Single-dose Anti-CD20 Antibody With Bortezomib for Relapsed Refractory Autoimmune Hemolytic Anemia

Autoimmune Hemolytic Anemia Clinical Trial

— RRAIHA01  

Official title:

An Open, One-arm, Prospective Study of a Single Dose Anti-CD20 Monoclonal Antibody Combined With Bortezomib for Treatment of Relapsed Refractory Autoimmune Hemolytic Anemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04083014
• Other study ID #: HS-2053
• Status: Completed
• Phase: Phase 2
• Start date: August 20, 2019
• Est. completion date: March 20, 2024

Study information

• Verified date: April 2024
• Source: Peking Union Medical College Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Patients of relapsed and refractory warm autoimmune hemolytic anemia or EVANS syndrome aged 18 to 80 will be included in this study. The treatment regimen is a single dose anti-CD20 antibody (500mg) combined with bortezomib (1.3mg/m2 twice a week for two weeks). The treatment course would be repeated three months later.

Description:

Glucocorticoids are the first-line treatment of warm AIHA. The overall response is 70-90%, but 10% to 20% patients are refractory to GCs and more than 50% patients will relapse after GCs tapering or cessation.

Anti-CD20 monoclonal antibody is the preferred second-line treatment for relapsed refractory wAIHA. Anti-CD20 antibody 375 mg/m2, once a week, four times, is the standard treatment regimen. Low dose anti-CD20 antibody, 100mg once a week, four times, also showed similar response rate. However, the use of four times of intravenous infusion is trouble. So the investigators intend to explore the efficiency of the singe dose of 500mg anti-CD20 antibody.

Anti-CD20 antibody takes median 6-8 weeks to response and only about 50% patients achieving long-term response. Plasma cells produce antibodies and long-lived plasma cells in bone marrow and spleen continuously work. Bortezomib is a proteasome inhibitor and targets plasma cells. Bortezomib has become a first-line treatment for clonal plasma cell diseases (such as multiple myeloma, systemic amyloidosis, POEMS syndrome, etc.). Bortezomib can also induce reactive plasma cell apoptosis and has a variety of immunomodulatory effects. The investigators try to combine bortezomib with anti-CD20 antibody, which may play a synergistic role and improve the efficacy.

Patients of relapsed and refractory warm autoimmune hemolytic anemia or EVANS syndrome will receive a single dose anti-CD20 antibody (500mg) and bortezomib (1.3mg/m2 twice a week for two weeks) twice for three months interval.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 33
• Est. completion date: March 20, 2024
• Est. primary completion date: March 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Diagnosis of warm autoimmune hemolytic anemia or EVANS syndrome, primary or secondary.

2. Patients refractory to glucocorticoids (HGB increase less than 20g/L after three weeks full dose glucocorticoids treatment). Or patients relapse after at least one course of glucocorticoids therapy (HGB < 110g/L in female and HGB < 120g/L in male). Or glucocorticoids dependence (prednisone maintenance dose > 10mg a day). Or glucocorticoids intolerance.

3. Normal heart function, liver function (total bilirubin < 1.5×ULN, ALT, AST < 3.0 ×ULN), and renal function (serum creatinine < 1.0 ×ULN).

4. No active infection.

5. No malignant tumors (except carcinoma in situ).

6. Patients understand the content of the study, participate the study and sign the informed consent voluntarily.

Exclusion Criteria:

1. Patients with malignant tumors (excluding carcinoma in situ);

2. With uncontrollable infections or other serious diseases;

3. Active hepatitis B, serume HBV-DNA > 104copies/ml;

4. Women during pregnancy or lactation;

5. Not strict contraception;

6. Psychiatric patients and those with severe mental illness.

7. Other conditions that researchers consider inappropriate to join the study.

Related Conditions & MeSH terms

• Anemia
• Anemia, Hemolytic
• Anemia, Hemolytic, Autoimmune
• Autoimmune Hemolytic Anemia
• Autoimmune Hemolytic Anemia and Autoimmune Thrombocytopenia
• Hemolysis
• Purpura, Thrombocytopenic, Idiopathic
• Thrombocytopenia

Intervention

Drug:
• combination of a single dose anti-CD20 antibody and bortezomib
Relapsed and refractory warm AIHA patients receive treatment of combination of a single dose anti-CD20 antibody and bortezomib twice during three months interval.

