Biomarker-driven management strategies for peripheral T cell lymphoma

Abstract

Peripheral T cell lymphomas are heterogeneous diseases which remain treatment challenges. Recent advances in molecular and genomic profiling have provided unprecedented insight into disease pathogenesis driven by distinct cells of origins and molecular pathways. The discovery and clinical application of molecular biomarkers in PTCL subtypes has the potential to transform personalized care for patients with PTCL in diagnosis, prognosis, and therapy. Targeting CD30+ PTCL with the antibody-drug conjugate brentuximab vedotin in the relapsed setting and in combination with chemotherapy in the frontline setting has improved patient survivals. Epigenetic modifying agents, including HDAC inhibitors and hypomethylating agents, have demonstrated broad clinical efficacy and durability and are in clinical development for combination strategies for both relapsed and frontline settings. Wideranging novel agents targeting critical intracellular pathways and tumor microenvironment are in active exploration to define clinical activities. This review summarizes PTCL-specific biomarkers which are increasingly incorporated in clinical practice to guide precision diagnosis and personalized treatment.

Molecular insights into pathogenesis and targeted therapy of peripheral T cell lymphoma

“…Moreover, in a global double-blind, randomized phase III study, BV plus CHP (CHOP without vincristine) demonstrated higher complete remission (CR) rate and superior overall survival relative to CHOP Xie et al Exp Hematol Oncol (2020) 9:30 as frontline treatment for patients with PTCL. However, non-ALCL cases such as PTCL-NOS enrolled in this study are less than 25% [8]. Kim et al [90] reported that the disease control rate was 48.5% in the patients with R/R high CD30-expressing NHL including PTCL-NOS (24.2%), ENKTL (21.2%) and AITL (3%).…”

“…Using GEP, two biological subgroups of PTCL-NOS have been identified, which include PTCL-GATA3 that is characterized by high expression of GATA3 and known target genes (CCR4, IL18RA, CXCR7, and IK), and PTCL-TBX21 that shows significantly higher expression of TBX21 (T-bet) and EOMES and their downstream targets (CXCR3, IL2RB, CCL3, IFN-γ) [6,7]. The transcription factors TBX21 and GATA3 promote differentiation of CD4 + T cells into TH1 and TH2 helper cells, respectively [8]. The PTCL-GATA3 subgroup, accounting for 33% of PTCL-NOS, has an enrichment of MYC and cytotoxic gene with poorer outcome while the PTCL-TBX21 subgroup that constitutes 49% of PTCL-NOS, has a tumor microenvironment gene signature and is associated with a favorable outcome.…”

“…Anaplastic large cell lymphoma (ALCL), characterized by sheets of CD30 (Ki-1)-positive anaplastic large cells, is another of the more common PTCL subtypes, accounting Xie et al Exp Hematol Oncol (2020) 9:30 for about 12% of all cases [8,49]. Four distinct entities of ALCL, including ALK + ALCL, ALK − ALCL (represent 15-25% of non-cutaneous PTCLs in total), primary cutaneous ALCL (PC-ALCL), and breast prosthesis implantation ALCL (BI-ALCL), share common pathological features: a large-cell anaplastic morphology, strong CD30 expression and frequent phospho-STAT3 activation.…”

“…Daratumumab is a CD38 mAb approved for treating R/R and untreated multiple myeloma. Because CD38 is universally expressed within ENKTL, Daratumumab has been recently investigated to assess its safety and efficacy within ENKTL (NCT02927925), which shows a promising overall response rate (ORR) of 35.7% in 16 patients [8,95].…”

Targeting Akt in cancer for precision therapy

“…The sensitivity to molecular targeted therapy usually varies among individual cancer patients and at different stages of tumor progression. Elucidation of the mechanisms underpinning the sensitivity to molecular targeted agents may help identify the appropriate biomarkers to stratify patients for precision cancer therapy [ 236 , 237 ]. Akt-dependent tumors may be vulnerable to therapeutic Akt inhibition.…”