Diffuse large B cell lymphoma (DLBCL), the most common type of Non‐Hodgkin lymphoma (NHL), comprises a heterogeneous group of diseases with different biology, clinical presentations, and response to ...treatment. R‐CHOP remains the mainstay of therapy and can achieve long‐term disease control in nearly 90% of patients presenting with limited‐stage and in up to 60% of those presenting with advanced stages. Advances on the understanding of the genetic landscape and molecular features of DLBCL have identified high‐risk subsets with poor outcomes to chemo‐immunotherapy that are actively being studied in clinical trials. Novel therapies could potentially improve outcomes for patients with high‐risk disease. Studies evaluating risk‐adapted therapy based on classification by cell of origin (COO) and molecular features are ongoing. Developments in the fields of immunotherapy, mostly with adoptive T‐cell therapy, have significantly improved the outcomes of patients with relapsed refractory disease. In this review, we will summarize the recent data and discuss ongoing efforts to improve DLBCL treatment in the frontline and relapsed refractory settings.
Disease Overview
Diffuse large B‐cell lymphoma (DLBCL) is the most common type of aggressive non‐Hodgkin lymphoma originating from the germinal center, and it represents a heterogeneous group of ...diseases with variable outcomes that are differentially characterized by clinical features, cell of origin (COO), molecular features, and most recently, frequently recurring mutations.
Diagnosis
DLBCL is ideally diagnosed from an excisional biopsy of a suspicious lymph node, which shows sheets of large cells that disrupt the underlying structural integrity of the follicle center and stain positive for pan‐B‐cell antigens, such as CD20 and CD79a. COO is determined by immunohistochemical stains, while molecular features such as double‐hit or triple‐hit disease are determined by fluorescent in situ hybridization analysis. Commercial tests for frequently recurring mutations are currently not routinely used to inform treatment.
Risk Stratification
Clinical prognostic systems for DLBCL, including the rituximab International Prognostic Index, age‐adjusted IPI, and NCCN‐IPI, use clinical factors for the risk stratification of patients, although this does not affect the treatment approach. Furthermore, DLBCL patients with non‐germinal center B‐cell (GCB)‐like DLBCL (activated B‐cell like and unclassifiable) have a poorer response to up‐front chemoimmunotherapy (CI) compared to patients with GCB‐like DLBCL. Those with c‐MYC‐altered disease alone and in combination with translocations in BCL2 and/or BCL6 (particularly when the MYC translocation partner is immunoglobulin) respond poorly to up‐front CI and salvage autologous stem cell transplant at relapse.
Risk‐Adapted Therapy
This review will focus on differential treatment of DLBCL up‐front and at the time of relapse by COO and molecular features.
Abstract
Diffuse large B‐cell lymphoma (DLBCL) is a heterogeneous disease with varying clinical outcomes. Our understanding of its molecular makeup continues to improve risk stratification, and ...artificial‐intelligence and ctDNA‐based analyses have the potential to enhance risk assessment and disease monitoring. R‐CHOP and Pola‐R‐CHP are used in the frontline setting; chimeric antigen receptor therapy (CART) is now the new standard‐of‐care for most with primary refractory disease; both CART and autologous stem cell transplantation are utilized in the relapsed and refractory setting. In this review, we summarize the classification and management of DLBCL with an emphasis on recent advances in the field.
Proteasome inhibitors disrupt multiple pathways in cells and the bone marrow microenvironment, resulting in apoptosis and inhibition of cell-cycle progression, angiogenesis, and proliferation. ...Bortezomib is a first-in-class proteasome inhibitor approved for the treatment of multiple myeloma and mantle cell lymphoma after one prior therapy. It is also effective in other plasma cell disorders and non-Hodgkin lymphomas. The main mechanism of action of bortezomib is to inhibit the chymotrypsin-like site of the 20S proteolytic core within the 26S proteasome, thereby inducing cell-cycle arrest and apoptosis. The pharmacokinetic profile of intravenous bortezomib is characterized by a two-compartment model with a rapid initial distribution phase followed by a longer elimination phase and a large volume of distribution. Bortezomib is available for subcutaneous and intravenous administration. Pharmacokinetic studies comparing subcutaneous and intravenous bortezomib demonstrated that systemic exposure was equivalent for both routes; pharmacodynamic parameters of 20S proteasome inhibition were also similar. Renal impairment does not influence the intrinsic pharmacokinetics of bortezomib. However, moderate or severe hepatic impairment causes an increase in plasma concentrations of bortezomib. Therefore, patients with moderate or severe hepatic impairment should start at a reduced dose. Because bortezomib undergoes extensive metabolism by hepatic cytochrome P450 3A4 and 2C19 enzymes, certain strong cytochrome P450 3A4 inducers and inhibitors can also alter the systemic exposure of bortezomib. This article critically reviews and summarizes the clinical pharmacokinetics and pharmacodynamics of bortezomib at various dosing levels and routes of administration as well as in specific patient subsets. In addition, we discuss the clinical efficacy and safety of bortezomib.
