Latest advances in the management of classical Hodgkin lymphoma: the era of novel therapies.
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ABSTRACT:
SUBMITTER: Mohty R
PROVIDER: S-EPMC8270913 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Standard treatment for relapsed and/or refractory (r/r) Hodgkin lymphoma (HL) consists of salvage therapy, historically consisting of multiagent cytotoxic chemotherapy, followed by autologous stem cell transplantation (autoHCT) in responding patients. With this approach, most patients can proceed to autoHCT, of whom approximately half are cured. However, the introduction of the novel agents brentuximab vedotin (BV) and the checkpoint inhibitors (CPI) nivolumab and pembrolizumab has changed the decision making and peri-transplant decision making, as early incorporation of one or more of these agents can reduce or even eliminate the need for cytotoxic chemotherapy prior to autoHCT. Furthermore, post-autoHCT maintenance therapy with BV has also been shown to decrease relapse in high-risk rel/ref HL patients. In this review, we survey the current data regarding autoHCT in HL with a focus on pre-autoHCT salvage as well as maintenance strategies, and we also talk about the emerging data challenging the long-held dogma of chemosensitivity being a requirement for successful autoHCT.
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Project description:Classical Hodgkin lymphoma (HL) relapses after or is refractory to upfront multiagent chemotherapy in 20%-30% of patients. Effective salvage therapy for relapsed or refractory HL is limited, and advancements are needed. Brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, has demonstrated significant activity and manageable toxicities in advanced HL. Currently approved as a monotherapy for patients with HL that is relapsed or refractory to multiple lines of chemotherapy or autologous stem cell transplantation, BV is now being evaluated earlier in the course of disease and in combination with other therapies. This review discusses the successful translation of BV from its conception to the clinical setting and highlights ongoing trials that may ultimately expand its role in relapsed or refractory HL and improve outcomes for patients.
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Project description:Hodgkin lymphoma (HL) is a rare cancer of the immune system that typically affects lymph nodes and sometimes other organs. Although the majority of patients can be potentially cured with the use of multi-agent chemotherapy and radiotherapy, a proportion of them will relapse or develop resistant disease for which treatment options are limited. In recent years, new agents have been developed and tested in HL with encouraging results. Two classes of drugs stand out as highly active in advanced HL based on recent study results: antibody-drug conjugates and programmed death 1 inhibitors. Clinical trials in HL with these agents have been completed in the past several years and the results have recently become available. In this review, we discuss the recent advances in the management of HL with a focus on strategies to decrease toxicity and a review of the two drug classes that have the potential to change the landscape of treatment of this disease.
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Project description:Addition of brentuximab vedotin, a CD30-targeted antibody-drug conjugate, and the programmed death 1 (PD-1) inhibitors nivolumab and pembrolizumab to the armamentarium for transplant-ineligible relapsed/refractory classical Hodgkin lymphoma has resulted in improved outcomes, including the potential for cure in a small minority of patients. For patients who have failed prior transplant or are unsuitable for dose-intense approaches based on age or comorbidities, an individualized approach with sequential use of single agents such as brentuximab vedotin, PD-1 inhibitors, everolimus, lenalidomide, or conventional agents such as gemcitabine or vinorelbine may result in prolonged survival with a minimal or modest effect on quality of life. Participation in clinical trials evaluating new approaches such as combination immune checkpoint inhibition, novel antibody-drug conjugates, or cellular therapies such as Epstein-Barr virus-directed cytotoxic T lymphocytes and chimeric antigen receptor T cells offer additional options for eligible patients.
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Project description:Pemphigus represents a group of rare and severe autoimmune intra-epidermal blistering diseases affecting the skin and mucous membranes. These painful and debilitating diseases are driven by the production of autoantibodies that are mainly directed against the desmosomal adhesion proteins, desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1). The search to define underlying triggers for anti-Dsg-antibody production has revealed genetic, environmental, and possible vaccine-driven factors, but our knowledge of the processes underlying disease initiation and pathology remains incomplete. Recent studies point to an important role of T cells in supporting auto-antibody production; yet the involvement of the myeloid compartment remains unexplored. Clinical management of pemphigus is beginning to move away from broad-spectrum immunosuppression and towards B-cell-targeted therapies, which reduce many patients' symptoms but can have significant side effects. Here, we review the latest developments in our understanding of the predisposing factors/conditions of pemphigus, the underlying pathogenic mechanisms, and new and emerging therapies to treat these devastating diseases.
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Project description:Hodgkin lymphoma, a hematological malignancy of lymphoid origin that typically arises from germinal-center B cells, has an excellent overall prognosis. However, the treatment of patients who relapse or develop resistant disease still poses a substantial clinical and research challenge, even though current risk-adapted and response-based treatment techniques produce overall survival rates of over 95%. The appearance of late malignancies after the successful cure of primary or relapsed disease continues to be a major concern, mostly because of high survival rates. Particularly in pediatric HL patients, the chance of developing secondary leukemia is manifold compared to that in the general pediatric population, and the prognosis for patients with secondary leukemia is much worse than that for patients with other hematological malignancies. Therefore, it is crucial to develop clinically useful biomarkers to stratify patients according to their risk of late malignancies and determine which require intense treatment regimens to maintain the ideal balance between maximizing survival rates and avoiding late consequences. In this article, we review HL's epidemiology, risk factors, staging, molecular and genetic biomarkers, and treatments for children and adults, as well as treatment-related adverse events and the late development of secondary malignancies in patients with the disease.
