Activity of brentuximab vedotin in AIDS-related primary effusion lymphoma.
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ABSTRACT:
SUBMITTER: Chang VA
PROVIDER: S-EPMC6418491 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
Publications
Activity of brentuximab vedotin in AIDS-related primary effusion lymphoma.
Chang Victoria A VA Wang Huan-You HY Reid Erin G EG
Blood advances 20190301 5
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Project description:Primary effusion lymphoma (PEL) is an aggressive subtype of non-Hodgkin lymphoma characterized by short survival with current therapies, emphasizing the urgent need to develop new therapeutic approaches. Brentuximab vedotin (SGN-35) is an anti-CD30 monoclonal antibody (cAC10) conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E. Brentuximab vedotin is an effective treatment of relapsed CD30-expressing Classical Hodgkin and systemic anaplastic large cell lymphomas. Herein, we demonstrated that PEL cell lines and primary tumors express CD30 and thus may serve as potential targets for brentuximab vedotin therapy. In vitro treatment with brentuximab vedotin decreased cell proliferation, induced cell cycle arrest, and triggered apoptosis of PEL cell lines. Furthermore, in vivo brentuximab vedotin promoted tumor regression and prolonged survival of mice bearing previously reported UM-PEL-1 tumors as well as UM-PEL-3 tumors derived from a newly established and characterized Kaposi's sarcoma-associated herpesvirus- and Epstein-Barr virus-positive PEL cell line. Overall, our results demonstrate for the first time that brentuximab vedotin may serve as an effective therapy for PEL and provide strong preclinical indications for evaluation of brentuximab vedotin in clinical studies of PEL patients.
| S-EPMC3744990 | biostudies-literature
Project description:Anaplastic large cell lymphoma (ALCL) is the most common type of mature T-cell non-Hodgkin lymphoma in children/adolescents. ALCL is characterized by expression of CD30 in the neoplastic lymphoid cells with frequent expression of anaplastic lymphoma kinase (ALK), especially within the pediatric population. Despite multiple efforts to optimize the use of conventional chemotherapy, outcomes in children, adolescents, and adults with ALCL remain suboptimal. Thus, there is a need to improve survival for those with high-risk disease and decrease therapy exposures and toxicities for those with low-risk disease. Targeted therapies, such as the anti-CD30 antibody-drug conjugate, brentuximab vedotin, are new important therapeutic options. Phase I and II studies in adults with relapsed/refractory CD30+ lymphomas, including ALCL, demonstrated the safety and efficacy of brentuximab vedotin, leading to FDA approval for relapsed/refractory ALCL in adults and successful incorporation into frontline therapies. Clinical trials in the pediatric population demonstrated similar results in those with relapsed/refractory ALCL. Incorporation of brentuximab vedotin into upfront therapy for children and adolescents with ALCL showed that this novel combination therapy has clinical advantages in comparison to conventional agents alone. Brentuximab vedotin is well-tolerated in both the pediatric and adult populations, even when used in combination with conventional agents. Brentuximab vedotin is an ideal agent to treat ALCL with excellent targeted activity and limited toxicity. Future studies are needed to identify how brentuximab vedotin should be utilized when combined with immunotherapy or other targeted agents (e.g., ALK inhibitors) in both the upfront and relapsed/refractory setting.
