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D. Qualls and G. Salles
and obinutuzumab, remains an option. Prior sensitivity to anti-CD20 treatment is essential when considering this option. Sensitivity has classically been defined as having a response to anti-CD20 treatment lasting at least 6 months.70-72
Several studies have evaluated anti-CD20 monothera- py re-challenge in the second or later line of therapy. A phase II trial of rituximab re-challenge in patients with relapsed indolent non-Hodgkin lymphoma (92% FL) demonstrated an overall response rate of 40%, with 11% attaining complete responses and the median time to pro- gression being 17.8 months.73 A case-control study demonstrated response rates of 76% with second-line rit- uximab monotherapy in FL, and a median PFS of 19.2 months.74 In the RESORT clinical trial, patients with low tumor burden FL with initial response to rituximab monotherapy were randomized to maintenance ritux- imab or re-treatment with rituximab at progression of disease, with patients in the re-treatment cohort demon- strating response rates of 61% at first re-treatment and 67% at second re-treatment.70
With regard to the choice of anti-CD20 agent, obinu- tuzumab has not been proven to be significantly superior to rituximab, but it can be used in patients with adverse reactions to rituximab, while ofatumumab appears inferi- or to rituximab.71,75
We consider single-agent rituximab (or rarely obinu- tuzumab) a useful option in instances of mild tumor bur- den where an indication to treat nonetheless exists and when rituximab-based combinations - providing deeper and more durable responses - are not suitable.
Immunomodulators
Lenalidomide is an immunomodulatory agent that functions via cereblon-mediated ubiquitination and degradation of target transcriptional factors, resulting in potential direct cellular toxicity to lymphoma cells as well as potentiation of immune effector cells in the tumor microenvironment. Lenalidomide has demonstrated syn- ergy with anti-CD20 antibodies such as obinutuzumab and rituximab, via reconstitution of a functional immune synapse, improved natural killer cell function, and greater antibody-dependent cellular cytotoxicity.76-78 This benefit was demonstrated in the phase III AUGMENT trial, which evaluated rituximab with or without lenalidomide in relapsed rituximab-sensitive FL, and found a significant PFS benefit with the combination of lenalidomide plus rituximab (R2).72 A post-hoc analysis also indicated an OS benefit for the combination, although patients in both study arms had very favorable outcomes (2-year OS of 86% and 95% in the rituximab/placebo and R2 arms, respectively), likely reflecting the select charactersitics of the study population. Of note, infections, neutropenia and skin rashes were more frequently encountered in patients receiving R2. Based on these results, and given the similar efficacy of this combination when compared with classical immunochemotherapy in the first-line set- ting (as demonstrated in the RELEVANCE study), R2 is now a standard of care for relapsed/refractory, rituximab- sensitive FL following anti-CD20 or chemoimmunothera- py.25 A single-arm, phase II study of obinutuzumab and lenalidomide in relapsed/refractory disease, including rit- uximab-refractory FL, showed similarly high response rates.79
Immunomodulators have intriguing potential in terms
of synergy, particularly with other immunotherapies, as already evidenced with rituximab and obinutuzumab. Further studies evaluating the addition of immunothera- pies to the R2 or obinutuzumab-lenalidomide backbone are underway. For example, a phase Ib/II study evaluated the use of atezolizumab combined with obinutuzumab- lenalidomide in patients who had received at least one prior line of immunochemotherapy, with encouraging rates of durable clinical responses (3-year PFS 68.4%, 3- year OS 90%).80 Another randomized study is evaluating the combination of R2 with tafasitamab, a CD19-directed Fc-engineered antibody, which had modest activity as a single agent in FL, but produced encouraging response rates in diffuse large B-cell lymphoma when combined with lenalidomide (NCT04680052).81
Cellular therapies
Recently, the Food and Drug Administration in the USA approved axicabtagene ciloleucel as the first CAR T-cell therapy for FL, based on results of the ZUMA-5 trial.82 This study evaluated axicabtagene ciloleucel CAR T-cell therapy in patients with indolent non-Hodgkin lym- phoma, including 127 with FL, who had relapsed/refrac- tory disease after two or more prior lines of therapy, including anti-CD20 and alkylator-containing therapy. The overall response rate was 94% and complete response rate 79% for FL patients; at 18 months PFS was 69% and OS was 88% (Table 2). Similar response rates, but a decreased PFS rate at 18 months, were noted in patients with POD24 disease compared to those without (55% vs. 84%, respectively).83 The results of this trial have been compared to those of an external propensity score- matched cohort of patients not enrolled in the study who otherwise met criteria for ZUMA-5, showing significant improvement in overall response rate, PFS, time to next treatment, and OS with CAR T-cell therapy compared to alternative therapies.84 Low-grade cytokine release syn- drome occurred in the majority of patients with FL, while 6% experienced grade ≥3 cytokine release syndrome; notably, 50% of patients received tocilizumab during therapy, indicating that close monitoring, similar to that necessary with large cell lymphoma, will still be required. For patients with FL, the frequency (56%) and severity (15% with grade ≥3 events) of neurological events, and their duration (median of 14 days), represent a significant hurdle for broader application of this therapy.
Interestingly, re-treatment with axicabtagene ciloleucel in patients who relapsed after initial therapy with this drug also generated favorable responses. Thirteen pa- tients (11 with FL) who had undergone initial axicabta- gene ciloleucel therapy, as per ZUMA-5, and achieved an initial response followed by progression, were treated with repeated axicabtagene ciloleucel administration after it had been confirmed that CD19 expression persist- ed on FL cells. The response rate was 100% with 77% achieving a complete response, and 58% being progres- sion-free at 12 months after re-treatment.
Evaluation of other CAR T-cell products is also under- way. A phase II study of tisagenlecleucel in relapsed/refractory FL after two or more lines of prior therapy is ongoing.85 At the most recent evaluation, there was a high overall response rate of 86% (95% CI: 56- 75%) with a complete response rate of 66% (95% CI: 78- 92%) and PFS at 6 months of 76% (95% CI: 65-84%). A favorable toxicity profile was noted with cytokine release
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haematologica | 2022; 107(1)