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Recent developments for patients with R/R FL
The co-stimulatory receptor 4-1BB (CD137) is found on many activated immune cell subtypes. Activation of 4-1BB is associated with increased T-cell proliferation, survival, cytokine production, and functional maturation.109 Resident T cells in FL have been shown to express 4-1BB at high levels, providing a biological rationale for 4-1BB ago- nist therapy.109 However, early clinical trials showed only modest anti-tumor activity, with the therapeutic index lim- ited by dose-related hepatotoxicity.110-112 It is thought that the hepatotoxicity seen in these studies was driven by off- tumor Fc-mediated 4-1BB cross-linking by Fc𝛾RIIb express- ing liver resident cells.113 While there remains a biological basis for 4-1BB co-stimulation in FL, a more tumor-specific mechanism is probably required. A possible solution is the use of bispecific therapies, which fuse 4-1BBL to a lym- phoma-specific target such as CD19, minimizing off-target toxicity. This approach has shown synergistic activity with CD3/CD20-targeted bispecific therapy in vitro and in vivo, and clinical trials are underway (NCT04077723).114
Sequencing therapies in patients with relapsed/refractory follicular lymphoma
When and how to utilize the growing array of therapies at our disposal remains a significant challenge. It is impor- tant to note that observation in many cases of relapsed or refractory FL remains a viable option if symptom burden is low and no absolute indications for treatment are met, such as the Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria. As shown above, the number of options available for the management of patients requiring sec- ond and subsequent lines of therapy has increased markedly in the last decade, and newcomers are emerg- ing. Several pivotal trials are under development, assess- ing the therapeutic value of single agents or various com- binations of active compounds, and emphasizing the
probable expansion of the field (Table 3). However, the lack of head-to-head evaluations of recently approved agents, and the usual pitfalls of cross-trial comparisons, represent obstacles to evidence-based decisions.
Second-line treatment
While there is no formal standard of care, the manage- ment algorithm (Figure 3) is relatively straightforward, since beside rituximab, alone or in combinations with lenalidomide, immunochemotherapy remains the princi- pal option recommended by the National Comprehensive Cancer Network and European Society for Medical Oncology guidelines in the absence of histo- logical transformation. These options achieve a clinical response in the majority of patients, which can be sus- tained for years. Choices among the different cytotoxic regimens and anti-CD20 antibodies have already been discussed above, as has the role of consolidation with anti-CD20 maintenance or ASCT.
In addition to the AUGMENT trial, the results of the front-line RELEVANCE study, which demonstrated com- parable efficacy between R2 and immunochemotherapy, reinforce the efficacy of R2, and this regimen should be strongly considered if immunochemotherapy was used in the first line of treatment.25 Advantages of this approach include using a strategy with a different mode of action and leaving an open space for initiating immunochemotherapy (with eventual consolidation) later in the management of FL.
Beyond prior therapy and disease characteristics, the patient’s ability to tolerate therapy must be considered. In patients of advanced age, who are frail, or have comor- bidities, options include rituximab as a single agent or in combination with lenalidomide (with the appropriate dose adaptations according to kidney function), alkylat- ing agents or localized radiation therapy. A personalized approach is recommended, and it remains possible to
Figure 3. Schema for treatment choice at the time of first disease progression. After ruling out histological transformation, the choice of agent depends on prior therapy, the timing of relapse, tumor burden, and patients’ ability to tolerate therapy. R: rituximab; O: obinutuzumab; CHOP: cyclophosphamide, adriamycin, vin- cristine, prednisone; CVP: cyclophosphamide, vincristine, prednisone: ASCT: autologous stem cell transplantation.
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