Orelabrutinib in the Treatment of Relapsed/Refractory AIHA

• wAIHA Treatment Regimen: Group A (50mg group): Orelabrutinib 50 mg, orally, once daily. After 4 weeks of treatment, if still transfusion-dependent or hemoglobin increase is < 20 g/L, the dose may be increased to 100 mg qd. Treatment can be discontinued if ineffective at 12 weeks.

Stable doses of glucocorticoids (e.g., prednisone ≤ 15 mg/day) are permitted, and their tapering process should be recorded.

Group B (100mg group): Orelabrutinib 100 mg, orally, once daily. The treatment course is at least 12 weeks. Treatment can be discontinued if ineffective at 12 weeks. Patients who respond and tolerate the drug well may continue treatment for up to 52 weeks or longer to observe long-term efficacy and safety.

Stable doses of glucocorticoids (e.g., prednisone ≤ 15 mg/day) are permitted, and their tapering process should be recorded.

• cAIHA Treatment Regimen: Group C (150mg group): Orelabrutinib 150 mg, orally, once daily. The treatment course is at least 12 weeks. Patients who respond and tolerate the drug well may continue treatment for up to 52 weeks or longer to observe long-term efficacy and safety.
• Red blood cell transfusion is permitted when hemoglobin (HGB) is below 60 g/L, or under necessary conditions. Platelet transfusion is permitted when platelet count is below 10×10^9^/L or with significant bleeding tendency. To ensure patient safety, in the above situations, intravenous immunoglobulin (IVIG) infusion for no more than 5 days or glucocorticoids at 1-2 mg/kg/day for no more than 2 weeks are allowed. Efficacy will not be assessed within 8 weeks of receiving IVIG or glucocorticoids. Recombinant human erythropoietin at 10,000-20,000 units/week is allowed.
• If the neutrophil count falls below 1.0×10^9^/L, G-CSF may be used until recovery to above 1.0×10^9^/L.
• Follow-up schedule: Every 1-2 weeks during the first month; at least monthly from the second month onwards; at least every 2 months from the fourth month onwards. Record patient symptoms, treatment-related adverse events, signs, transfusion requirements, direct antiglobulin test (DAT), complete blood count (including reticulocytes), biochemistry (liver and kidney function) to monitor efficacy and safety. At 12 weeks, 24 weeks, and 52 weeks, re-assess immunoglobulins, lymphocyte subset analysis, and cytokines to evaluate immune function status.

Inclusion criteria

• Age ≥ 18 years.
• Patients with a definitive diagnosis of AIHA. wAIHA or Evans syndrome, primary or secondary to connective tissue disease (CTD) or lymphoproliferative disorder (LPD). If secondary, CTD should have no indication for treatment for other system involvement, and LPD should be in an asymptomatic, observation phase without treatment indication.

cAIHA, primary or secondary to LPD. If secondary, LPD should be in an asymptomatic, observation phase without treatment indication.

• For wAIHA: No response (no partial response after 3 weeks) to full-dose glucocorticoid therapy (1-2 mg/kg/day), intolerance, or relapse (after initial response, hemoglobin drop ≥20 g/L or requiring re-initiation of immunosuppressive therapy). And hemoglobin ≤ 100 g/L.
• For cAIHA: No response or relapse after anti-CD20 monoclonal antibody therapy (after initial response, hemoglobin drop ≥20 g/L or recurrence of vascular symptoms, or requiring re-initiation of immunosuppressive therapy), or unsuitable for anti-CD20 therapy. And hemoglobin ≤ 100 g/L or presence of vascular symptoms.
• Baseline liver and kidney function (ALT, Cr) within 2 times the upper limit of normal (elevated AST, LDH, Bil due to hemolysis are not used as indicators for liver function assessment).
• Agreement to sign the informed consent form.

Exclusion criteria

• Active involvement of other major organs due to connective tissue disease.
• Uncontrolled infection or bleeding per standard treatment.
• Uncontrolled active HIV, HCV, or HBV infection per standard treatment.
• Concurrent advanced uncontrolled malignancy, lymphoma.
• Presence of other uncorrected types of anemia at screening, such as nutritional anemia, thalassemia, etc.
• Currently receiving glucocorticoid therapy at screening and unable to discontinue or taper to ≤ 15 mg/day (prednisone equivalent) within 1 week before enrollment.
• Currently receiving treatment with medications such as cyclosporine, tacrolimus, sirolimus, cyclophosphamide, azathioprine, stanozolol, testosterone undecanoate, danazol, etc., at screening, and the treatment duration at a stable dose is < 12 weeks, or unable to discontinue directly.
• Last dose of rituximab < 3 months prior to enrollment.
• Prior treatment with any BTK inhibitor.
• Liver cirrhosis or portal hypertension.
• Pregnant or breastfeeding women.
• Participation in another clinical trial within the past 3 months.