A groundbreaking prospective phase II trial has demonstrated that CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy can achieve complete remission in all patients with relapsed CD19-positive t(8;21) acute myeloid leukemia (AML), though durability remains a significant challenge. The study, conducted at the First Affiliated Hospital of Soochow University, represents the largest cohort evaluation of this therapeutic approach in this molecularly defined AML subgroup.
Universal Response with Limited Durability
The single-center trial enrolled 10 patients with relapsed t(8;21) AML between October 2017 and December 2023. All patients achieved complete remission following CD19 CAR-T cell infusion, with 60% attaining molecularly measurable residual disease (MRD)-negative complete remission. The RUNX1::RUNX1T1 fusion transcript levels demonstrated a median 2.5-log reduction (range: 0.7–4.5 log; P = 0.002).
However, the clinical benefit proved short-lived. The median leukemia-free survival was only 3.8 months, with a median overall survival of 11.6 months. The 12-month cumulative incidence of relapse reached 53.3%, highlighting the transient nature of the therapeutic response.
Patient Characteristics and Treatment Protocol
The study cohort comprised eight males and two females with a median age of 31 years. Eight patients had hematologic relapse while two had molecular relapse. The median bone marrow blast percentage was 12.4% (0.1–50.2%), with blasts exhibiting a median CD19 positivity of 55.7% (22.6–97.1%).
Genetic profiling revealed additional mutations including KIT mutations in three patients, ASXL1 mutations in four patients, and single cases of TP53 alterations, FLT3-ITD, and NRAS mutations. Following lymphodepletion with fludarabine and cyclophosphamide, patients received 5–20 × 10⁶ CAR-T cells per kilogram.
Safety Profile and Toxicity Management
The therapy demonstrated a manageable safety profile. All patients experienced grade 3 or higher hematologic toxicities following tumor-reduction chemotherapy and lymphodepletion, which resolved within a median of two weeks after CAR-T treatment. The median time to neutrophil recovery was 12 days, with platelet transfusion independence achieved at a median of 14 days.
Cytokine release syndrome (CRS) occurred in nine patients (90%), with most cases being mild to moderate (grades 1-2 in eight patients, grade 3 in one patient). The single grade 3 CRS case was successfully managed with steroid intervention and supportive care. Notably, no cases of immune effector cell-associated neurotoxicity syndrome were observed.
Consolidation Strategies and Outcomes
Post-CAR-T consolidation varied among patients. Three patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), two received decitabine-based maintenance regimens, and five declined further consolidation treatment. Among the allo-HSCT recipients, one patient died from grade IV acute graft-versus-host disease, one succumbed to relapse despite having TP53 alterations, and one remained alive in remission with decitabine maintenance.
Seven patients experienced relapse at a median time of 3.4 months post-CAR-T therapy, with five cases showing CD19-negative relapse and one maintaining CD19-positive disease. By the final follow-up, three patients remained alive.
Clinical Implications for t(8;21) AML
The findings address a critical unmet need in t(8;21) AML management. Despite initial favorable responses to standard chemotherapy, approximately 35% of patients experience relapse or persistent MRD positivity, resulting in a dismal 5-year overall survival rate of ≤20%. The aberrant CD19 expression observed in 78.3% of t(8;21) AML cases provides a unique therapeutic target distinct from traditional AML antigens like CD33 and CD123, which are also expressed on normal hematopoietic stem cells.
The study builds upon earlier proof-of-concept reports, including initial cases from the same research group and validation by Israeli investigators. The current trial represents the first comprehensive evaluation of CD19 CAR-T therapy specifically in t(8;21) AML with extended follow-up data.
Future Directions and Treatment Optimization
The researchers emphasize that while CD19 CAR-T therapy demonstrates clear efficacy in inducing remission, the short duration of response necessitates immediate consolidation strategies. The data suggest that sequential allo-HSCT or maintenance treatment may help consolidate CAR-T-induced remission, though larger multi-center trials are needed to optimize these approaches.
The predominance of CD19-negative relapses (71.4% of relapsed cases) indicates that alternative resistance mechanisms may emerge, potentially requiring combination approaches or sequential targeting of multiple antigens. The study authors advocate for larger sample sizes and collaborative multi-center trials to refine treatment strategies and improve long-term outcomes in this challenging patient population.
