Sirolimus Treatment for Newly Diagnosed Primary Acquired PRCA

Study Overview
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Brief Summary
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Pure red cell aplasia (PRCA) is a kind of anemia characterized by severe reticulocytopenia and obvious bone marrow erythroblastic cells decreased. Cyclosporine A and /or steroids are the first line therapy but some patients were refractory or intolerance to the treatment. The effects of the second line therapy are also not satisfactory and sometimes not available. The investigators aim to explore the efficacy and side-effect of sirolimus for newly diagnosed primary acquired PRCA.

Detailed Description
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Pure red cell aplasia (PRCA) is a rare normocytic normochromic anemia with reticulocytopenia, characterized by a reduction of erythroid precursors from the bone marrow, could be divided into congenital and acquired PRCA according to pathogenesis. Congenital PRCA, also known as Diamond-Blackfan syndrome, has been associated with pathogenic variant in GATA1 and TSR2 and gene encode ribosomal proteins. Acquired PRCA can be a primary disease which is usually mediated by immunology, or secondary to other diseases, such as lymphoproliferative diseases, autoimmune diseases, thymoma, infection, or drugs. The first line therapy of acquired PRCA is Cyclosporine A (CsA) and steroids, the second line therapy are anti-CD20, anti-human thymocyte immunoglobulin, immunosuppressive drugs like cyclophosphamide, bone marrow transplantation. Unfortunately, some patients did not response or tolerate the above treatments. Sirolimus (rapamycin) is an agent produced by the bacterium Streptomyces hygroscopicus, inhibits the mammalian target of rapamycin (mTOR). mTOR is a serine/threonine kinase that regulates cell growth, proliferation, metabolism and survival in eukaryotic cells, and is identified as two interacting complex, mTORC1 and mTORC2. Sirolimus primarily inhibits mTORC1, has been approved for prevent organ transplant rejection, especially in renal transplantation. Sirolimus also promises to treat autoimmune, degenerative and hyperproliferative disorders. Recently, sirolimus has been reported to be effective and well tolerated for many immune-mediated cytopenias, such as autoimmune lymphoproliferative syndrome, immune thrombocytopenia, EVANS syndrome, etc. Some case reports and our previous retrospective study showed that sirolimus was effective for refractory/relapse PRCA with good tolerance. However, due to the rare occurrence of PRCA and good response rate to CsA, there are very few studies of sirolimus on newly diagnosed PRCA so far. In this study, It is anticipated to evaluate the efficacy and safety of sirolimus versus CsA in patients with newly diagnosed PRCA . The side-effects will be documented and plasma concentration of sirolimus will be monitored. Furthermore, an interim analysis will be performed to assess the treatment efficacy and safety of sirolimus versus CsA in primary PRCA patients when a total of 56 eligible participants finished the designed treatment.

Official Title
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Sirolimus Treatment for Newly Diagnosed Primary Acquired Pure Red Cell Aplasia: a Single Center Prospective Study

Conditions
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Pure Red Cell Aplasia, Acquired

Intervention / Treatment
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* Drug: Sirolimus
* Drug: Cyclosporine A


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age >18 years old. hemoglobin (Hb) <90 g/L before treatment. no history of immunosuppression therapy prior to sirolimus or CsA treatment. adequate hepatic functions with alanine transaminase (ALT)/aspartate. transaminase (AST) levels within 3 times of the normal upper limit and total bilirubin levels within 2 times of the normal upper limit. documented patient consent. Exclusion Criteria: diagnosis of secondary aPRCA. history of treatment with immunosuppression therapy before enrollment. history of leukemia, stem cell transplantation, or treatment-related myelodysplastic syndromes (MDS). creatinine/transaminase ≥ 3 normal upper limit. complicated with active or uncontrolled infections or uncontrolled cardiovascular disease. presence of other diseases that may cause anemia. presence of malignancies. pregnant and lactating women.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 88 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sirolimus on newly diagnosed primary acquired PRCA<br>A prospective research of the sirolimus efficiency on newly diagnosed primary acquired PRCA patients. Sirolimus dosage: 2mg QD with plasma concentration 4-15ng/mL. Medication time should last at least 6 months | Drug: Sirolimus<br>* Sirolimus treats in experimental group<br>* Other names: Sirolimus Tablets;|
| Active Comparator: Cyclosporine A on newly diagnosed primary acquired PRCA<br>Cyclosporine A (CsA) efficiency on newly diagnosed primary acquired PRCA patients. CsA dosage: 4mg/kg QD. Medication time should last at least 6 months | Drug: Cyclosporine A<br>* Cyclosporine A uses for active comparator group.<br>* Other names: Cyclosporine A Tablets;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemoglobin level | Hemoglobin level in g/L | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemoglobin level | Hemoglobin level in g/L | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sirolimus, newly diagnosed pure red cell aplasia, prospective study