Drug development in MZL: caring for the forgotten child Open Access

Marginal zone lymphoma (MZL) encompasses biologically heterogenous group of indolent B-cell lymphomas that remains substantially underrepresented in clinical research. Despite recent and significant therapeutic advancess in B-cell malignancies, trial design in MZL continues to face persistent challenges including diagnostic heterogeneity, inconsistent control arms, suboptimal endpoints, and economic barriers. In this narrative review, we examine these key obstacles and discuss emerging strategies to overcome them, such as the standardization of diagnostic criteria, implementation of subtype-specific treatment approaches, validation of surrogate endpoints, and integration of novel response assessment modalities such as metabolic imaging (positron emission tomography), minimal residual disease assessment in flow cytometry or single cell molecular evaluation, and circulating tumor DNA measurement, but need to be evaluated and harmonized for full appreciation We contend that MZL should be understood as a methodological paradigm, rather than as a clinical exception. This may facilitate the refinement of trial design and ultimately accelerate therapeutic innovation across the broad spectrum of indolent lymphomas.