Moving towards biologically informed treatment strategies for T-cell lymphomas

Abstract

The rarity and biological heterogeneity of the peripheral T-cell lymphomas has made subtype- and biomarker-driven approaches challenging to realize and even more challenging to evaluate in clinical practice. Out of necessity, treatment of T-cell lymphomas has historically been derivative of other aggressive lymphomas, utilizing intensive combination chemotherapy programs in the upfront setting and non-overlapping cytotoxic regimens upon relapse. However, due to tremendous work in understanding the oncogenic basis of these varied diseases, an increasing exploration of rational, targeted therapies is underway. Still, clinical successes have at times lagged behind pathobiological realizations, and there is an evolving need for biologically based, subtype-specific strategies in the clinic. Herein we propose a framework for future success that relies upon optimizing standard therapy in populations known to benefit from combination chemotherapy, building upon CHOP (or CHOP-like) induction with the CHOP + X model, exploring the use of targeted platforms in the relapsed and refractory setting, and designing biomarker-informed clinical trials that target-specific subhistologies and unique molecular subsets.

Keywords: Anaplastic large-cell lymphoma; Cutaneous T-cell lymphoma; Peripheral T-cell lymphoma; T-cell lymphoma.

Figure 1.. Emerging Biomarker-Driven Strategies in T-cell Lymphomas.

From top left, clockwise: Targeting CD30: CD30 is ubiquitous in anaplastic large cell lymphoma and variably seen in other T-cell lymphomas; strategies to target CD30 include antibody-drug conjugate therapy, bispecific antibodies, and anti-CD30 CAR T-cell therapy. Inhibiting Oncogenic Pathways: Examples include the JAK/STAT and PI3K/AKT/mTOR pathways; validated markers of pathway activation are unclear. Epigenetic Therapy: Certain histologies, such as T-cell lymphomas derived from T-follicular helper cells, have shown greater sensitivity to HDAC inhibition, and potentially other epigenetic-based therapies. Immune & Cell Surface Targets: Checkpoint inhibition via the PD-L1-PD-1 axis appears most efficacious in certain histologies, notably NK/T-cell lymphoma and cutaneous T-cell lymphomas. Other checkpoints and cell surface targets are being explored. Chemorefractory Disease: Emerging evidence shows certain mutational and gene expression profiles may be associated with worse outcomes with anthracycline-based induction. Strategies for these patients are needed. Approved therapies are shown in bold. AC, acetyl; CAR, chimeric antigen rector; EZH, enhancer of zeste homolog; HDAC, histone deacetylase inhibitor; JAK, Janus kinase; Me, methyl; mTOR, mammalian target of rapamycin; NK, natural killer; PI3K, phosphoinositide 3-kinases; 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. Created with BioRender.com.