Seminars in hematology最新文献

Diffuse Large B Cell Lymphoma (DLBCL) is an aggressive but often curable malignancy. Older patients, especially those 80 years and older, have poor outcomes compared to those < 60, likely due to a number of reasons including disease biology, comorbidities, and treatment intolerance. Prospective data informing the treatment of older patients and those with multiple co-morbidities is limited. Here, we intend to review available data for regimens other than standard R-CHOP (rituximab, cyclophosphamide, adriamycin, prednisone) or R-pola-CHP (rituximab, polatuzumab vedotin [pola], cyclophosphamide, adriamycin, prednisone), tools available that may aid in treatment selection, and future directions, including the incorporation of newer treatment modalities into therapy for more vulnerable patients.

F-fluorodeoxyglucose positron emission tomography-computerised tomography (¹⁸ FDG-PET/CT) is the gold-standard imaging modality for staging and response assessment for most lymphomas. This review focuses on the utility of ¹⁸ FDG-PET/CT, and its role in staging, prognostication and response assessment in diffuse large B-cell lymphoma (DLBCL), including emerging possibilities for future use.

In the era of immunochemotherapy, approximately 60%–70% of diffuse large B-cell lymphoma (DLBCL) patients achieve remission with first-line rituximab-based chemoimmunotherapy. However, 30-40% relapse after initial response to first line therapy and, out of them, 20% to 50% are refractory or experience early relapse. The second-line therapy algorithm for DLBCL has recently evolved, thanks to the recent approval of new therapeutic agents or their combinations. The new guidelines suggest a stratification of relapsed/refractory (R/R) DLBCL based on the time to relapse. For transplant-eligible patients, autologous stem cell transplant remains the preferred option when the patient relapses after 12 months from diagnosis, while anti-CD19 CART-cell therapy is the current preferred choice for high-risk DLBCL, defined as primary refractory or relapse ≤ 12 month. For transplant-ineligible or CAR T-cell therapy-ineligible patients, the therapeutic arsenal historically lacked effective options. However, new therapeutic options, including polatuzumab vedotin combined with bendamustine-rituximab and tafasitamab with lenalidomide, have been recently approved, and novel agents such as loncastuximab tesirine, selinexor, anti-CD19 CAR T-cell therapy and bispecific antibodies have shown promising efficacy and manageable safety in this setting offering new hope to patients in this challenging scenario.

Over the last decade, CD19-targeting chimeric antigen receptor (CAR) T-cell therapy has profoundly changed the management of relapsed/refractory large-B-cell lymphoma (LBCL). At present, there are three FDA-approved anti-CD19 CAR T-cell products for LBCL: axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), and tisagenlecleucel (tisa-cel). Two of these (axi-cel & liso-cel) are approved for use in the second-line setting under certain conditions. As CAR T-cell therapy continues to define a new role in the treatment armamentarium for LBCL, questions remain regarding which product to use and how to sequence CAR T-cell therapy with other therapeutic options. Here we will briefly review the key features of each FDA-approved anti-CD19 CAR T-cell product and the data that led to regulatory approval for each. Next, we will focus on the recent landmark studies that have established the use of CAR T-cell therapy as second-line treatment. While no direct prospective head-to-head comparisons exist of the three constructs, we will review some retrospective studies that suggest some emerging differences between the products. Lastly, we will turn our attention to the horizon as we explore some of the ongoing questions of how to best leverage the curative potential of CAR T-cell therapy for the most effective management of LBCL. These areas include the consideration of CAR T-cell therapy in the frontline setting, the optimal timing for CAR T-cell referral, the optimal bridging approach, and how to continue advancing novel CAR T-cell approaches in the context of the current treatment landscape.

Chimeric antigen receptor T (CAR-T) cell therapy is an effective treatment for relapsed or refractory diffuse large B cell lymphoma (DLBCL) with three CD19 targeting products now FDA-approved for this indication. However, up to 60% of patients ultimately progress or relapse following CAR-T cell therapy. Mechanisms of resistance to CAR-T cell therapy in patients with DLBCL are likely multifactorial and have yet to be fully elucidated. Determining patient, tumor and therapy-related factors that may predict an individual's response to CAR-T cell therapy requires on-going analysis of data from clinical trials and real-world experience in this population. In this review we will discuss the factors identified to-date that may contribute to failure of CAR-T cell therapy in achieving durable remissions in patients with DLBCL.

