Sirolimus Treatment for Newly Diagnosed Primary Acquired PRCA

Pure Red Cell Aplasia, Acquired Clinical Trial

— PRCA  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04470804
• Other study ID #: PRCA-2
• Status: Completed
• Phase: Phase 4
• Start date: July 1, 2020
• Est. completion date: July 31, 2022

Study information

• Verified date: February 2023
• Source: Peking Union Medical College Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 56
• Est. completion date: July 31, 2022
• Est. primary completion date: July 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 88 Years

Eligibility

Inclusion Criteria:

1. age >18 years old.

2. hemoglobin (Hb) <90 g/L before treatment.

3. no history of immunosuppression therapy prior to sirolimus or CsA treatment.

4. 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.

5. documented patient consent.

Exclusion Criteria:

1. diagnosis of secondary aPRCA.

2. history of treatment with immunosuppression therapy before enrollment.

3. history of leukemia, stem cell transplantation, or treatment-related myelodysplastic syndromes (MDS).

4. creatinine/transaminase = 3 normal upper limit.

5. complicated with active or uncontrolled infections or uncontrolled cardiovascular disease.

6. presence of other diseases that may cause anemia.

7. presence of malignancies.

8. pregnant and lactating women.

Related Conditions & MeSH terms

• Pure Red Cell Aplasia, Acquired
• Red-Cell Aplasia, Pure

Intervention

Drug:
• Sirolimus
Sirolimus treats in experimental group
• Cyclosporine A
Cyclosporine A uses for active comparator group.

Locations

Country	Name	City	State
China	Peking Union Medical College Hospital	Beijing

Sponsors (1)

Lead Sponsor	Collaborator
Bing Han

Country where clinical trial is conducted

China, 

References & Publications (6)

Bride KL, Vincent T, Smith-Whitley K, Lambert MP, Bleesing JJ, Seif AE, Manno CS, Casper J, Grupp SA, Teachey DT. Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial. Blood. 2016 Jan 7;12 — View Citation

Chen Z, Liu X, Chen M, Yang C, Han B. Successful sirolimus treatment of patients with pure red cell aplasia complicated with renal insufficiency. Ann Hematol. 2020 Apr;99(4):737-741. doi: 10.1007/s00277-020-03946-2. Epub 2020 Feb 6. — View Citation

Li J, Wang Z, Dai L, Cao L, Su J, Zhu M, Yu Z, Bai X, Ruan C. Effects of rapamycin combined with low dose prednisone in patients with chronic immune thrombocytopenia. Clin Dev Immunol. 2013;2013:548085. doi: 10.1155/2013/548085. Epub 2013 Dec 2. — View Citation

Long Z, Yu F, Du Y, Li H, Chen M, Zhuang J, Han B. Successful treatment of refractory/relapsed acquired pure red cell aplasia with sirolimus. Ann Hematol. 2018 Nov;97(11):2047-2054. doi: 10.1007/s00277-018-3431-5. Epub 2018 Jul 7. — View Citation

Means RT Jr. Pure red cell aplasia. Blood. 2016 Nov 24;128(21):2504-2509. doi: 10.1182/blood-2016-05-717140. — View Citation

Teachey DT, Greiner R, Seif A, Attiyeh E, Bleesing J, Choi J, Manno C, Rappaport E, Schwabe D, Sheen C, Sullivan KE, Zhuang H, Wechsler DS, Grupp SA. Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative sy — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Overall response	complete response plus partial response	1 year
Other	Complete response	Hemoglobin >120 g/L in males or Hemoglobin >110 g/L in females, and lasting for at least 2 months	1 year
Primary	Hemoglobin level	Hemoglobin level in g/L	6 months
Secondary	Hemoglobin level	Hemoglobin level in g/L	2 years