Page 13 - 2022_01-Haematologica-web

Introduction to series on indolent lymphomas
described by Qualls and Salles,3 in whom relapse is nei- ther early nor yet refractory. The challenge here is that we have a myriad of options ranging from anti-CD20 anti- bodies alone, chemo-immunotherapy, immunomodula- tory agents, phosphoinositide-3 kinase inhibitors, an EZH2 inhibitor, transplantation and even cellular therapy. We have no data on sequencing, minimal comparative data, and no inclusion of precision approaches with the exception of better outcomes for patients with EZH2- mutated FL treated with tazemetostat (as compared to patients without the EZH2 mutation). As the authors saliently note, this plethora of agents in the second line and beyond is largely marked by phase II data, gained from studies with heterogeneous inclusion criteria, and no indication on whether one treatment might preclude the use of another later on. Furthermore, although Haematologica has an international readership, it is impor- tant to acknowledge that many of the options presented will not be available to patients in the majority of the world and, even within wealthy nations, not all patients will have equal access. Qualls and Salles also highlight that newer options should not mean that the old ones have no place; as discussed in their review, radiotherapy and/or chemotherapy in the relapsed/refractory setting, while not typically preferred when alternatives are avail- able, is valuable. An additional challenge is that many of these treatment options were designed for indefinite treatment and there is no guidance on when it is appro- priate to stop treatment or consider a treatment holiday.
Extending this dilemma of an expanding toolbox with- out data on how to best sequence or select a specific treatment is the challenge presented by cellular therapy, or chimeric antigen receptor T-cell therapy (CAR-T). This exciting modality engineers autologous T cells to recog- nize CD19 on tumor cells with subsequent T-cell activa- tion, expansion, and tumor eradication. The attendant toxicities include cytokine release syndrome and neuro- toxicity, and the “financial toxicity” is considerable. Nevertheless, CAR-T has dramatically changed the algo- rithm for aggressive lymphomas and offers the potential for durable remission and possibly cure; its precise role in indolent lymphomas is unknown, but CAR-T with axi- cabtagene ciloleucel is now approved for FL. As discussed by Qualls and Salles, in the ZUMA-5 trial the response rate to CAR-T was 94% (with a complete response rate of 80%) in heavily pretreated FL patients although the follow up is still less than 2 years. A careful review of the inclusion criteria in both the ZUMA-5 and ELARA trials shows that many patients had early progression, double refractory disease, refractory disease to the most recent treatment, and a high baseline FLIPI score.5,6 Clinicians will be asking, when should a patient with indolent lym- phoma be referred for this therapy? To date, there is no consensus on this topic, but following the inclusion crite- ria of the published studies is reasonable.
An important aspect to furthering precision medicine in indolent lymphomas is understanding the biology and pathogenesis of the diseases, with an aim of identifying therapeutic vulnerabilities. FL is a complex and biological- ly heterogeneous disease, but recent insights provide valuable opportunities with several emerging themes.7-9 First, the t(14;18) rearrangement, long known as a hall- mark lesion, is insufficient for FL and is present in a sig- nificant portion of the normal population. Second, FL pro- gression occurs via divergent evolution from a common
progenitor cell. This critical observation may underlie the inability of our current tools to eradicate (or cure!) the dis- ease. A reservoir population of common progenitor cells may account for the eventual resurgence of disease, even when there is clinical evidence of a complete remission. Third, sequencing of large databases of FL patients has identified epigenetic deregulation as a consistent and early event, with mutations involving KMT2D, CREBBP, H1 histones, EZH2, and EP300 collectively occurring in the majority of patients. Finally, FL biology and clinical behavior appear heavily reliant on the tumor microenvi- ronment and immune composition. While these areas of FL biology under scrutiny are listed here, there are clearly other areas in active development, and the field is in an exciting phase as we contemplate the next generation of therapies.
Marginal zone lymphoma
The third paper in this series focuses on marginal zone lymphomas (MZL), a complex and heterogeneous group of diseases. MZL is a paradigmatic disease to study the role of antigenic stimuli, inflammation, and immune “irritation” leading to the development of cancer; the prototypic antigen-driven lymphoma is Helicobacter pylori-associatedextranodalMZLofgastriclymphoidtis- sue. As described in the article by Cheah and colleagues,4 the three main clinicopathological entities have both common and distinct features. For example, deregulation of epigenetic pathways and NOTCH2 signaling are seen across multiple MZL subsets, while mutations such as PTPRD are restricted to nodal MZL.10 The treatment for MZL remains largely based on the site of clinical involve- ment, and is often influenced by issues of local control. A major gap in MZL is the relative paucity of disease-spe- cific therapeutic trials; most treatment data for dissemi- nated disease are derived from trials of FL patients. However, as many trials suggest, MZL is biologically dis- tinct and often has disparate outcomes compared to FL; this argues for disease-specific trials and not simply lumping MZL into other trials of indolent lymphomas. An example of this observation is quite clear in cellular therapy trials in which it appears that the CAR-T approach leading to regulatory approval for FL had min- imal activity in MZL.6 Despite these caveats, outcomes are generally favorable with current guidelines and a focus on short- and long-term toxicity is an essential ele- ment of the therapeutic approach. Ideally, the emerging mutational landscape and insights into the often inflam- matory microenvironment will lead to more targeted therapies in the future.
Concluding remarks
When reading these reviews side-by-side, a number of common themes and struggles emerge. On a positive note, there has been dramatic progress in terms of sur- vival and a general shift away from cytotoxic agents. A relatively new concept is that not all relapses are the same. However, several common challenges persist: inability to determine individual prognosis at the time of diagnosis, lack of data on optimal sequencing, no clear biologically driven indication for treatment selection, lim-
haematologica | 2022; 107(1)
5