Recent Advances in the Management of Patients with Relapsed/Refractory Follicular Lymphoma.
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ABSTRACT:
SUBMITTER: Pongas G
PROVIDER: S-EPMC8331102 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Follicular lymphoma (FL) is the second most common lymphoma in the United States and is characterized by a variable clinical course, disease heterogeneity, and a relapse-and-remittance pattern historically accompanied by successive shortening of clinical response with every line of treatment. Factors such as progression of disease within 24 months of initial treatment are associated with poor survival outcomes. Although rituximab-based regimens are preferred for early lines of treatment, no clear standard of care exists for treatment of FL in the third-line setting or later as approved third-line treatments have not been compared in a prospective, randomized clinical trial. Rather, physicians may choose from several therapeutic classes with different safety profiles and dosing regimens, with consideration of patient and disease factors. Here we describe 2 hypothetical patients with relapsing or remitting FL, an elderly patient with comorbidities, and a younger patient whose FL progressed within 24 months. These cases are used to highlight key factors that clinicians should consider when selecting therapies for relapsed or refractory FL, such as patient frailty, age, comorbidities, as well as quality of life and patient-specific preferences for less intrusive treatment regimens or longer remission times.
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Project description:Large strides have been made in the treatment of follicular lymphoma (FL) over the last few years. Although the majority of patients respond to upfront therapy, many experience disease progression with a progressive shortening of subsequent treatment free intervals. New treatment options are therefore crucial for such patients. Tazemetostat is a first-in-class, selective, oral inhibitor of enhancer of zester homolog 2 (EZH2), a histone methyltransferase that is mutated in about a quarter of FL cases. Tazemetostat was recently approved for the treatment of patients with relapsed FL after 2 or more prior lines of therapy in the presence of an EZH2 mutation and for those without any other available therapeutic option, independently of EZH2 mutation status. In this review, we will summarize the background and key data that led to the development of tazemetostat, and, ultimately, to its approval for this indication.
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Project description:Hodgkin's lymphoma (HL) is diagnosed in 20,000 men and women annually in North America and Europe. Despite treatment advancements for HL resulting in an overall survival rate of 80%, patients with advanced stage disease continue to have suboptimal outcomes, with relapse rates of 30%-40%. An additional 10%-15% of patients present with primary refractory disease. For patients who relapse after initial treatment, salvage chemotherapy followed by autologous stem cell transplant in those with chemotherapy-sensitive disease is the standard of care. Patients who relapse after second-line therapy have a median survival time in the range of 6-36 months, and the optimal management of these patients remains unclear. Unfortunately, there have been no new agents approved for relapsed HL treatment since the 1970s. Consequently, clinical decision making in this population is difficult. Recently however, several agents have emerged that have shown clinical promise in this poor-risk population. This review discusses the management of these patients and also discusses several newer agents showing clinical promise in the treatment of HL.
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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:With no treatment standard having been established for relapsed and refractory follicular lymphoma, a number of therapeutic approaches are used in Canada. In patients who relapse early or who eventually become resistant to subsequent treatment, prognosis is poor, and new approaches are needed. A number of novel therapies are being examined in this setting, including monoclonal antibodies, immunoconjugates, immunomodulatory agents, and signal transduction inhibitors. With the body of evidence for those emerging therapies accumulating and the standard upfront treatment changing from rituximab and chop (cyclophosphamide-doxorubicin-vincristine-prednisone) or rituximab and cvp (cyclophosphamide-vincristine-prednisone) to bendamustine and rituximab, treatment decisions in the relapsed and refractory setting have become more complex. The choice of subsequent treatment must consider type of upfront treatment; duration of remission; and patient-related factors such as age, comorbidities, and treatment preferences. This paper summarizes the evidence for novel therapies and proposes recommendations for subsequent treatment options by remission duration after induction and maintenance.
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Project description:The ELARA trial indicates tisagenlecleucel (tisa-cel) is an effective anti-CD19 chimeric antigen receptor T-cell therapy for relapsed or refractory follicular lymphoma (r/r FL). As ELARA is a single-arm trial, this study compares tisa-cel outcomes from the ELARA trial with usual care from a real-world cohort. ELARA enrolled 98 patients as of 29 March 2021 (median follow-up: 15 months from enrollment). Usual care data were obtained from ReCORD-FL, a global retrospective study of patients with r/r FL, who met similar eligibility criteria to ELARA. With a data cutoff date of 31 December 2020, 187 patients with ≥2 preceding treatment lines were included in the ReCORD-FL (median follow-up: 57 months from third-line) study. An indirect treatment comparison was performed for 97 patients from the ELARA trial and 143 patients from the ReCORD-FL study with no missing data on baseline factors. The line of therapy for which outcomes were assessed was selected or matched between cohorts using propensity score modeling. After baseline factor adjustment via weighting by odds, complete response rate (CRR; 95% confidence interval) was 69.1% (59.8%-78.3%) for tisa-cel vs. 37.3% (26.4%-48.3%) for usual care; overall response rate was 85.6% (78.7%-92.5%) vs. 63.6% (52.5%-74.7%). Kaplan-Meier probability of being progression/event-free at 12 months was 70.5% (61.4%-79.7%) for tisa-cel vs. 51.9% (40.6%-63.3%) for usual care, with hazard ratio (HR)=0.60 (0.34-0.86); 12-month overall survival was 96.6% (92.9%-100%) vs. 71.7% (61.2%-82.2%), with HR=0.2 (0.02-0.38). In conclusion, tisa-cel was associated with a 1.9-fold higher complete response rate and a 1.4-fold higher rate of being progression or event free at 12 months vs usual care, as well as a death risk reduction of 80%. The findings provide additional evidence on the benefit of tisa-cel in patients with r/r FL after ≥2 treatment lines. This trial was registered at www.clinicaltrials.gov as NCT03568461.
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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:The management of follicular lymphoma (FL) in the relapsed and refractory setting is challenging and an area of ongoing investigation. Epigenetic dysregulation has recently been shown to be a hallmark of FL. Mutations in histone-modifying genes are likely early, driver events in FL pathogenesis, and so are attractive targets to drug. Gain-of-function mutations in the histone methyltransferase EZH2 are common in FL and maintained through disease evolution. With mounting data supporting a critical role for EZH2 as an oncogenic driver for FL, the small molecule inhibitor, tazemetostat, was developed. Tazemetostat has shown promising activity in preclinical models and early phase trials. Importantly, responses were seen in patients with high-risk features. Based on these data, tazemetostat was approved in the US in 2020 for EZH2mut patients with FL who had received at least two prior lines of systemic therapy, or for EZH2wt patients without alternative treatment options. Here, we will review the biology of FL as it pertains to tazemetostat, the available clinical trial data, and future directions for this new therapy.
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Project description:Marginal zone lymphomas (MZLs) consist of a diverse family of malignancies, which are derived from B-cells. The disease subtypes are recognized extranodal, nodal, and splenic MZLs. The disease characteristics, clinical course, and treatment vary considerably based on the site of involvement. In 2017, the US Food and Drug Administration approved ibrutinib, a first in class Bruton's tyrosine kinase inhibitor that revolutionized the care of chronic lymphocytic leukemia patients; for, the treatment of relapsed/refractory MZL based on pivotal open-label Phase II trial demonstrated an overall response rate of 48%, with a complete response rate of 3%, median progression-free survival of 14.2 months, and median overall survival not yet reached at a median follow-up of 19.4 months. In this review, we aim to summarize the current conundrums in the management of MZL and the evolving role of ibrutinib in the treatment of MZL.
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