Likewise, given the CR rate with the early BiTE therapy trials in greatly treated FL patients, these treatments will also likely play a role in the POD24 patient as well. Conclusions Despite a better understanding of the genetic, epigenetic, and immunological scenery of FL, biomarker-driven Tasimelteon and personalized approaches have remained elusive in the front-line treatment of FL, with one size fits all chemoimmunotherapy still being the most common approach for front line advanced FL treatment. therapies will likely reshape the treatment approach for patients with relapsed and refractory FL in the coming years. In this article, we provide a comprehensive review of the emerging and investigational therapies in FL and discuss how these brokers will impact the therapeutic scenery in FL. [FL][FL][FL] /th th align=”left” rowspan=”1″ colspan=”1″ Median lines of prior therapy /th th align=”left” rowspan=”1″ colspan=”1″ % POD24 /th th align=”left” rowspan=”1″ colspan=”1″ ORR%a [CR%] /th th align=”left” rowspan=”1″ colspan=”1″ mPFS /th th align=”left” rowspan=”1″ colspan=”1″ CRS % [G??3] /th th align=”left” rowspan=”1″ colspan=”1″ Neuro % [G??3] /th th align=”left” rowspan=”1″ colspan=”1″ Approved /th /thead Mosunetuzumab[96]IV Qweekly for cycle 1, Q21 days for cycles??2, stopped after cycle 8 for CR162 [62]34868 [50]11.820COdronextumab[97]IV Qweekly for weeks 1C12, Q2 weeks for weeks 12C36196 [25]3NP93 [71]NP73COdronextumab”type”:”clinical-trial”,”attrs”:”text”:”NCT03888105″,”term_id”:”NCT03888105″NCT03888105 [98]IV Qweekly for weeks 1C12, Q2 weeks for weeks 12C36IINAbNAbNAbNAbNAbNAbNAbCEpcoritamab[100]sq Qweekly C1-2, Q2 weeks C3-6, Q4 weeks thereafter, 28?day cyclesI67 [12]3NP100 [25]NP03CGlofitamab[108]Obinutuzumab on D-7, weekly for two weeks then Q2 weeks for 28?weeksI171 [44]3NP62 RAF1 [52]c11.83.51.2C Open in a separate window Abbreviations: CRScytokine release syndrome; CRcomplete response rate; Neuroneurotoxicity; NPnot offered; ORRoverall response rate; PFSprogression-free Tasimelteon survival; POD24progression of disease within 24?months following chemoimmunotherapy; sqsubcutaneous; Qweeklyevery week; Q2 weeksevery 2?weeks aResponse rates in FL subset bNot available, clinical trial is usually ongoing cfor cohorts receiving??10?mg dosing Mosunetuzumab Mosunetuzumab is a CD20 directed BiTe that has been investigated in DLBCL and FL with updated results recently reported from a phase I dose escalation study in FL [96]. After weekly step-up administration during the first cycle, infusions were continued every 21?days for 8 cycles in patients who also achieve CR or was continued for up to 17 cycles for patients who had Tasimelteon stable or partial responses. The median quantity of prior treatments was 3 with 48% of patients with POD24 and 6% of patients who experienced prior CART therapy. The ORR and CR rate was 68% and 50%, respectively. At a median follow-up of 14.4?months, 62% of patients remained in remission with a median PFS of 11.8?months. SAEs occurred in 35% of patients, but only 21% of patients experienced CRS (one with grade??3) and 45% had neurologic AE (none with grade??3). The FDA has granted breakthrough therapy designation for mosunetuzumab in FL after 2 prior lines of therapy. Odronextamab Odronextamab (REGN1979), a CD20/CD3 BiTe, is an IgG4 antibody that is modified to reduce binding to the Fc receptor which Tasimelteon has been analyzed in rel/ref B cell NHL [97]. Odronextamab was given every week for a total of 12?weeks followed by biweekly dosing for 12 more doses. Ninety-six patients were enrolled (25 with FL), 12 patients with prior CART. The CRS rate was 57% ( em n /em ?=?7 with grade??3). Grade 3 or higher neurotoxicity occurred in two patients [97]. The trial was suspended temporarily due to a patient’s death from TLS for any protocol amendment. Responses were evaluated over a broad range of dosages with dosage-dependent responses seen. With treatment??80?mg, the FL cohort demonstrated an ORR of 95.5% (CR rate?=?77.3%) with??5?mg [97]. A global phase II study is currently enrolling 5 individual disease cohorts of rel/ref NHLs, one of which is usually rel/ref FL [98]. However, at the time of this writing, Tasimelteon a temporary hold was placed on both clinical trials due to a higher than anticipated rate of grade??3 CRS with a protocol amendment awaited to mitigate this risk. Epcoritamab Epcoritamab (GEN3013), a CD20/CD3 BiTe, is an IgG1 antibody that is unique in that it is administered subcutaneously rather than IV [99]. In pre-clinical models, subcutaneous administration exhibited comparable bioavailability and B cell depletion as IV administration but with lower plasma cytokine levels and was hypothesized to result in less CRS but with the same responses in.