Follicular lymphoma (FL) is the most common non-Hodgkin lymphoma in the United States and Europe1. The disease is potentially incurable and, treatment options comprise a wide spectrum from local radiotherapy to chemoimmunotherapy, based on the risk factors. The outcome of follicular lymphoma patient requiring treatment significantly improved with the introduction of rituximab2,3. Rituximab or obinituzumab in combination with cyclophosphamide, adriamycin, vincristine, prednisolone (G/R-CHOP) or with bendamustine (BR/OR) are preferred in the frontline setting4. RELEVANCE study showed that lenalidomide-rituximab (R2) has similar efficacy to R-chemotherapy approach in the first-line treatment5.The response rate to first-line chemoimmunotherapy is around 65% and, about 20% of the cases responding to chemoimmunotherapy experience progression of disease within 24 months (POD24) and have poorer overall survival6,7. Current prognostic scores are not efficient to predict POD24 cases.

AUGMENT study showed improved efficacy with R2 compared to R in the second line treatment of indolent lymphomas. Eighty-three percent of the cases had FL and 31% of the cohort experienced POD24. The overall response rate (ORR) was 78%, with an improved 2-year progression-free survival rate of 58% compared to 36% with R alone8. MAGNIFY study evaluating R2 maintenance following R2 induction reported an ORR of 65% and a median PFS of 27.4 months for POD24 group9.

Tazemetostat is an oral EZH2 inhibitor. EZH2 is mutated in 20-30% of FL patients. It offered an ORR of 69%, with a median PFS of 13.8 months in early relapsed FL cases with EZH2 mutation. Although the ORR was lower compared to late relapsing cases, the PFS was longer in EZH2 mutant group compared to 5.8 months in wild-type cases10. Copanlisib,a pan-class I phosphatidylinositol 3-kinase inhibitor was evaluated in a phase II study in both indolet and aggressive lymphoma patients. The ORR was 58.7% in indolent lymphoma patients11. Chronos-3 trial revealed that when copanlisib was combined with rituximab, median PFS was improved to 21.5 months compared to 13.8 months with R monotherapy12. Idealisib, duvelisib and umralisib removed their indications for relapsed and refractory FL due to a trend toward lower overall survival (OS) in patients exposed to these agents13.

CAR-T cell therapy changed the treatment paradigm in B-cell lymphomas. In the ZUMA-5 trial, Axicabtagene ciloleucel reported an ORR of 92% in both POD24 and without POD24 cohort.The 18-months estimated duration of response, PFS and OS rates were 60%, 55% and 85% in POD24 cases, whereas they were 78%, 84% and 94% in patients without POD2414. Treatment with Tisagenlecleucel showed lower complete response rates in POD24 patients compared to those without POD24, reported to be 59% vs 87.9%15.

Treatment with bispecific antibodies, suc as epcoritamab, mosutetuzumab and glofitamab, constitute an alternative to CAR-T. The ORR ranged between 80% and 90% with bispecific antibody monotherapy in early-relapsing FL cases16-18.

Nonchemotherapeutic approaches have promising outcomes and are currently preferred in second line setting for POD24 patients. The role of stem cell transplantation in controversial in FL. However, there is not any solid data comparing transplantation with nonchemotherapeutic options.