Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial

Prince, H. Miles; Kim, Youn H; Horwitz, Steven M.; Dummer, Reinhard; Scarisbrick, Julia; Quaglino, Pietro; Zinzani, Pier Luigi; Wolter, Pascal; Ortiz‐Romero, Pablo L.; Geskin, Larisa J.; Trotman, Judith; Taylor, Kerry; Dalle, S.; Weichenthal, Michael; Walewski, Jan; Dréno, Brigitte; Stadler, Rudolf; Feldman, Tatyana; Wang, Yinghui; Palanca-Wessels, Maria Corinna; Zagadailov, Erin; Trepicchio, William L.; Zhang, Wenwen; Lin, Huimin; Liu, Yi; Huebner, Dirk; Little, Meredith; Whittaker, Sean; Duvic, Madeleine; Joske, David; Lewis, Ian D.; Jonak, Constanze; Trautinger, Franz; Bechter, Oliver; Bron, Dominique; Lima, Vladmir Cláudio Cordeiro de; Sanches, José Antônio; Klasa, Richard; Bagot, M.; Beylot‐Barry, M.; D’Incan, M.; Grange, Florent; Nicolay, Jan P.; Wobser, Marion; Assaf, Chalid; Loquai, Carmen; Spina, Michele; Bosi, Alberto; Fattori, Pier Paolo; Grzanka, Alina; López-Hernández, Andrés; Roca, José J. Rifón; Novelli, Silvana; Illidge, Tim; Johnson, Rod; Morris, Stephen; McKay, Pam; Akilov, Oleg E.; Horwitz, Steve; Pro, Barbara; Kuzel, Timothy M.; Lerner, Adam; Eradat, Herbert; Sokol, Lubomir; Fisher, David C.; Hughey, S. Morgan

doi:10.1016/s0140-6736(17)31266-7

Cited by 457 publications

(444 citation statements)

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“…Multiple systemic therapies exist for advanced CTCL. With the recent exception of brentuximab vedotin which has a 65% objective response rate for CD30+ CTCL [4], most systemic CTCL therapies have at best a 30%-40% objective response rate. They are rarely curative, and each has its own unique set of clinically significant side effects.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Studies Support Combined Inhibition of BET Family Proteins and Histone Deacetylases as Epigenetic Therapy for Cutaneous T-Cell Lymphoma

et al. 2019

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Advanced-stage cutaneous T-cell lymphoma (CTCL) is usually a fatal malignancy despite optimal use of currently available treatments. In this preclinical study of novel CTCL therapy, we performed in vitro and ex vivo experiments to determine the efficacy of combination treatment with a panel of BET bromodomain inhibitors (BETi) (JQ1, OTX015, CPI-0610, I-BET762) and HDAC inhibitors (HDACi) (SAHA/Vorinostat, Romidepsin). BETi/HDACi combinations were synergistic (combination index <1) against cell viability and induced G0/G1 cell cycle arrest. Apoptosis was uniformly enhanced. From a mechanistic standpoint, proliferative drivers c-Myc, Cyclin D1, NFkB, and IL-15Rα were reduced. Inhibitory CDKN1A was increased. CDKN1B, IL-7R, IL-17Rα, STAT3, and STAT5 alterations varied. There were significant increases in extrinsic apoptotic pathway death receptors and ligands (FasL, DR4, DR5, TRAIL, and TNFR1). At clinically tolerable levels of single agents, Romidepsin (1 nM) + OTX015 (125 nM) induced the greatest apoptosis (60%_80%) at 96 hours. Ex vivo studies of leukemic CTCL cells obtained from patients with Sezary syndrome also showed higher levels of apoptosis (about 60%-90%) in response to combination treatments relative to single agents. In contrast, combination treatment of normal CD4+ T cells induced only minimal apoptosis (<10%). Our findings show that the mechanism of action of BETi/HDACi therapy in CTCL involves induction of both cell cycle arrest and apoptosis with reduced proliferative drivers and enhanced expression of apoptotic extrinsic pathway death receptors and ligands. Relative to single agents, the superior anti-CTCL effects of BETi/HDACi combinations in vitro and ex vivo provide a rationale for clinical trials exploring their efficacy as therapy for CTCL.

