Sequencing Therapies in Peripheral T-Cell Lymphoma

Résumé

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of clinically aggressive mature T-cell neoplasms that represent approximately 10% of all non-Hodgkin lymphoma cases.1 According to the most recent World Health Organization (WHO) classification and the International Consensus Classification (ICC),2,3 there are over 30 distinct T and natural killer (NK) cell lymphomas. Although genetic and environmental factors are implicated in certain subtypes (e.g., HTLV-1 in adult T-cell leukemia/lymphoma [ATLL]), most PTCLs are associated with genomic alterations acquired during normal T-cell development and differentiation.1 The most common nodal PTCL subtypes, which will be the focus of this review, are PTCL-not otherwise specified (NOS), nodal T-follicular helper (TFH) lymphoma, including angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large cell lymphoma (ALCL). TFH lymphomas are defined by the expression of at least two markers characteristic of normal TFH cells (CD10, BCL6, CXCL13, PD1, and ICOS).2 This group comprises 3 distinct entities (angioimmunoblastic-type, follicular-type, and NOS) that have unique histologic patterns but share a common genetic landscape characterized by mutations in genes that regulate DNA and histone methylation, including TET2, DNMT3A, and IDH2.4 Based on their pathogenesis involving epigenome dysregulation, these lymphomas appear particularly sensitive to epigenetic therapies, such as histone deacetylase (HDAC) inhibitors and azacitidine.5,6 PTCL-NOS encompasses a heterogeneous group of diseases and remains a diagnosis of exclusion. Among cases not classified as TFH lymphomas, two molecularly defined subgroups have been identified: PTCL-GATA3 and PTCL-TBX21, which resemble T helper 1 (Th1) and T helper 2 (Th2) cells, respectively.4 These subgroups are associated with distinct clinical outcomes, with PTCL-GATA3 conferring a particularly poor prognosis. Importantly, these signatures may have treatment implications, as PTCL-GATA3 is associated with activation of the PI3K pathway, whereas PTCL-TBX21 appears more closely linked to STAT3 pathway activation. Ongoing research in this area will hopefully facilitate the development of more biologically targeted therapies and ultimately improve outcomes for these distinct PTCL subsets. ALCLs are composed of large, pleomorphic CD30-positive T cells and are classified into four distinct entities: ALK-positive ALCL, ALK-negative ALCL, breast-implant-associated ALCL, and primary cutaneous ALCL. ALK-positive ALCL generally carries a more favourable prognosis than ALK-negative ALCL, in part due to the younger age at presentation.7 Given the uniform expression of CD30 in ALCL, brentuximab vedotin (BV) has become a cornerstone of front-line therapy following the landmark ECHELON-2 trial, discussed below, which demonstrated both progression-free survival (PFS) and overall survival (OS) benefits with the incorporation of BV into an anthracycline-based regimen (BV-CHP).8 Historically, PTCL has been associated with inferior outcomes compared with aggressive B-cell lymphomas, with multiple national and international registry studies reporting 5-year PFS rates of approximately 20%–30% and 5-year OS rates of 30%–40%.9 However, recent advances in identifying molecular biomarkers and understanding disease biology are increasingly enabling more individualized treatment approaches. This review will discuss an evidence-based approach to sequencing therapies for PTCL in both the front-line and relapsed/refractory settings.