nov 18.
• Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004 Jun 17;350(25):2572-81.

• 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:

• 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 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 antiHBc or HBsAG

History of clinically significant arrhythmia

Known anaphylaxis or 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.