Chimeric antigen receptor T-cell therapy may induce sustained remission in multirefractory autoimmune hemolytic anemia

1. In this prospective cohort study, CD19-directed chimeric antigen receptor (CAR) T-cell therapy was found to elicit a complete response in eleven patients with autoimmune hemolytic anemia who had previously failed at least three lines of therapy.

2. Treatment was associated with an acceptable safety profile, with adverse events including mild cytokine-release syndrome and mild to moderate infections. 

Evidence Rating Level: 2 (Good)

Study Rundown: Patients with autoimmune hemolytic anemia (AIHA) face a high risk of relapse, with those unresponsive to three or more therapies classified as having multirefractory disease. CD19-directed chimeric antigen receptor (CAR) T-cell therapy depletes B cells and thus may reduce autoreactive B-cell activity in AIHA. This prospective clinical trial examined the safety and efficacy of a single infusion of CD19 CAR T-cell therapy in treating adults with multirefractory AIHA. All eleven patients enrolled achieved a complete response to the treatment, defined as symptom resolution, improved anemia, and normalization of hemolysis markers, in a median time of under two months. Relapse occurred in two of the eleven patients over a median follow-up of over twelve months. The most commonly reported adverse events were mild to moderate infections, but others included mild cytokine release syndrome, one instance of immune effector cell-associated neurotoxicity syndrome, and one instance of immune effector cell-associated hematotoxicity. Strengths of the study were inclusion of patients with different subtypes of AIHA as well as the analysis of the cellular mechanisms of relapse that were observed. Some limitations were a small sample size and a relatively short follow-up duration. Overall, this study suggests that CD19 CAR T-cell therapy may be a relatively safe treatment to achieve rapid, prolonged remission in patients with multirefractory AIHA. 

Click to read the study in NEJM

Relevant Reading: BCMA-Targeted T-Cell Engager for Autoimmune Hemolytic Anemia after CD19 CAR T-Cell Therapy

In-Depth [prospective cohort]: This prospective cohort study aimed to study the safety and efficacy of CD19 CAR T-cell therapy in treatment of multirefractory AIHA. Patients with primary AIHA who were previously unresponsive to three or more previous therapies were enrolled from a compassionate-use program (n=5) and from a phase 1 study (n=6). Patients with lymphoproliferative disorders, secondary AIHA, or previous organ or stem-cell transplantation were excluded. Participants underwent monthly testing of flow cytometry, cell counts, and hemolysis markers for six months. Complete response was defined as a resolution of symptoms, hemoglobin level of 11 in women and 12 in men and normalization of hemolysis markers including lactate dehydrogenase and unconjugated bilirubin. Among this cohort, CAR T cells persisted for a median of 68 days (interquartile range [IQR], 39.5 to 128.8 days), and B cell aplasia persisted for 69 days (IQR, 51 to 90 days). All patients had complete response to the drug by a median of 45 days (range, 21 to 153 days). The median duration of drug-free remission was 11.5 months. There were a total of 67 adverse events among the 11 participants, including grade 3 infections, immune effector cell-associated hematotoxicity (ICAH), mild cytokine release syndrome, and grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS). There were no severe cases of neutropenia or leukopenia, nor any increase in mutation burden in marrow T cells. Two patients did relapse 7 to 8 months after the infusion, but further targeted therapy then induced a complete response in both patients. Altogether, these results suggest that CD19 CAR T-cell therapy may be an effective therapy for patients with multirefractory AIHA. 

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