Chemotherapy‐Sparing Strategies in Follicular Lymphoma: Emerging Targeted and Immune‐Based Approaches

ABSTRACT Follicular lymphoma (FL), traditionally considered an indolent yet incurable malignancy, is experiencing a substantial evolution in its therapeutic landscape with the emergence of chemo‐free treatment strategies. These novel approaches challenge conventional chemotherapy‐based paradigms and offer promising alternatives for both newly diagnosed and relapsed/refractory (RR) FL patients. Among these innovations, bispecific antibodies (BsAbs) have demonstrated compelling efficacy while providing practical advantages, including outpatient administration and generally manageable safety profiles. Chimeric antigen receptor (CAR) T‐cell therapies have further expanded the therapeutic armamentarium, achieving unprecedented response rates in heavily pretreated and high‐risk populations, although their implementation remains limited by logistical complexity and high associated costs. Additional targeted agents—such as Enhancer of zeste homolog 2 (EZH2) inhibitors, lenalidomide, and Bruton tyrosine kinase (BTK) inhibitors—also contribute meaningfully to chemo‐free treatment options, particularly within combination regimens that may enhance clinical benefit. Despite these advances, several challenges persist. Early disease progression (POD24) remains one of the most powerful prognostic determinants in FL. The FLIPI‐C model, incorporating machine‐learning–derived risk stratification, has shown promise in identifying high‐risk patients who may benefit most from innovative approaches. Introducing chemo‐free therapies earlier in the treatment algorithm may improve outcomes for these patients while mitigating the long‐term toxicities associated with conventional chemotherapy. Ongoing validation through prospective clinical trials and real‐world evidence will be essential to define the optimal integration of these therapies. Overall, this evolving paradigm highlights the urgent need for continued innovation, multidisciplinary collaboration, and equitable access to ensure that the full potential of chemo‐free strategies can be realized for patients with this complex disease.