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Section: Introductionmentioning

confidence: 99%

Preclinical Studies Support Combined Inhibition of BET Family Proteins and Histone Deacetylases as Epigenetic Therapy for Cutaneous T-Cell Lymphoma

et al. 2019

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“…The introduction of targeted therapy in CD30‐expressing CTCL is promising in the response rate and response duration in multifocal disease with respect to conventional systemic therapies (MTX and bexarotene), but in the case of brentuximab vedotin, it is accompanied by a peripheral neuropathy in more than half of patients, and long‐term effects are still unknown.…”

Section: Discussionmentioning

confidence: 99%

Radiotherapy of primary cutaneous anaplastic large cell lymphoma: our experience in 30 cases

et al. 2020

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Background Since the observation of new cases of primary cutaneous anaplastic large cell lymphoma (PCALCL) with a seemingly aggressive clinical presentation and a favorable response to radiation therapy (RT), a review of our series has been performed to evaluate the results of RT. Materials and methods The study is a retrospective analysis of 30 patients with PCALCL treated with conventional energy RT. Results About 55 fields of irradiation were performed. Complete clinical response (CCR) was obtained in 29 cases and a partial clinical response (PCR) in one. Two lesions had a marginal relapse at 7 and 37 months, respectively. In eight cases, new lesions appeared in the same body district and in six cases, in body sites at distance from the field of treatment. Total radiation dose ranged from 15 to 35 Gy (median 25 Gy). Follow‐up range was 2–218 months (median 38.5 months) with a local control rate of 85% and a relapse‐free rate of 49% at 5 years from RT. Three cases developed a nodal involvement. Conclusions PCALCL belongs to the group of primary cutaneous CD30+ lymphoproliferative disorders, accounting for 25–30% of cutaneous T‐cell lymphomas. RT is considered of choice as alternative to surgical excision of solitary lesions. Recent studies have focused on ideal dose to obtain local control indicating 30 Gy as adequate, but others have hypothesized that lower doses may suffice. Our study confirms the excellent role of RT in the local control of the disease with total doses ≤25 Gy.

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“…Brentuximab vedotin is an antibody‐drug‐conjugate directed against the CD30 antigen. A clinical trial of brentuximab vedotin in relapsed/refractory peripheral T‐cell lymphoma demonstrated an overall response rate of 41%, while another trial demonstrated a response rate of 56% in CD30 + CTCL . Additionally, expression of CD30 5% or greater in MF/Sézary syndrome patients correlates with more frequent response …”

Section: Discussionmentioning

confidence: 99%

Primary cutaneous aggressive epidermotropic cytotoxic CD8⁺ T‐cell lymphoma: long‐term remission after brentuximab vedotin

et al. 2017

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Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial

Cited by 457 publications

References 25 publications

Preclinical Studies Support Combined Inhibition of BET Family Proteins and Histone Deacetylases as Epigenetic Therapy for Cutaneous T-Cell Lymphoma

Preclinical Studies Support Combined Inhibition of BET Family Proteins and Histone Deacetylases as Epigenetic Therapy for Cutaneous T-Cell Lymphoma

Radiotherapy of primary cutaneous anaplastic large cell lymphoma: our experience in 30 cases

Primary cutaneous aggressive epidermotropic cytotoxic CD8⁺ T‐cell lymphoma: long‐term remission after brentuximab vedotin

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Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial

Cited by 457 publications

References 25 publications

Preclinical Studies Support Combined Inhibition of BET Family Proteins and Histone Deacetylases as Epigenetic Therapy for Cutaneous T-Cell Lymphoma

Preclinical Studies Support Combined Inhibition of BET Family Proteins and Histone Deacetylases as Epigenetic Therapy for Cutaneous T-Cell Lymphoma

Radiotherapy of primary cutaneous anaplastic large cell lymphoma: our experience in 30 cases

Primary cutaneous aggressive epidermotropic cytotoxic CD8+ T‐cell lymphoma: long‐term remission after brentuximab vedotin

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Product

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Primary cutaneous aggressive epidermotropic cytotoxic CD8⁺ T‐cell lymphoma: long‐term remission after brentuximab vedotin