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Project description:Classical Hodgkin lymphoma (cHL) is one of the most prevalent lymphomas with a unique cell composition compared to other lymphoma entities. Rare, malignant Hodgkin and Reed-Sternberg (HRS) cells embedded with an extensive but ineffective immune infiltration were previously characterized by a large number of genetic and epigenetic alterations. Recently, microRNA profiling studies highlighted the importance of small non-coding RNA in cHL. This review summarizes available literature data and provides a detailed comparison of four studies where cHL cell lines and microdissected HRS cells were used. Several microRNAs were found to be consistently up- (let-7-f, mir-9, mir-21, mir-23a, mir-27a, mir-155, and mir-196a) or downregulated (mir-138 and mir-150) in cHL. These deregulated microRNAs are involved in the processes crucial for cHL pathogenesis, such as impaired B cell development (mir-9, mir-150, and mir-155), NFκB hyperactivation (mir-155 and mir-196a), and immune evasion (mir-138). Therefore, the deregulation of microRNA expression can be considered a complementary mechanism to genetic alterations promoting lymphomagenesis. Moreover, the expression of let-7f, mir-9 and mir-27a is specific for cHL and can serve as a biomarker to distinguish this lymphoma from other B cell lymphomas. However, additional in-depth and high throughput analysis of microRNA expression in HRS cells is necessary to decipher the complete picture of microRNA in cHL.
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Project description:Classical Hodgkin lymphoma (cHL) is the most common type of HL that occurs mainly in people aged between 15-30 and over 55 years. Although its general prognosis is favorable, 10%-30% of patients with cHL will ultimately develop relapsed or refractory disease (r/r cHL). Improving the cure rate of r/r cHL has proven to be challenging. Some novel agents, such as brentuximab vedotin and immune checkpoint inhibitors, which have been used in conventional regimens for patients with r/r cHL in the past decade, have been shown to have good curative effects. This paper reviews the conventional regimens for patients with r/r cHL and focuses on the newest clinical trials and treatment measures to prolong prognosis and reduce adverse events. The evaluation of prognosis plays a vital role in analyzing the risk of relapse or disease progression; thus, finding new predictive strategies may help treat patients with r/r cHL more efficaciously.
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Project description:The current standard approach for relapsed or refractory (R/R) Hodgkin lymphoma (HL) is salvage chemotherapy, followed by autologous stem cell transplantation (ASCT). However, this therapeutic regimen is successful in only half of patients with relapsed or refractory classical HL. In addition, some patients with R/R HL are ineligible for ASCT. To improve survival time and quality of life and decrease the acute and long-term toxicities of therapy, many schemes for the treatment of R/R HL have emerged. Recently, the use of targeted therapy and immunotherapy represents an important advance in the treatment of R/R HL. The CD30 antibody drug conjugate brentuximab vedotin (BV) and programmed death-1 (PD-1) receptor checkpoint inhibitors nivolumab and pembrolizumab are effective and well-tolerated treatments for R/R HL patients, broadening treatment options for these patients. BV and anti-PD-1 antibodies can be used as monotherapy or combined with other chemotherapy regimens for rescue treatment, consolidation treatment and second-line treatment of R/R HL. In this article, we review current pathobiology knowledge of R/R HL and summarize recent advances in therapy schemes.
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Project description:Classical Hodgkin lymphoma (cHL) is a hematopoietic malignancy with a characteristic cellular composition. The tumor mass is made up of infiltrated lymphocytes and other cells of hematologic origin but only very few neoplastic cells that are mainly identified by the diagnostic marker CD30. While most patients with early stage cHL can be cured by standard therapy, treatment options for relapsed or refractory cHL are still not sufficient, although immunotherapy-based approaches for the treatment of cHL patients have gained ground in the last decade. Here, we suggest a novel therapeutic concept based on oncolytic viruses selectively destroying the CD30+-positive cHL tumor cells. Relying on a recently described CD30-specific scFv we have generated CD30-targeted measles virus (MV-CD30) and vesicular stomatitis virus (VSV-CD30). For VSV-CD30 the VSV glycoprotein G reading frame was replaced by those of the CD30-targeted MV glycoproteins. Both viruses were found to be highly selective for CD30-positive cells as demonstrated by infection of co-cultures of target and non-target cells as well as through blocking infection by soluble CD30. Notably, VSV-CD30 yielded much higher titers than MV-CD30 and resulted in a more rapid and efficient killing of cultivated cHL-derived cell lines. Mouse tumor models revealed that intratumorally, as well as systemically injected VSV-CD30, infected cHL xenografts and significantly slowed down tumor growth resulting in a substantially prolonged survival of tumor-bearing mice. Taken together, the data support further preclinical testing of VSV-CD30 as novel therapeutic agent for the treatment of cHL and other CD30+-positive malignancies.
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