Diffuse large B-cell lymphoma (DLBCL) is heterogeneous both in clinical outcomes and the underlying disease biology. Over the last two decades, several different approaches for dissecting biological heterogeneity have emerged. Gene expression profiling (GEP) stratifies DLBCL into three broad groups (ABC, GCB, and DZsig/MHG), each with parallels to different normal mature B cell developmental states and prognostic implications. More recently, several different genomic approaches have been developed to categorize DLBCL based on the co-occurrence of tumor somatic mutations, identifying more granular biologically unified subgroups that complement GEP-based approaches. We review the molecular approaches and clinical evidence supporting the stratification of DLBCL patients based on tumor biology. By offering a platform for subtype-guided therapy, these divisions remain a promising avenue for improving patient outcomes, especially in subgroups with inferior outcomes with current standard-of-care therapy.

Central nervous system (CNS) lymphoma has traditionally had very poor outcomes however advances in management have resulted in dramatic improvements and long-term survival of patients. We describe the evidence for treatment strategies in these aggressive disorders. In primary CNS lymphoma (PCNSL) there are randomised trial data to inform treatment decisions but these are lacking to guide management in secondary CNS lymphoma (SCNSL). Dynamic assessment of patient fitness and frailty is key throughout treatment, alongside delivery of CNS-bioavailable therapy and enrolment in clinical trials, at each stage of the disease. Intensive high-dose methotrexate-containing induction followed by consolidation with autologous stem cell transplantation with thiotepa-based conditioning is recommended for patients who are fit. Less intensive chemoimmunotherapy, novel agents (including Bruton tyrosine kinase inhibitors, cereblon targeting immunomodulatory agents and checkpoint inhibitors in the context of clinical trials) and whole brain radiotherapy may be reserved for less fit patients or disease which is chemoresistant. Data regarding the efficacy of CAR-T therapy is emerging, and concerns regarding greater toxicity have not been realised. Future areas of prospective studies include identification of those at high risk of developing CNS lymphoma, management in elderly or frail patients as well as incorporating novel agents into regimens particularly for those with chemoresistant disease.

As the most common non-Hodgkin lymphoma subtype, diffuse large B-cell lymphoma (DLBCL) incidence patterns generally parallel that for NHL overall. Globally, DLBCL accounts for a third of all NHLs, ranging between 20%-50% by country. Based on U.S. cancer registry data, age-standardized incidence rate for DLBCL was 7.2 per 100,000. DLBCL incidence rises with age and is generally higher in males than females; in the U.S., incidence is highest among non-Hispanic whites (9.2 per 100,000). Like NHL incidence, DLBCL incidence rose in the first half of the 20^th century but has largely plateaued. However, there is some evidence that incidence rates are rising in areas of historically low rates, such as Asia; there are also estimates for rising DLBCL incidence in the near future due to the changing demographics in developed countries whose aging population is growing. Established risk factors for DLBCL include those that result in severe immune deficiency such as HIV/AIDS, inherited immunodeficiency syndromes, and organ transplant recipients. Factors that lead to chronic immune dysregulations are also established risk factors, and include a number of autoimmune conditions (e.g., Sjögren syndrome, systemic lupus erythematosus, rheumatoid arthritis), viral infections (e.g., HIV, KSHV/HHV8, HCV, EBV), and obesity. Family history of NHL/DLBCL, personal history of cancer, and multiple genetic susceptibility loci are also well-established risk factors for DLBCL. There is strong evidence for multiple environmental exposures in DLBCL etiology, including exposure to trichloroethylene, benzene, and pesticides and herbicides, with recent associations noted with glyphosate. There is also strong evidence for associations with other viruses, such as HBV. Recent estimates suggest that obesity accounts for nearly a quarter of DLBCLs that develop, but despite recent gains in the understanding of DLBCL etiology, the majority of disease remain unexplained. An understanding of the host and environmental contributions to disease etiology, and concerted efforts to expand our understanding to multiple race/ethnic groups, will be essential for constructing clinically relevant risk prediction models and develop effective strategies for disease prevention.

Transformation to diffuse large B-cell lymphoma (DLBCL) is a recognized, but unpredictable, clinical inflection point in the natural history of indolent lymphomas. Large retrospective studies highlight a wide variability in the incidence of transformation across the indolent lymphomas and the adverse outcomes associated with transformed lymphomas. Opportunities to dissect the biology of transformed indolent lymphomas have arisen with evolving technologies and unique tissue collections enabling a growing appreciation, particularly, of their genetic basis, how they relate to the preceding indolent lymphomas and the comparative biology with de novo DLBCL. This review summarizes our current understanding of both the clinical and biological aspects of transformed lymphomas and the outstanding questions that remain.