Positioning CD19-Directed Therapies in the Greater Follicular Lymphoma Treatment Landscape

The introduction of CD19 as a major therapeutic target has complicated the treatment landscape for follicular lymphoma, challenging the long-standing dominance of CD20-directed agents. The most powerful CD19-directed treatment currently available is CAR T-cell therapy, but its high efficacy must be weighed against its associated short- and long-term toxicities. This creates a sequencing dilemma in an often-indolent disease.

The optimal position for these therapies depends on the aggressiveness of the patient's disease trajectory. Patients with a favorable history—such as those who achieve sequential, multi-year remissions after initial chemoimmunotherapy and subsequent anti-CD20 treatment—are generally not ideal candidates for immediate CAR T-cell therapy. Conversely, patients who experience early progression immediately after initial treatment are prime candidates for the earliest possible use of CAR T-cells due to their high-risk biology.

A primary concern in sequencing is preserving the CD19 target, ensuring that prior CD19-directed therapies do not "burn the bridge" by causing antigen loss. This risk is highlighted by observations in other drug classes: while CD20 loss is rare after standard rituximab, it is seen more frequently after potent CD20-targeting bispecific antibodies. Clinicians must remain vigilant, performing repeat biopsies to confirm CD19 expression and closely following the emerging literature. It is expected that the risk of CD19-negative variants may vary significantly among different CD19-directed agents, necessitating a data-driven approach to sequencing.