Marginal zone lymphoma (MZL) is often an afterthought in the practice and research of lymphoma. It feels rare; in many cases it feels straightforward to treat, and in other cases it feels like follicular lymphoma (FL) and approachable as such. But it is not really any of those. In terms of frequency, it ranks as the third most common B-cell non-Hodgkin lymphoma in the United States (excluding chronic lymphocytic leukemia).1 Although first-line treatment of all MZL subtypes can most often successfully palliate the disease for several years (or even cure it in the case of limited-stage disease, especially extranodal MZL), little beyond this is so simple. The biology of MZL is still poorly understood, including its etiopathologic relationship with chronic antigen stimulation, the basis for its distinctive manifestations (extranodal, splenic, nodal, pediatric nodal and primary cutaneous), and the mechanisms of histologic transformation. To date, no therapy for MZL has truly been developed on the basis of our biologic understanding of the disease. Furthermore, the clinical trials that have enrolled patients with MZL were mostly designed and powered for FL, and there is a dearth of phase 3 studies dedicated specifically to MZL (only one published to date2). And although treatments, such as chemoimmunotherapy, Bruton tyrosine kinase inhibitors, lenalidomide, chimeric antigen T-cells, and bispecific antibodies, all have activity, there are only a few US Food and Drug Administration approvals in MZL, and the only full approval, lenalidomide, was based on a phase 3 trial that in fact showed no benefit among patients with MZL.3
Fortunately, in recent years, there have been more dedicated scientific studies and clinical trials. In support of this shift, we invite our readers to this review series dedicated to MZL with the following articles:
Camille Laurent and Francesco Bertoni, “The biology of marginal zone lymphoma subtypes: challenge and relevance of classification”: The authors review recent biologic insights in MZL with a specific focus on the differences between the various MZL subtypes. Such knowledge will be essential to designing optimal therapeutic strategies, not just for MZL generally, but for its biologically distinct subtypes.
Juan Pablo Alderuccio and Ariela Noy, “The treatment of marginal zone lymphoma”: The authors review the treatment approach to MZL and highlight some of the nuances that clinicians should consider in treatment selection and the numerous gaps that clinical research still has to fill. They further demonstrate that MZL should not routinely be treated like FL. Indeed, if we continue to pursue MZL research and administer MZL treatment based on what we know of FL at a time when we have the capacity and the collaborative networks to pursue MZL-specific research, we will be doing a disservice to our patients. The ability to cover this topic in a single review, as the authors elegantly do, is, in itself, a testimony to the need for additional dedicated research in this disease.
Catherine Thieblemont, Sylvain Carras, and Côme Bommier, “Drug development in MZL: caring for the forgotten child”: In this review, the authors point out many of the challenges inherent in the conduct of MZL-specific clinical trials and outline a creative and realistic path toward this goal. In the meantime, the list of ongoing international studies dedicated to MZL, which the authors provide, should at least fuel optimism for the future of MZL treatment.
We hope that these reviews provide our readers with a concise and up-to-date understanding of the current state of the scientific and clinical knowledge in MZL and confirm for them that MZL is not FL and that it should not be an afterthought anymore. Instead, it is a diverse, fascinating, and, occasionally, very challenging disease to treat with much more to learn and much work ahead.
Conflict-of-interest disclosure: P.A. reports serving as a consultant for Merck, Bristol Myers Squibb (BMS)/Celgene, GenMab, Enterome, Genentech/Roche, ATB Therapeutics, Regeneron, Pfizer, and Lilly Loxo; receiving research funding from Kite; and receiving institutional funding from Merck, BMS/Celgene, Adaptive, Genentech, IGM, AstraZeneca, and Lilly Loxo.