Locations

Country	Name	City	State
China	Peking Union Medical College Hospital	Beijing	Beijing

Sponsors (1)

Lead Sponsor	Collaborator
Peking Union Medical College Hospital

Country where clinical trial is conducted

China, 

References & Publications (13)

Berges C, Haberstock H, Fuchs D, Miltz M, Sadeghi M, Opelz G, Daniel V, Naujokat C. Proteasome inhibition suppresses essential immune functions of human CD4+ T cells. Immunology. 2008 Jun;124(2):234-46. doi: 10.1111/j.1365-2567.2007.02761.x. Epub 2008 Jan 23. — View Citation

Cao L, Koh LP, Linn YC. Successful treatment of refractory autoimmune hemolytic anemia after allogeneic hematopoietic stem cell transplantation with bortezomib. Leuk Lymphoma. 2018 Oct;59(10):2500-2502. doi: 10.1080/10428194.2017.1421759. Epub 2018 Jan 18. No abstract available. — View Citation

Danchaivijitr P, Yared J, Rapoport AP. Successful treatment of IgG and complement-mediated autoimmune hemolytic anemia with bortezomib and low-dose cyclophosphamide. Am J Hematol. 2011 Mar;86(3):331-2. doi: 10.1002/ajh.21950. Epub 2011 Jan 26. No abstract available. — View Citation

Goldberg AL, Cascio P, Saric T, Rock KL. The importance of the proteasome and subsequent proteolytic steps in the generation of antigenic peptides. Mol Immunol. 2002 Oct;39(3-4):147-64. doi: 10.1016/s0161-5890(02)00098-6. — View Citation

Group, Chinese Society of Hematology, Chinese Medical Association. [Chinese expert consensus on the diagnosis and treatment of autoimmune hemolytic anemia (2017) Red Blood Cell Disease (Anemia)]. Zhonghua Xue Ye Xue Za Zhi. 2017 Apr 14;38(4):265-267. doi: 10.3760/cma.j.issn.0253-2727.2017.04.001. No abstract available. Chinese. — View Citation

Hill A, Hill QA. Autoimmune hemolytic anemia. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):382-389. doi: 10.1182/asheducation-2018.1.382. — View Citation

Hosoba S, Jaye DL, Cohen C, Roback JD, Waller EK. Successful treatment of severe immune hemolytic anemia after allogeneic stem cell transplantation with bortezomib: report of a case and review of literature. Transfusion. 2015 Feb;55(2):259-64. doi: 10.1111/trf.12815. Epub 2014 Aug 25. — View Citation

Lechner K, Jager U. How I treat autoimmune hemolytic anemias in adults. Blood. 2010 Sep 16;116(11):1831-8. doi: 10.1182/blood-2010-03-259325. Epub 2010 Jun 14. — View Citation

Muhsen IN, Alahmari A, Alnahedh M, Alkhudair NA, Samarkandi H, El Fakih R. Bortezomib for immune thrombocytopenia and autoimmune hemolytic anemia. Hematol Oncol Stem Cell Ther. 2020 Dec;13(4):251-254. doi: 10.1016/j.hemonc.2019.05.006. Epub 2019 Jun 10. No abstract available. — View Citation

Palombella VJ, Rando OJ, Goldberg AL, Maniatis T. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell. 1994 Sep 9;78(5):773-85. doi: 10.1016/s0092-8674(94)90482-0. — View Citation

Perry DK, Burns JM, Pollinger HS, Amiot BP, Gloor JM, Gores GJ, Stegall MD. Proteasome inhibition causes apoptosis of normal human plasma cells preventing alloantibody production. Am J Transplant. 2009 Jan;9(1):201-9. doi: 10.1111/j.1600-6143.2008.02461.x. Epub 2008 Oct 31. — View Citation

Ratnasingam S, Walker PA, Tran H, Kaplan ZS, McFadyen JD, Tran H, Teh TC, Fleming S, Catalano JV, Chunilal SD, Johnston A, Opat SS, Shortt J. Bortezomib-based antibody depletion for refractory autoimmune hematological diseases. Blood Adv. 2016 Nov 22;1(1):31-35. doi: 10.1182/bloodadvances.2016001412. eCollection 2016 Nov 29. — View Citation

Reynaud Q, Durieu I, Dutertre M, Ledochowski S, Durupt S, Michallet AS, Vital-Durand D, Lega JC. Efficacy and safety of rituximab in auto-immune hemolytic anemia: A meta-analysis of 21 studies. Autoimmun Rev. 2015 Apr;14(4):304-13. doi: 10.1016/j.autrev.2014.11.014. Epub 2014 Dec 9. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	response time	days hemoglobin increasing more than 20g/L	two years
Primary	overall response	total of complete response and partial response	two years
Primary	complete response	rate of achieving complete response	two years
Primary	relapse rate	relapse rate of responders	two years
Secondary	relapse free survival	time duration of responders from first treatment to recurrence of decompensated hemolysis	two years
Secondary	overall survival	time from first treatment to death of any causes	two years
Secondary	side effects	side effects due to the combination of anti-CD20 antibody and bortezomib	two years