Zanubrutinib in the Treatment of Relapsed/Refractory wAIHA

Sponsor

Chen Miao (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05922839

Collaborator

(none)

Enrollment

Location

Arm

Anticipated Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Autoimmune hemolytic anemia (AIHA) is a rare and heterogeneous disorder characterized by the destruction of red blood cells through warm or cold antibodies. Glucocorticoid (combined with rituximab) is the first-line treatment.

However, the recurrence rate is very high and some patients may not respond to steroids. Second-line therapies include cyclosporine A (CsA), cyclophosphamide, rituximab, azathioprine, and even splenectomy.

Bruton's tyrosine kinase (BTK) plays a crucial role in the signaling pathway of B-cell receptor (BCR), and has been found to be a major source of pathogenic signal transduction for various lymphoproliferative malignancies. The activity of BTK is related to the occurrence and progression of various B-cell lymphomas. Currently, BTK inhibitors are widely used in the treatment of B-cell lymphomas, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WM), and other B-cell lymphomas, showing significant efficacy. BTK affects the production of messenger molecules and regulates the BCR signaling pathway, causing B cells to transform into self-reactive B cells, which can trigger autoimmune diseases. Current research has shown that BTK activity increases in several autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) . Therefore, BTK inhibitors (BTKi) are important for the treatment of autoimmune diseases.

Ibrutinib, one kind of BTKi, has been proven to treat secondary autoimmune hemolytic anemia (AIHA) in CLL and control CLL progression, and is an effective drug for treating lymphoma-associated AIHA . One kind of second-generation selective BTKi, acalabrutinib, can also reduce the incidence of AIHA in relapsed or refractory CLL patients. Currently, phase-II clinical studies exploring the treatment of AIHA using Ibrutinib, acalabrutinib, and rilzabrutinib, another BTKi, are underway.

Zanubrutinib (BGB-3111, Brukinsa®, BeiGene) is a second-generation irreversible BTKi developed by Chinese company BeiGene. Compared to Ibrutinib, zanubrutinib has shown stronger effective activity and higher selectivity towards BTK, and weaker effects on other targets such as TEC, EGFR, and Src families, with low off-target side effects. Its efficacy, durability, oral absorption, and targeting are better than those of Ibrutinib. Zanubrutinib is approved for the treatment of various B-cell lymphomas, and clinical trials have shown excellent efficacy and tolerability in CLL and WM patients. In previously treated CLL patients, zanubrutinib exhibits better efficacy and safety than Ibrutinib. Currently, phase II clinical studies of zanubrutinib in ITP, antiphospholipid syndrome, IgG4-related immune diseases, and active proliferative lupus nephritis are underway. The therapeutic effect of zanubrutinib on refractory warm autoimmune hemolytic anemia, is worth exploring through exploratory research.

Condition or Disease	Intervention/Treatment	Phase
Warm Autoimmune Hemolytic Anemia	Drug: Zanubrutinib	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

22 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Zanubrutinib in Relapsed or Refractory Warm Autoimmune Hemolytic Anemia: a Prospective Cohort Study

Anticipated Study Start Date :

Jun 1, 2023

Anticipated Primary Completion Date :

Dec 1, 2024

Anticipated Study Completion Date :

Dec 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Zanubrutinib in the Treatment of Relapsed/Refractory wAIHA Zanubrutinib 160mg, orally, twice daily, for a minimum of 3 months For effective patients, continue to use for 2 years after achieving optimal therapeutic effect.	Drug: Zanubrutinib Zanubrutinib 160mg, orally, twice daily, for a minimum of 3 months, and for effective patients, continue to use for 2 years after achieving optimal therapeutic effect.

Arm

Intervention/Treatment

Experimental: Zanubrutinib in the Treatment of Relapsed/Refractory wAIHA

Zanubrutinib 160mg, orally, twice daily, for a minimum of 3 months For effective patients, continue to use for 2 years after achieving optimal therapeutic effect.

Drug: Zanubrutinib

Zanubrutinib 160mg, orally, twice daily, for a minimum of 3 months, and for effective patients, continue to use for 2 years after achieving optimal therapeutic effect.

Outcome Measures

Primary Outcome Measures

Overall response rate (ORR) [3/6 months]
ORR defined as the proportion of patients who met the criteria of either complete response (CR) or partial response (PR)
Complete response rate (CRR) [3/6 months]
CRR defined as the proportion of patients who met the criteria of complete response.

Secondary Outcome Measures

Relapse rate [3/6 months]
Relapse rate defined as the proportion of patients whose response shift from PR or CR to no response (NR).
Adverse events [3/6 months]
Safety analyses include assessments of the incidence and severity of adverse events; all adverse events that occurred or worsened during the treatment period will be reported, as well as adverse events that occurred later but are considered by the investigator to be related to the trial drug.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 90 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age ≥18 years.
Confirmed diagnosis of wAIHA or Evans syndrome, primary or secondary to connective tissue disease. If it is secondary, there are no other treatment indications for systemic involvement of primary connective tissue disease.
No response or relapse after glucocorticoid treatment.
Baseline liver and kidney function (ALT, AST, Cr) is less than 2 times the normal range.
Consent to sign the informed consent form.

Exclusion Criteria:

Other important organ involvement in connective tissue disease.
Uncontrolled infection or bleeding with standard treatment.
Active HIV, HCV or HBV infection uncontrolled with standard treatment.
Concurrent uncontrolled advanced malignant tumors or lymphoma.
The subject is receiving any of the following drugs and has not met the following conditions of stable drug treatment duration at a fixed dose during screening: corticosteroids for at least 4 weeks; iron, vitamin B12 or folic acid for at least 4 weeks;
Liver cirrhosis or portal hypertension.
Pregnant or lactating women.
Participation in other clinical trials within the last 3 months.