Therapeutic Advances in Relapsed and Refractory Peripheral T-Cell Lymphoma

Abstract

Historic outcomes for patients with relapsed or refractory nodal-based T-cell lymphomas are poor, with survival generally measured in months in multiple reports from the late 20th and early 21st century. Until recently, salvage strategies have mostly been borrowed from other aggressive lymphomas. However, dedicated investigations into the pathogenesis of T-cell lymphomas have resulted in an outpouring of therapies that target these diseases in biologically rational strategies. In particular, an evolving appreciation of the multiple complex oncogenic pathways and epigenetic changes that underlie these diseases has led to numerous agents targeting these aberrancies. Moreover, large reports of salvage allogeneic stem cell transplants in T-cell lymphoma have now been published, showing that adaptive immunotherapy is a potentially curative strategy for patients with relapsed or refractory disease. This review highlights therapeutic advances for relapsed or refractory T-cell lymphomas, including cellular therapy and allogeneic stem cell transplant, and provides a framework for management.

Keywords: T-cell; T-cell lymphoma; anaplastic; large-cell; lymphoma.

Figure 1

Selected therapeutic advances in peripheral T-cell lymphomas. From top left, clockwise: PI3K inhibition: Duvelisib and tenalisib are dual inhibitors of the PI3K/AKT/mTOR pathway through PI3Kγδ inhibition. JAK/STAT inhibition: Cerdulatinib is a dual inhibitor of JAK/SYK. Ruxolitinib and golidocitinib are JAK1/2 and JAK1 inhibitors of the JAK/STAT pathway, respectively. CAR T-cell therapy: CAR T-cell therapy remains in early study in T-cell lymphoma, with targets including CD30, CD70, CD5, and others. Epigenetic therapies: Epigenetic therapies include continued use of HDAC inhibition, as well as exploration of combination therapies using HDAC inhibitors plus other molecules. Valemetostat is an EZH1/2 inhibitor. ALK inhibition: Alectinib and crizotinib inhibit ALK fusion proteins in ALK + ALCL. Immune recognition: Immune recognition strategies include interruption of the CD47-SIRPα axis and checkpoint blockade in particular histologies (EBV+ T-cell lymphoma, NK/T-cell lymphoma, cutaneous T-cell lymphoma). Abbreviations: ALK, anaplastic lymphoma kinase; CAR, chimeric antigen rector; EZH, enhancer of zeste homolog; HDAC, histone deacetylase inhibitor; JAK, Janus kinase; Me, methyl; mTOR, mammalian target of rapamycin; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; SIRPa, signal regulatory protein α; STAT, signal transducer and activator of transcription; SYK, spleen tyrosine kinase; TCR, T-cell receptor; Zap-70, Zeta-chain-associated protein kinase-70. Created in BioRender.com.