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Recent developments for patients with R/R FL
treatment-free interval) are present, and after having ruled out the possibility of histological transformation, strate- gies offering a higher response rate and prolonged PFS should be considered with the patient. While ASCT or allogeneic transplant were reasonable options in this set- ting (if not used before), the availability of CAR T cells - despite the limited follow-up presently available - repre- sents an important opportunity to consider prior to trans- plantation. For all patients, the consideration of a clinical trial is encouraged, given the rapid evolution in the field with effective agents and combinations. Overall, the risk/benefit ratio of each option should be assessed in the context of the patients’ overall condition and their indi- vidual goals for therapy.
Remaining gaps and perspectives
Several questions remain unanswered regarding the optimal sequencing of new agents. Overall, we know lit- tle about how prior treatment affects disease biology, and hence influences the response to the next class of agent. It is suspected that the use of T-cell-depleting agents, such as bendamustine or purine analogues, may affect the quality of host T cells and result in suboptimal results of CAR T-cell therapy, and possibly other immunotherapies such as immunomodulators and bispecific antibodies. Further translational and clinical evaluation regarding the impact of prior treatment on the mechanism of action and efficacy of subsequent treatments is needed.
Markers able to predict response to therapy are also lacking. The potential influence of specific molecular alterations has not been explored in the relapsed/refracto- ry setting (except for higher response rates to tazemeto- stat when an EZH2 mutation is present). It is conceivable that alterations in the B-cell receptor signaling pathway or in the metabolic regulatory pathway may affect the effi- cacy of agents targeting those pathways. Likewise, muta- tions affecting MHC expression or T-cell subpopulation might potentially influence some immunotherapies. Further investigations in this area, such as circulating tumor DNA assays to characterize the mutational land- scape, will be of interest.
Another important challenge is the design and clinical execution of more rational therapeutic combinations, and many possible examples have been outlined above. Phase II studies with early and standardized evaluation end-
points, such as positron emission tomography/computed tomography response or circulating tumor DNA evalua- tion, are desirable. Despite the difficulty of aligning dif- ferent stakeholders with potential competing interests, conducting drug development in parallel may allow a more direct comparison of the respective benefits of these different strategies. Evaluating patients’ quality of life and assessing their potential preferences when facing options with different routes of administration, treatment dura- tions and toxicity patterns fully deserves additional methodological efforts and investment.
Two major therapeutic mechanisms carry hope for future progress. Given the central role of epigenetic alter- ations in the development of FL, we anticipate that epige- netic modifiers will be able to eradicate – or substantially deplete - the pool of lymphoma clonal precursor cells, providing an avenue toward cure. Tazemetostat repre- sents an important proof of concept, but the development of more efficacious agents remains in its infancy, and specificity and tolerability of epigenetic-directed drugs remain challenging. Immune-based therapies represent another area of significant potential, with promising results observed with cellular therapies and bispecific antibodies. It is likely that various immunotherapies will represent the backbone of future combinations and progress, as shown by multiple studies currently in devel- opment. While it remains uncertain whether harnessing immune cells to efficiently eliminate FL cells will let us envision the cure of this disease, the remarkable survival improvements achieved in the last 20 years with anti- CD20 monoclonal antibodies allow us to continue to be optimistic.
Disclosures
In the last 12 months GS has received financial compensa- tions for participating in advisory boards or consulting from : Abbvie, Bayer, Beigene, BMS/Celgene, Epizyme, Genentech/Roche, Genmab, Incyte, Janssen, Kite/Gilead, Loxo, Milteniy, Morphosys, Novartis, Rapt, Regeneron and Takeda.
Contributions
Both authors collected and analyzed data, wrote and approved the manuscript
Funding
This research was funded in part through the NIH/NCI Cancer Center support grant P30 CA008748.
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