Orelabrutinib in the Treatment of Relapsed/Refractory AIHA

Official title

Orelabrutinib in the Treatment of Relapsed/Refractory Autoimmune Hemolytic Anemia: A Prospective, Dose-Escalation Cohort Study

Overview

1. 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. 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. 2. 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.

Detailed description

1. 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. 2. 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. 3. 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. 4. 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. 5. 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.

Interventions

• Drug Orelabrutinib-50
  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.
• Drug Orelabrutinib-100
  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.
• Drug Orelabrutinib-150
  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.

Primary outcome measures

• ORR [Time frame: 12weeks]

Secondary outcome measures (1)

• The incidence of adverse events [Time frame: 12weeks]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Peking Union Medical College Hospital — Beijing

Publications

• Yan S, Zhou H, Huang R, Wang F, Mei H, Lin L, Guo J, Zhou X, Li Z, Liu Y, Li S, Zhou W, Hou Y, Hou M. A phase 2 trial of orelabrutinib showing promising efficacy and safety in patients with persistent or chronic primary immune thrombocytopenia. Am J Hematol. 2024 Jul;99(7):1392-1395. doi: 10.1002/ajh.27303. Epub 2024 Mar 28. No abstract available. PMID 38546375
• Yu TS, Han SQ, Wang LJ, Wang HY, Ni XF, Wang RT, Li GS, Hou Y, Peng J, Yan ZY, Zhao YJ, Hou M, Liu XG. Effects of orelabrutinib, a BTK inhibitor, on antibody-mediated platelet destruction in primary immune thrombocytopenia. Br J Haematol. 2025 Apr;206(4):1186-1199. doi: 10.1111/bjh.20045. Epub 2025 Mar 11. PMID 40069128
• Robak E, Robak T. Bruton's Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives. J Clin Med. 2022 May 16;11(10):2807. doi: 10.3390/jcm11102807. PMID 35628931
• Byrd JC, Wierda WG, Schuh A, Devereux S, Chaves JM, Brown JR, Hillmen P, Martin P, Awan FT, Stephens DM, Ghia P, Barrientos J, Pagel JM, Woyach JA, Burke K, Covey T, Gulrajani M, Hamdy A, Izumi R, Frigault MM, Patel P, Rothbaum W, Wang MH, O'Brien S, Furman RR. Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 results. Blood. 2020 Apr 9;13 PMID 31876911
• Galinier A, Delwail V, Puyade M. Ibrutinib Is Effective in the Treatment of Autoimmune Haemolytic Anaemia in Mantle Cell Lymphoma. Case Rep Oncol. 2017 Jan 27;10(1):127-129. doi: 10.1159/000456002. eCollection 2017 Jan-Apr. PMID 28203175
• Manda S, Dunbar N, Marx-Wood CR, Danilov AV. Ibrutinib is an effective treatment of autoimmune haemolytic anaemia in chronic lymphocytic leukaemia. Br J Haematol. 2015 Sep;170(5):734-6. doi: 10.1111/bjh.13328. Epub 2015 Feb 25. No abstract available. PMID 25716177
• Rogers KA, Ruppert AS, Bingman A, Andritsos LA, Awan FT, Blum KA, Flynn JM, Jaglowski SM, Lozanski G, Maddocks KJ, Byrd JC, Woyach JA, Jones JA. Incidence and description of autoimmune cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia. Leukemia. 2016 Feb;30(2):346-50. doi: 10.1038/leu.2015.273. Epub 2015 Oct 7. PMID 26442611
• Montillo M, O'Brien S, Tedeschi A, Byrd JC, Dearden C, Gill D, Brown JR, Barrientos JC, Mulligan SP, Furman RR, Cymbalista F, Plascencia C, Chang S, Hsu E, James DF, Hillmen P. Ibrutinib in previously treated chronic lymphocytic leukemia patients with autoimmune cytopenias in the RESONATE study. Blood Cancer J. 2017 Feb 3;7(2):e524. doi: 10.1038/bcj.2017.5. No abstract available. PMID 28157216

Identifiers

NCT: NCT07453368 · Orelabrutinib-AIHA

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