Follicular lymphoma research: an open dialogue for a collaborative roadmap

Abstract

Follicular lymphoma (FL) is the second most common type of lymphoma (20% of all non-Hodgkin lymphomas), derived from germinal centre (GC) B cells, and is characterised by its significant clinical, prognostic and biological heterogeneity, leading to complexity in management. Despite significant biological investigation and indisputable clinical progress since the advent of the immunotherapy era more than 20 years ago, much remains to be done to understand and cure this lymphoma. Today, FL is metaphorically a giant puzzle on the table with patches of sky, landscape and foliage clearly appearing. However, many of the remaining pieces are held by various stakeholders (e.g. clinicians, pathologists, researchers, drug developers) without global agreement on what the gaps are, or any clear blueprint on how to solve the puzzle of understanding the heterogeneity of this disease and create curative and tailored therapies. With the advent of new investigation and drug technologies, together with recent advances in our capacity to manage big data, the time seems ripe for a change of scale. More than ever, this will require collaboration between and within all stakeholders to overcome the current bottlenecks in the field. As for every investigator, we acknowledge that this first draft is necessarily biased, incomplete and some FL expert readers might recognise some remaining gaps not addressed. We hope they will reply to make this effort a collaborative one to assemble all the pieces in the most ideal fashion. As such, this review intends to be a first step and an interactive platform to a collaborative roadmap towards better understanding and care of FL.

Figure 1

A model of FL oncogenesis: t(14;18) is occurring during pro‐B cell development in the bone marrow and leads to ectopic BCL2 expression without preventing further B cell maturation. Upon cognate antigen stimulation, peripheral naïve BCL2+ cells are preferentially activated by TFH and GCs. There, ectopic BCL2 expression uncouples GC check‐point selection from affinity maturation, leading to clonal expansion, differentiation and exit of BCL2+ memory‐like B cells with heterogeneous, unselected, low‐affinity and potentially polyreactive BCR. The propensity of such large pools of BCL2+ clones to disseminate in blood, niche in SLO and iteratively visit GC can be assumed as the second (immunological) hit, heading to the accumulation of mutations. Although most will be passengers, some will directly and recurrently impact further steps of oncogenesis either through providing competitive advantage (e.g. proliferation) or resistance to the host immunity and/or to therapy (e.g. quiescence). FL, follicular lymphoma; BCL, B cell lymphoma, TFH, T follicular helper cell; BCR, B cell receptor; GC, germinal centres; SLO, secondary lymphoid organs.