Introduction to a review series on high-risk aggressive lymphoma

Lymphoid malignancies include a diverse group of clinicopathologic entities that are biologically heterogeneous with variable clinical presentation and outcomes. The descriptive term “aggressive” is generally applied to lymphomas with rapid growth rate that present acutely and require timely intervention. Multiagent chemotherapy strategies that exploit the vulnerabilities of rapidly replicating cancer cells have proven successful in aggressive lymphoma and remain the mainstay of initial therapy. Although many aggressive lymphomas are curable with frontline therapy, a significant percentage of patients will exhibit treatment resistance and require alternative strategies resulting in poorer outcomes. The current review series addresses some of the more challenging subtypes of aggressive lymphoma with focus on what constitutes a high-risk patient and unique management approaches that may be used. The articles within this review series are as follows:

• Anna Dabrowska-Iwanicka and Grzegorz S. Nowakowski, “DLBCL: who is high risk and how should treatment be optimized?”

• Andrew J. Davies, “The high-grade B-cell lymphomas: double hit and more”

• Mark Roschewski, James D. Phelan, and Elaine S. Jaffe, “Primary large B-cell lymphomas of immune-privileged sites”

• Lauren Shea and Neha Mehta-Shah, “Peripheral T-cell lymphoma: are all patients high risk?”

Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), is the most common aggressive lymphoma. Despite its known biological heterogeneity, management strategies remain uniform and rely on anthracycline-based chemotherapy combined with the monoclonal antibody rituximab. Which patients may benefit from alternative frontline approaches remains a large debate. Clinical prognostic indices help stratify patients on clinical trials but have limited utility in guiding therapy given that they fail to identify patients with very poor outcomes. Gene expression profiling has identified 2 molecular subgroups, activated B cell (ABC) and germinal center B cell (GCB), with different oncogenic mechanisms and prognoses. Numerous trials have attempted to incorporate targeted agents into frontline therapy, in some cases with enrichment for ABC DLBCL, with limited success. Importantly, the introduction of polatuzumab vedotin into frontline treatment demonstrated improved progression-free survival, although there was an apparent preferential activity in ABC subtype. Recently, genomic analyses have led to novel proposed taxonomies that have refined DLBCL classification beyond cell of origin. However, further validation and prospective studies will be required before they are routinely used in clinical care. The review article by Dabrowska-Iwanicka and Nowakowski catalogs the various trials reported to date, highlighting subgroups of patients who may benefit from novel approaches, and dissects the rationale for ongoing trials. Thoughtful trial design, incorporation of biomarkers, and response adaptation will likely be required to achieve a patient-tailored approach.

High-grade B-cell lymphoma (HGBCL) is a recently designated category within the World Health Organization (WHO) classification of lymphoid neoplasms, which recognizes 2 subtypes, HGBCL with dual rearrangement of MYC and BCL2 and HGBCL, NOS. HGBCL with dual rearrangement of MYC and BCL2 (commonly referred to as double-hit lymphoma) can have either DLBCL or high-grade morphology and is identified through fluorescence in situ hybridization (FISH) testing. Due to the uncertain relevance of BCL6 rearrangement, it has been omitted from the latest definition. Recently, transcriptional studies have identified a broader group of patients (without dual rearrangement by FISH) with shared high-grade biology (termed molecular high-grade or dark zone lymphoma), suggesting that more sensitive tools will be required to identify this clinically relevant group. There is no consensus on optimal management of HGBCL with dual rearrangement of MYC and BCL2, although it is recognized that standard chemoimmunotherapy is associated with poorer outcomes. Although dose intensification strategies, such as DA-EPOCHR (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab), are commonly used, this approach has not been validated with randomized trials. HGBCL, NOS, remains a diagnosis of exclusion and likely reflects a more heterogeneous population. Few studies have focused on this subgroup, and thus, standard of care is not defined. The article by Davies in this series summarizes the current biological understanding of HGBCL and explores novel approaches to improve future outcomes.

Primary large B-cell lymphoma of immune-privileged sites is a newly introduced category within the WHO classification. It is an umbrella term that encompasses a group of rare lymphomas with shared features. The current category includes primary aggressive B-cell lymphomas that arise in the central nervous system, vitreoretinal compartment, or the testes in immunocompetent patients. Typically, these lymphomas arise in anatomic sanctuary sites, protected from chemotherapy exposure and host-immune mechanisms. They also share immunophenotypic and molecular features, including ABC subtype, comutations of MYD88 and CD79B, and genetic alterations promoting immune evasion. Clinical management requires consideration of the unique features of each entity, but novel agents that exploit common biological mechanisms may have value. Bruton tyrosine kinase inhibitors and immunomodulatory agents such as lenalidomide have demonstrated efficacy and warrant evaluation in combination regimens. The review article by Roschewski, Phelan, and Jaffe evaluates the rationale for the creation of this new lymphoma category and explores the opportunity for a precision-care approach. It is likely that this category may be further expanded, as other extranodal lymphomas, including breast, adrenal glands, and skin, also share commonalities.

Peripheral T-cell lymphoma (PTCL) represents a heterogeneous group of mature T-cell neoplasms with >30 distinct subtypes within the WHO classification. Collectively, patients with PTCL have poor outcomes after standard anthracycline-based chemotherapy, thus representing a therapeutic challenge. Consolidative strategies including stem cell transplantation are frequently considered with uncertain benefit. However, recent biological insight has served to dissect the pathogenesis of these lymphomas, raising the possibility of improved risk stratification and individualized treatment. In addition to clinical prognostic factors, molecular and genomic evaluation is assuming a more prominent role in defining risk, both between and within individual subtypes. As an example, recent gene expression profiling studies suggest 2 identifiable subgroups within PTCL-NOS (GATA3 subgroup and TBX21 subgroup) that may have prognostic and predictive implications, with differential sensitivity to novel therapeutics. Improved response assessment tools, including positron emission tomography scanning and measures of minimal residual disease, may enable identification of patients most likely to benefit from dose intensification strategies. The review article by Shea and Mehta-Shah explores the current role of biological, clinical, and dynamic assessment tools in guiding management for patients with PTCL.

The 4 articles in this review series highlight the increasing complexity of aggressive lymphoma management. It is imperative that clinicians be aware of the expanding list of unique entities, including the oncogenic drivers that may be exploited for differential management. There is reason to be optimistic that ongoing biological studies and prospective clinical trials will lead to additional insight and further advance care.