Autoimmune hemolytic anemia (AIHA) has a relatively high incidence (1.8–3.0 per 100,000 person-years) and prevalence (17 per 100,000), with a substantial proportion of patients experiencing refractory or relapsed disease. Nearly 50% of patients relapse multiple times despite receiving first-line glucocorticoids, second-line CD20 monoclonal antibodies, and multiple conventional immunosuppressants, often becoming dependent on long-term drug therapy. As a result, patients with this otherwise benign disease frequently face a poor quality of life, complicated by thrombotic events, severe infections, and avascular necrosis of the femoral head, with disability or death occurring in 10–30% of cases. There is an urgent clinical need for innovative therapies capable of achieving durable, drug-free remissions.In recent years, CD19 CAR T-cell therapy has demonstrated remarkable efficacy in various autoimmune diseases, offering deep B-cell depletion and rapid, sustained, long-term remissions in patients refractory to conventional therapies . In a cohort of 11 patients with heavily pretreated refractory AIHA, autologous CD19 CAR T-cell therapy achieved rapid responses in all cases, with 9 patients maintaining durable remission. However, 2 patients relapsed after 7–8 months of remission, facing significant risks upon relapse. Currently, there are no established salvage strategies for autoimmune disease patients who relapse after CD19 CAR T-cell therapy, making such cases particularly challenging to manage.
On June 11, 2025, Dr. Jun Shi’s team from the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences, published their latest research in The New England Journal of Medicine (Impact Factor 96.3) under the title “BCMA-Targeted T-Cell Engager for Autoimmune Hemolytic Anemia after CD19 CAR T-Cell Therapy” [4]. This study is the first to report successful salvage treatment using a BCMA-targeted bispecific T-cell engager in two AIHA patients who relapsed after autologous CD19 CAR T-cell therapy.
The two reported cases involved patients who had failed multiple lines of immunosuppressive therapy. The first patient was a 10-year-old girl with a 9-year history of Evans syndrome who achieved remission 14 days after autologous CD19 CAR T-cell therapy, maintaining drug-free remission for 6.8 months. The second patient was a 22-year-old woman with a 12-year history of AIHA who achieved remission 10 days after CD19 CAR T-cell therapy and remained in remission for 8.1 months before relapsing.
Based on the hypothesis that both autoreactive B cells and plasma cells contribute to autoantibody production, relapse after CD19 CAR T-cell therapy may be related to the persistence of long-lived autoreactive plasma cells. Further testing confirmed elevated proportions of BCMA-positive plasma cells at relapse in both patients. Therefore, the researchers administered a novel BCMA-targeted bispecific T-cell engager, CM336.
Following CM336 treatment, both patients showed marked improvements in hemolysis:
- The first patient achieved partial remission by day 13 and normalization of hemoglobin by day 17.
- The second patient reached partial remission by day 19 and complete remission by day 21, without requiring any additional medications during treatment.
Both patients demonstrated sustained decreases in hemolysis markers (reticulocyte percentage, lactate dehydrogenase, and indirect bilirubin) and remained in drug-free remission throughout six months of follow-up. Adverse events were limited to grade 1 skin induration and hypogammaglobulinemia, with no other serious adverse events observed.
This study marks the first successful application of BCMA-targeted bispecific T-cell engager therapy in patients with AIHA relapsing after CD19 CAR T-cell treatment. The findings suggest that BCMA-directed therapies may serve as an effective salvage strategy for autoimmune disease patients who relapse after CD19 CAR T-cell therapy and open new avenues for clinical research in AIHA patients who have failed second-line immunosuppressive treatments.
References:
1. Michel M, Crickx E, Fattizzo B, Barcellini W. Autoimmune haemolytic anaemias. Nat Rev Dis Primers 2024;10:82.
2. Schett G, Müller F, Taubmann J, et al. Advancements and challenges in CAR T cell therapy in autoimmune diseases. Nat Rev Rheumatol 2024;20:531-44.
3. Müller F, Taubmann J, Bucci L, et al. CD19 CAR T-Cell Therapy in Autoimmune Disease – A Case Series with Follow-up. N Engl J Med 2024;390:687-700.
4.Lele Z, Zhen G, Hong P, et al. BCMA-Targeted T-Cell Engager for Autoimmune Hemolytic Anemia after CD19 CAR T-Cell Therapy. N Engl J Med 392;22, June 12, 2025.
