Chemoimmunotherapy has been a hallmark of treatment of indolent B-cell non-Hodgkin lymphomas for the past 2 decades, with high response rates seen but relapses nearly inevitable and patients spending, on average, 20 years on and off treatment. Treatment advances, then, should be aimed at maintaining efficacy while minimizing toxicity or at achieving cure. Improved understanding of the genetic and molecular features of these diseases, as well as of the interaction between the tumor cell and its immune microenvironment, has resulted in an accelerated expansion of tolerable treatment options for patients, with new combinations of therapy holding promise that definitive therapy in these diseases is possible. These drugs include immunomodulating agents such as lenalidomide, small-molecule inhibitors of the B-cell receptor signaling pathway such as ibrutinib and idelalisib, B-cell lymphoma 2 homology 3 mimetics such as venetoclax, and enhancer of zeste homolog 2 inhibitors such as tazemetostat. Therapies that improve the host immune response against the malignant B cell are also of great interest, given the durable remission seen after allogeneic stem cell transplant in these diseases, and immune checkpoint inhibitors, agonist antibodies against immunostimulatory T-cell receptors, antibody–drug conjugates, bispecific antibodies, and finally chimeric antigen receptor T cells are all being investigated, with promising early efficacy signals. These treatments may not necessarily replace chemotherapy but rather augment it in an attempt to improve quality of life and survival for these patients.

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