| S-EPMC10232850 | biostudies-literature
Project description:Intravenous brentuximab vedotin (ADCETRIS®) is a targeted antibody-drug conjugate (ADC) active against CD30-positive cancer cells such as those associated with classical Hodgkin lymphoma (HL). In noncomparative, phase 2 trials and in the real-world setting, salvage therapy with brentuximab vedotin resulted in high objective response (complete plus partial remission) rates in patients with relapsed or refractory CD30-positive HL, including as retreatment in patients who had an objective response to previous brentuximab vedotin therapy and subsequently relapsed. These beneficial outcomes were durable during long-term follow-up. As consolidation therapy after autologous haematopoietic stem cell transplant (ASCT) in the multinational, phase 3 AETHERA trial, brentuximab vedotin prolonged progression-free-survival (PFS) compared with placebo at a median follow-up of 30 months (primary analysis), with a 43% reduction in the risk of disease progression or death. The beneficial effects of brentuximab vedotin consolidation therapy were maintained during long-term follow-up. In the clinical trial and real-world setting, brentuximab vedotin had an acceptable tolerability and safety profile, with most adverse events manageable with dose reductions and/or delays [including peripheral sensory neuropathy (PSN) and neutropenia]. With a paucity of treatments available for many patients with relapsed or refractory HL, brentuximab vedotin represents an important option for the management of patients who have failed high-dose chemotherapy/ASCT or at least two prior chemotherapy regimens and as post-ASCT consolidation therapy in patients who are at increased risk/high-risk of relapse or progression after ASCT.
| S-EPMC7102329 | biostudies-literature
Project description:Brentuximab vedotin (SGN-35; Adcetris®) is an anti-CD30 antibody conjugated via a protease-cleavable linker to the potent anti-microtubule agent monomethyl auristatin E (MMAE). Following binding to CD30, brentuximab vedotin is rapidly internalized and transported to lysosomes where MMAE is released and binds to tubulin, leading to cell cycle arrest and apoptosis. Several trials have shown durable antitumor activity with a manageable safety profile in patients with relapsed/refractory Hodgkin lymphoma, systemic anaplastic large cell lymphoma, or primary cutaneous CD30-positive lymphoproliferative disorders. Peripheral sensory neuropathy is a significant adverse event associated with brentuximab vedotin administration. Neuropathy symptoms are cumulative and dose-related. Multiple ongoing trials are currently evaluating brentuximab vedotin alone or in combination with other agents in relapsed/refractory patients, as well as patients with newly diagnosed disease.
| S-EPMC3499340 | biostudies-literature
Project description:Brentuximab vedotin (cAC10-vcMMAE; SGN 35; SGN-35) is an anticancer antibody-drug conjugate under development by Seattle Genetics Inc. and its licensee Millennium: The Takeda Oncology Company. It comprises the anti-CD30 monoclonal antibody cAC10 conjugated to the cytotoxic agent monomethyl auristatin E, a synthetic analog of the tubulin polymerization inhibitor dolastatin 10. It is under investigation for use in Hodgkin lymphoma and non-Hodgkin lymphoma (specifically anaplastic large cell lymphoma) in North America and Europe. This review discusses the key development milestones and therapeutic trials of this drug.
| S-EPMC3585690 | biostudies-literature
Project description:Despite the relative success of chemotherapy for Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL), novel therapeutic agents are needed for refractory or relapsed patients. Targeted immunotherapy has emerged as a novel treatment option for these patients. Although unconjugated anti-cluster of differentiation (CD)30 antibodies showed minimal antitumor activity in early clinical trials, development of antibody-drug conjugates (ADCs) appears promising. Brentuximab vedotin is an ADC composed of an anti-CD30 antibody linked to a potent microtubule-disrupting agent monomethyl auristatin E (MMAE). It has the ability to target CD30-positive tumor cells and, once bound to CD30, brentuximab vedotin is internalized and MMAE is released to induce cell cycle arrest and apoptosis. In two Phase II trials, objective response was reported in 75% and 86% of patients with refractory or relapsed HL and systemic ALCL, respectively, with an acceptable toxicity profile. Based on these studies, the US Food and Drug Administration (FDA) granted accelerated approval of brentuximab vedotin in August 2011 for the treatment of refractory and relapsed HL and ALCL. We review the key characteristics of brentuximab vedotin, clinical data supporting its therapeutic efficacy, and current ongoing trials to explore its utility in other CD30-positive malignancies.
