Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression

Jacobsen, Eric; Sharman, Jeff P.; Oki, Yasuhiro; Advani, Ranjana H.; Winter, Jane N.; Bello, Celeste M.; Spitzer, Gary; Palanca-Wessels, Maria Corinna; Kennedy, Dallas C.; Levine, Pamela; Yang, Jing; Bartlett, Nancy L.

doi:10.1182/blood-2014-09-598763

Cited by 252 publications

(222 citation statements)

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“…To date, four studies have already addressed this issue and failed to demonstrate any correlation between response to BV and the level of CD30 expression on tumor cells. 4,5,6,10 In the previous report on systemic non-ALCL PTCL, 4 more than 80% of the cases featured no or low levels of CD30 expression (<25% of CD30 + tumor cells), and as in our study, some patients with only a weak CD30 expression on tumor cells responded to BV, raising the question of the mechanism of BV action in these cases. However, the heterogeneity of CD30 expression in our population highlights the likelihood for better response for patients with strong CD30 expression by tumor cells.…”

Section: Letters To the Editormentioning

confidence: 48%

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Brentuximab vedotin in refractory or relapsed peripheral T-cell lymphomas: the French named patient program experience in 56 patients

et al. 2015

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Section: Letters To the Editormentioning

confidence: 48%

“…Mathilde Lamarque, 1,2,3 Céline Bossard, 4 Adrien Contejean, 5,6 Pauline Brice, 6 Marie Parrens, 7 Steven Le Gouill, 8,9 Josette Brière, 10 Reda Bouabdallah, 11 …”

Section: 1112unclassified

Brentuximab vedotin in refractory or relapsed peripheral T-cell lymphomas: the French named patient program experience in 56 patients

et al. 2015

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“…Importantly, another phase II clinical trial proved the efficacy of brentuximab vedotin in CD30-positive non-Hodgkin lymphoma with lower CD30 expression levels. The objective response rate in CD30-positive diffuse large B-cell lymphoma was 44% (13). Moreover, this study concluded that brentuximab vedotin can be combined safely with rituximab for simultaneous treatment of CD20-positive lymphomas.…”

mentioning

confidence: 71%

“…Clinical studies have also highlighted the lack of precise quantification methods to estimate CD30 expression in lymphomas as a current impediment to optimum patient management (11)(12)(13)(14). At present, it remains unclear whether there exists a threshold level of CD30-positive lymphoma cells that is required for effective brentuximab vedotin treatment.…”

mentioning

confidence: 99%

Immuno-PET Imaging of CD30-Positive Lymphoma Using ⁸⁹Zr-Desferrioxamine–Labeled CD30-Specific AC-10 Antibody

