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Home > "I" Clinical Trials Conditions > Improving Immunosuppressive Treatment for Patients with Severe Aplastic Anemia  Improving Immunosuppressive Treatment for Patients with Severe Aplastic Anemia
Improving Immunosuppressive Treatment for Patients with Severe Aplastic Anemia
For Condition: Aplastic Anemia
Status: Recruiting
Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) ,
Synopsis: Immunosuppressive treatment (administering drugs that suppress the immune system) is often successful for people with severe aplastic anemia (SAA). However, SAA patients tend to be highly susceptible to relapse, even after successful immunosuppressive treatment. Research suggests that SAA is an autoimmune disease and thus may require longer immunosuppressive treatment with different drugs. The purpose of this study is to compare two immunosuppressive regimens with the goal of decreasing relapse in SAA patients. Study participants will be placed in one of two study groups. One group will receive a combined drug treatment of antithymocyte globulin (ATG), cyclosporine (CsA) and sirolimus for six months. The other group will receive a combined treatment of ATG and CsA for 6 months, followed by a slow taper of CsA over the next 18 months. Upon admission to NIH, patients will undergo several days of preliminary testing and receive the medications; they will be hospitalized during this period (7-10 days). Study participants will have blood drawn periodically during treatment.
Details: Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder characterized by pancytopenia and a hypocellular bone marrow. Allogeneic bone marrow transplantation and immunosuppressive treatment with anti-thymocyte globulin (ATG) and cyclosporine (CsA) have dramatically changed the natural course of this illness, with 5 year survival of 75% in patients undergoing either treatment. Since most patients are not suitable candidates for hematopoietic stem cell transplantation (HSCT) due to advanced age or lack of a histocompatible sibling, efforts at NHLBI have focused on improving immunosuppression treatment in order to improve response rates, survival, and to decrease relapse. In our experience of 122 patients treated at NHLBI with the combination of ATG and cyclosporine, one quarter to one third did not respond; about 50% of responders relapsed; and 5 year survival was correlated with the robustness in blood cell count improvement at 3 months (reticulocyte or platelet count greater than or equal to 50,000 /uL). Why some patients do not respond initially while others relapse is unclear. Autoreactive T cells may be resistant to the effect of ATG/CsA (nonresponders), while in others residual autoreactive T cells expand post-treatment leading to hematopoietic stem cell destruction and recurrent pancytopenia (relapse). Therefore, novel immunosuppressive regimens to increase response rates and hematologic recovery at 3 months and to decrease relapse rates are needed. An ongoing NHLBI trial, which is close to completing accrual, has added mycophenolate mofetil (MMF) for a total of 18 months to standard ATG + CsA in an attempt to reduce the relapse rate after cyclosporine is discontinued. Preliminary results have been disappointing, with no marked reduction in relapse among patients who received MMF. Sirolimus (rapamycin, Rapamune ® (Registered Trademark), RAPA) is a novel immunosuppressive agent, which acts synergistically with cyclosporine by blocking T cell activation through CsA-resistant pathways. The potentiation of the combination of CsA-RAPA has been established in vitro and in the clinical setting, mainly in islet cell and solid organ transplantation. The significant increase in response rate seen with the addition of CsA to ATG indicated that an inhibitory effect on T lymphocytes is important in blocking autoreactive T cells in aplastic anemia. The combination of CsA-RAPA may further block activated autoreactive T cells and therefore lead to improved response rates (and survival) and decreased relapse rates. This prospective randomized phase II study will investigate two different immunosuppressive regimens in patients with severe aplastic anemia who have not received prior immunosuppressive therapy. One arm will receive ATG + CsA in addition to sirolimus for 6 months, and the second arm will receive standard ATG + CsA for 6 months followed by a slow taper of CsA with a 25% dose reduction every 3 months for the subsequent 18 months. This trial will determine the effectiveness of sirolimus in patients with aplastic anemia as well as the role of a cyclosporine taper in preventing relapses. Primary endpoint will be no longer meeting criteria for severe aplastic anemia while secondary endpoints are relapse, robustness of hematologic recovery at 3 months, survival, clonal evolution to PNH, myelodysplasia and acute leukemia.
Eligibility:
Study Type: Interventional, Treatment, Safety/Efficacy
Minimum Age/Maximum Age: /
Genders: Both
Protocol Entry Criteria: INCLUSION CRITERIA: Severe aplastic anemia confirmed at NIH by: a.. Bone marrow cellularity less than 30% (excluding lymphocytes) b.. At least two of the following: Absolute neutrophil count less than 500/ uL; Platelet count less than 20,000/ uL; Absolute reticulocyte count less than 60,000/ uL Age greater than or equal to 2 years old Weight greater than 12 kg EXCLUSION CRITERIA: Serum creatinine greater than 2.5 mg/dL Underlying carcinoma (except local cervical, basal cell, squamous cell) Prior immunosuppressive therapy with ATG, ALG, or cyclophospamide. Current pregnancy or lactation or unwillingness to take oral contraceptives or use an effective method of birth control. Diagnosis of Fanconi anemia or other congenital bone marrow failure syndromes Evidence of a clonal disorder on cytogenetics Underlying immunodeficiency state including seropositivity for HIV Inability to understand the investigational nature of the study or give informed consent ECOG performance status greater than 2 Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patients ability to tolerate protocol therapy, or that death within 7-10 days is likely.
Total Enrollment: 120
Location and Contact Information:
National Heart, Lung and Blood Institute (NHLBI) *Recruiting*
Bethesda, Maryland, 20892
United States
Recruiting Patient and Public Liaison Office 1-800-411-1222
Additional Information:
Study ID Numbers: 030193; 03-H-0193
Study Start Date: May 19, 2003
Record last reviewed: March 9, 2004
Additional information available at: clinicaltrials.gov
Clinicaltrials.gov Reference link: NCT00061360
Other Aplastic Anemia Studies:
1. Phase II Study of Bone Marrow Transplantation Using Related Donors in Patients with Aplastic Anemia
2. A Study to Determine whether Therapy with Daclizumab Will Benefit Patients with Bone Marrow Failure
3. Investigating Voriconazole to Prevent Systemic Fungal Infection
4. Rabbit Antithymocyte Globulin Versus Campath-1H for Treating Severe Aplastic Anemia
5. Comparing Therapies for the Treatment of Severe Aplastic Anemia
Related Studies:
Other Aplastic Anemia Clinical Trials
Other Maryland Clinical Trials
Other Bethesda Clinical Trials
Improving Immunosuppressive Treatment for Patients with Severe Aplastic Anemia
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