| S-EPMC3872218 | biostudies-other
Project description:The arrival of the CD30 directed antibody-drug conjugate, brentuximab vedotin (BV), has altered the approach to patients with classical Hodgkin lymphoma. Since initial approval in 2011, BV has been extensively studied in previously untreated and relapsed/refractory patients. Treatment indications for the antibody-drug conjugate have been expanded from the previously treated population to include maintenance therapy after autologous stem cell transplantation and recently, combination with chemotherapy in newly diagnosed advanced stage patients. This article will review the evolution of BV in classical Hodgkin lymphoma, detailing the studies that led to the approved indications and discussion of recent trials in combination with chemotherapy and immunotherapy.
| S-EPMC6910100 | biostudies-literature
Project description:BackgroundIn adults with advanced-stage Hodgkin's lymphoma, the CD30-directed antibody-drug conjugate brentuximab vedotin combined with multiagent chemotherapy has been shown to have greater efficacy, but also more toxic effects, than chemotherapy alone. The efficacy of this targeted therapy approach in children and adolescents with Hodgkin's lymphoma is unclear.MethodsWe conducted an open-label, multicenter, randomized, phase 3 trial involving patients 2 to 21 years of age with previously untreated Hodgkin's lymphoma of stage IIB with bulk tumor or stage IIIB, IVA, or IVB. Patients were assigned to receive five 21-day cycles of brentuximab vedotin with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (brentuximab vedotin group) or the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (standard-care group). Slow-responding lesions, defined by a score of 4 or 5 (on a 5-point scale, with scores of 1 to 3 indicating rapid-responding lesions), were identified on centrally reviewed positron-emission tomography-computed tomography after two cycles. Involved-site radiation therapy was administered after the fifth cycle of therapy to slow-responding lesions and to large mediastinal adenopathy that was present at diagnosis. The primary end point was event-free survival, defined as the time until disease progression occurred, relapse occurred, a second malignant neoplasm developed, or the patient died. Safety and overall survival were assessed.ResultsOf 600 patients who were enrolled across 153 institutions, 587 were eligible. At a median follow-up of 42.1 months (range, 0.1 to 80.9), the 3-year event-free survival was 92.1% (95% confidence interval [CI], 88.4 to 94.7) in the brentuximab vedotin group, as compared with 82.5% (95% CI, 77.4 to 86.5) in the standard-care group (hazard ratio for event or death, 0.41; 95% CI, 0.25 to 0.67; P<0.001). The percentage of patients who received involved-site radiation therapy did not differ substantially between the brentuximab vedotin group and the standard-care group (53.4% and 56.8%, respectively). Toxic effects were similar in the two groups. Overall survival at 3 years was 99.3% (95% CI, 97.3 to 99.8) in the brentuximab vedotin group and 98.5% (95% CI, 96.0 to 99.4) in the standard-care group.ConclusionsThe addition of brentuximab vedotin to standard chemotherapy resulted in superior efficacy, with a 59% lower risk of an event or death, and no increase in the incidence of toxic effects at 3 years. (Funded by the National Institutes of Health and others; AHOD1331 ClinicalTrials.gov number, NCT02166463.).
| S-EPMC9945772 | biostudies-literature
Project description:Monoclonal antibodies (mAb) have become an effective treatment strategy for hematologic malignancies. CD30 is a rational target for therapy due to its limited expression on normal tissues and the strong and uniform expression on malignant cells in classical Hodgkin's lymphoma (cHL) and anaplastic large-cell lymphoma (ALCL). Brentuximab vedotin, an anti-CD30 antibody-drug conjugate, utilizes the targeting properties of mAb to deliver a cytotoxic agent inside the malignant cell. Brentuximab vedotin has significant clinical activity in patients with relapsed or refractory cHL and relapsed or refractory ALCL, and has the potential to represent a significant advance in modern oncology.
| S-EPMC3873074 | biostudies-other
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.
| S-EPMC4418463 | biostudies-literature