The development of brentuximab vedotin has opened a new era in the management of peripheral T-cell lymphomas (PTCLs). The improved outcomes with brentuximab vedotin (BV) in combination with ...cyclophosphamide, doxorubicin, and prednisone (BV-CHP) vs cyclophosphamide, doxorubicin, vincristine, and prednisone in the ECHELON-2 trial are practice changing for common nodal CD30+ PTCLs. Questions regarding the optimal cutoff of CD30 expression for BV-CHP therapy and the efficacy and safety of BV-CHP in less common subtypes of CD30+ PTCL subtypes await clarification.
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The success of programmed cell death protein 1 (PD-1)/PD-L1-based immunotherapy highlights the critical role played by PD-L1 in cancer progression and reveals an urgent need to develop new approaches ...to attenuate PD-L1 function by gaining insight into how its expression is controlled. Anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK+ ALCL) expresses a high level of PD-L1 as a result of the constitutive activation of multiple oncogenic signaling pathways downstream of ALK activity, making it an excellent model in which to define the signaling processes responsible for PD-L1 upregulation in tumor cells. Here, using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 library screening, we sought a comprehensive understanding of the molecular effectors required for PD-L1 regulation in ALK+ ALCL. Indeed, we determined that PD-L1 induction is dependent on the nucleophosmin-ALK oncoprotein activation of STAT3, as well as a signalosome containing GRB2/SOS1, which activates the MEK-ERK and PI3K-AKT signaling pathways. These signaling networks, through STAT3 and the GRB2/SOS1, ultimately induce PD-L1 expression through the action of transcription factors IRF4 and BATF3 on the enhancer region of the PD-L1 gene. IRF4 and BATF3 are essential for PD-L1 upregulation, and IRF4 expression is correlated with PD-L1 levels in primary ALK+ ALCL tissues. Targeting this oncogenic signaling pathway in ALK+ ALCL largely inhibited the ability of PD-L1-mediated tumor immune escape when cocultured with PD-1-positive T cells and natural killer cells. Thus, our identification of this previously unrecognized regulatory hub not only accelerates our understanding of the molecular circuitry that drives tumor immune escape but also provides novel opportunities to improve immunotherapeutic intervention strategies.
•Unbiased CRISPR screens revealed a novel transcription hub containing IRF4 and BATF3, which directly control PD-L1 expression in ALK+ ALCL.•IRF4 and BATF3 are tightly regulated by a signaling network downstream of the nucleophosmin-ALK, through STAT3 and the GRB2/SOS1 signalosome.
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Non-Hodgkin lymphomas (NHL) are cancers of mature B-, T-, and NK-cells which display marked biological heterogeneity between different subtypes. Mature T- and NK-cell neoplasms are an ...often-aggressive subgroup of NHL and make up approximately 15% of all NHL. Long-term follow up studies have demonstrated that patients with relapsed/refractory disease have dismal outcomes; in particular, secondary central nervous system (CNS) involvement is associated with higher mortality, though it remains controversial whether this independently confers worse outcomes or if it simply reflects more aggressive systemic disease. Possible risk factors predictive of CNS involvement, such as an elevated lactate dehydrogenase and more than two sites of extranodal involvement, may suggest the latter, though several studies have suggested that discrete sites of anatomic involvement or tumor histology may be independent risk factors as well. Ultimately, small retrospective case series form the basis of our understanding of this rare but devastating event but have not yet demonstrated a consistent benefit of CNS-directed prophylaxis in preventing this outcome. Nonetheless, ongoing efforts are working to establish the epidemiology of CNS progression/relapse in mature T- and NK-cell lymphomas with the goal of identifying clinicopathologic risk factors, which may potentially help discern which patients may benefit from CNS-directed prophylactic therapy or more aggressive systemic therapy.
Mantle cell lymphoma (MCL) is a rare, heterogeneous B-cell non-Hodgkin's lymphoma. The standard front-line treatment utilizes chemotherapy, often followed by consolidation with an autologous ...hematopoietic cell transplant; however, in most patients, the lymphoma will recur and require subsequent treatments. Additionally, mantle cell lymphoma primarily affects older patients and is frequently chemotherapy-resistant, which has further fostered the necessity for new, chemotherapy-free treatment options. In the past decade, targeted therapies in mantle cell lymphoma have been practice-changing as the treatment paradigm shifts further away from relying primarily on cytotoxic agents. Here, we will review the pathophysiology of mantle cell lymphoma and discuss the emergence of targeted, chemotherapy-free treatments aimed at disrupting the abnormal biology driving its lymphomagenesis. Treatments targeting the constitutive activation of NF-kB, Bruton's Tyrosine Kinase signaling, and anti-apoptosis will be the primary focus as we discuss their clinical data and toxicities. Our review will also focus primarily on the emergence and use of targeted therapies in the relapsed/refractory setting but will also discuss the emergence of their use in front-line therapy and in combination with other agents.
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