Indolent non-Hodgkin lymphoma (iNHL), including follicular (FL) and marginal zone (MZL) lymphoma, now enjoy durable disease control with first-line immunochemotherapy, with a median overall survival (OS) of over 15 years in most series (Kahl and Yang 2016). However, iNHL is still widely considered incurable in most cases, and disease history remains characterized by a relapsing and remitting course, with each remission period shorter than the previous one, and OS and progression-free survival (PFS) decrease with each subsequent line of conventional therapy (Batlevi et al. 2020). Patients with unmet needs include approximately 20% of FL patients who experience disease progression within 24 months (POD24) after initial chemoimmunotherapy (with a 5-year OS of 48% (Casulo et al. 2015)—although it remains unclear how much this worse outcome is driven by misdiagnosed transformed follicular lymphoma (Freeman et al. 2019)) and those who fail multiple regimens (5-year PFS of 23%) (Rivas-Delgado et al. 2019) have double refractory disease (Gopal et al. 2017) or experience relapse after autologous stem cell transplantation (ASCT) (Sesques et al. 2020). Although promising results were obtained with an immunomodulatory regimen combining anti-C20 Moab and lenalidomide (Leonard et al. 2019; Morschhauser et al. 2019), most current approved therapies do not overcome incremental disease resistance, resulting in multiple lines of treatment with cumulative toxicity over a patient’s lifetime. The autologous anti-CD19 chimeric antigen receptor T cell (CAR-T) therapies tisa-cel and axi-cel, which are now approved for patients with relapsed/refractory (r/r) large B cell lymphoma (LBCL), have also been tested in iNHL, with promising results.
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