CD19-negative relapse after CAR-T cell therapy: mechanisms of antigen escape and lineage switch.

CD19 chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of relapsed/refractory B-cell malignancies, achieving high remission rates. Nonetheless, 20%-40% of patients eventually relapse, classified as either CD19 or CD19 relapse. Most relapses are CD19, largely due to reduced potency and poor persistence of CAR-T cells after infusion. In contrast, a substantial fraction of patients develops CD19 relapse driven by selective pressure from CAR-T cell therapy. Post-CAR-T cell CD19 relapse primarily arises through three mechanisms. First, pre-existing CD19 subclones, particularly those with progenitor-like features, expand because of their survival advantages. Second, CD19 expression is downregulated through pre-existing or newly acquired genetic alterations (mutations and abnormal splicing), epigenetic silencing, and post-transcriptional dysregulation. Third, lineage switching to a myeloid phenotype increases notably after CAR-T cell treatment. This myeloid conversion is frequently associated with KMT2A rearrangements and is driven by epigenetic reprogramming, impaired expression of B-cell regulators, and the presence of bipotent progenitors within leukemia or lymphoma. CD19 relapse constitutes a major clinical barrier to the durable efficacy of CD19-CAR T-cell therapy. Understanding these diverse escape mechanisms is crucial for developing preventive strategies and effective salvage therapies to maintain long-term remission. To mitigate CD19 relapse, a coordinated dual strategy is needed. First, novel therapeutic approaches should be developed, including CAR products targeting alternative antigens, optimized salvage regimens, and CD19 re-induction strategies. Second, high-resolution molecular profiling should be used to identify high-risk patients and guide pre-emptive or combinatorial interventions based on the molecular underpinnings of CD19 relapse. Together, these approaches will deepen mechanistic insight into CD19 relapse and enable targeted prevention and management of this key limitation of CAR T-cell therapy.