Novel Therapies for Follicular Lymphoma and Other Indolent Non-Hodgkin Lymphomas

The field of lymphoma oncology is becoming increasingly complex as we transition into the personalized medicine era. Not only are more treatment options becoming available, but lymphomas are being further subclassified with nearly 100 subtypes in the most recent World Health Organization classification [1]. One of the main challenges in iNHL is the absence of identified predictive markers to aide in treatment selection and sequencing. Although chemoimmunotherapy (CIT) remains the preferred frontline option for most patients with FL requiring therapy, there is interest in shifting towards chemotherapy-free approaches. Marginal zone lymphoma subtypes are more variable, with the radiation therapy or rituximab monotherapy as the preferred frontline approach for extranodal (EMZL) and splenic (SMZL), and rituximab monotherapy or CIT the favored approach for treatment-naive nodal marginal zone (NMZL). A continued challenge in the frontline treatment of iNHL in patients with iNHL is the lack of predictive and prognostic markers that can identify those at increased risk of poor outcomes. The FL international prognostic index (FLIPI), FLIPI-2, and m7-FLIPI consider clinical and/or molecular features to help risk-stratify patients; however, significant heterogeneity remains among patients in various risk groups and these prognostic scores have different implications if applied to a patient treated with CIT versus a chemotherapy-free approach [2–4]. In the frontline setting, we are still unable to accurately identify patients at increased risk for early relapse, such as progression of disease within 2 years of frontline CIT (POD24), which remains an area of unmet need. Once these patients can be identified prior to starting therapy, novel approaches can be explored in an attempt to change the natural history of disease for these patients. In the relapsed or refractory (R/R) setting, CIT may be appropriate for a minority of patients, but a targeted approach is preferred for most. From June 2020 through March 2021, the Food and Drug Administration (FDA) granted accelerated approval for three new targeted therapies in R/R FL and one for R/R MZL. Chemotherapy-free options in R/R FL now include lenalidomide-based therapy, four different phosphoinositide 3-kinase (PI3K) inhibitors, tazemetostat, and anti-CD19 chimeric antigen receptor T cell (CAR-T) therapy. It has become clear that responses to targeted therapies are different among iNHL subtypes, and options for R/R MZL differ significantly from R/R FL. For example, ibrutinib is active across most iNHL subtypes and FDA-approved for R/R MZL, SLL, WM, and R/R MCL but due to disappointing efficacy is not approved in FL (Table ​(Table1,1, Figure ​Figure11). Table 1 Targeted therapies in indolent non-Hodgkin lymphomas