et al. 2015

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The CD30-specific antibody-drug conjugate, brentuximab vedotin, is approved for the treatment of relapsed, refractory Hodgkin lymphomas and systemic anaplastic large T-cell lymphomas. Multiple ongoing clinical trials are investigating brentuximab vedotin efficacy in other CD30-positive hematologic malignancies. Because CD30 expression varies among different types of lymphoma and can also change during the course of treatment, companion diagnostic imaging of CD30 could be a valuable tool in optimizing patient-specific brentuximab vedotin treatment regimens. Methods: The mouse antihuman CD30 antibody AC-10 was radiolabeled with the positron-emitting radionuclide 89 Zr. The stability and specificity of 89 Zr-desferrioxamine (DFO)-labeled CD30-specific AC-10 antibody ( 89 Zr-DFO-AC-10) was evaluated in vitro. The pharmacokinetics of 89 Zr-DFO-AC-10 was studied in BALB/c nude mice bearing subcutaneous human Karpas 299 tumors (CD30-positive model) or A-431 tumors (CD30-negative model) using PET/CT imaging, biodistribution studies, and autoradiography. Results: AC-10 was conjugated with a DFO B chelator and radiolabeled with 89 Zr to give formulated 89 Zr-DFO-AC-10 with a radiochemical yield of 80%, radiochemical purity greater than 99%, and specific activity of 111-148 MBq/mg. 89 Zr-DFO-AC-10 was stable in mouse and human sera and preserved the immunoreactivity toward CD30. Biodistribution data showed the highest tissue accumulation of 89 Zr-DFO-AC-10 in CD30-positive tumors, with 37.9% ± 8.2% injected activity per gram of tissue at 72 h after injection, whereas uptake in CD30-negative tumors was 11.0% ± 0.4%. The specificity of 89 Zr-DFO-AC-10 binding to CD30 in vivo was confirmed by blocking studies. Time-activity curves showed that between 24 and 144 h after injection, tumor-to-muscle ratios increased from 18.9 to 51.8 in the CD30-positive model and from 4.8 to 8.7 in the CD30-negative model. Tumor-to-blood ratios also increased, from 3.2 to 13.6 and from 1 to 2 in the CD30-positive and -negative models, respectively. Conclusion: Our results demonstrate that for measuring CD30 expression, 89 Zr-DFO-AC-10 is a sensitive PET agent with high tumor-to-normal-tissue contrast. 89 Zr-DFO-AC-10 is a promising CD30-imaging radiotracer for clinical translation in patients with various lymphomas and other diseases. CD30,amemberoft he tumor necrosis factor receptor superfamily, is expressed by Reed-Sternberg cells and used as a primary diagnostic marker for Hodgkin lymphoma (1). CD30 is also highly expressed on the surface of some T-cell lymphomas, especially on anaplastic large cell lymphoma, and at variable levels on a subset of other non-Hodgkin lymphomas, including diffuse large B-cell lymphoma (2-4). Expression of CD30 in healthy tissues is restricted to activated T and B cells, and the receptor cannot be found outside the immune system (2,5). High expression levels on specific cancers and limited presentation in healthy tissues make CD30 an ideal target for antibody-based molecular therapies.Brentuximab vedotin (Adcentri...

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“…Fázis II. klinikai vizsgálatban refrakter/relabáló DLBCL esetén a brentuximab vedotin (ADCETRIS) monoterápia kedvező eredményeket mutatott [46]. Az eredmények alapján további vizsgála-tok indulnak a brentuximab vedotin kombinációs kezelés alkalmazásával DLBCL első vonalban is.…”

Section: A Dlbcl Kezelése Maunclassified

A diffúz nagy B-sejtes lymphoma modern szemlélete és kezelése

Gergely

Illés

2016

Orvosi Hetilap

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A diffúz nagy B-sejtes lymphoma a leggyakoribb a non-Hodgkin-lymphomák között. A ciklofoszfamid-vincristinadriablastin-prednisolon kemoterápiával a betegeknek már közel 50%-a meggyógyítható volt, majd a rituximab hozzáadásával a gyógyulási arány már 60% fölé emelkedett. Ez a javulás jelentős, de további növekedést kellene elérni a betegek gyógyulási arányában. Az utóbbi években elvégzett genetikai vizsgálatok számos új, a patogenezisben is szerepet játszó és terápiás célpontként is szolgáló mutációt azonosítottak a betegségben. A diagnosztika ma már rutinszerűen alkalmazza a 18-fluoro-deoxi-glükóz-pozitronemissziós komputertomográfiás vizsgálatokat a Lugano klasszifikációs rendszer részeként. Ezen adatok alapján egyre pontosabban meghatározható a betegek prognózisa, és kiválaszthatók azok a betegek, akik valamelyik új, szelektíven ható gyógyszerre esetleg reagálhatnak. Mindezeknek a kérdéseknek a megválaszolása, az újabb kezelések bevezetése várhatóan a közeli jövőben tovább fogja javítani a betegek túlélési esélyeit. Az összefoglaló közlemény áttekintést ad a közelmúlt újdonságairól, kiemeli a ma használatos és javasolt kezeléseket, továbbá áttekintést ad a jelenleg kipróbálás alatt álló és bevezetendő kezelésekről is. Orv. Hetil., 2016, 157(31), 1232-1241. Kulcsszavak: lymphoma, DLBCL, kezelés Recent advances in the understanding and treatment of diffuse large B-cell lymphomaDiffuse large B-cell lymphoma is the most common type of non-Hodgkin's lymphoma. Using the conventional cyclophosphamide adriablastin vincristin prednisolon polychemotherapy about 50% of the patients were cured. The addition of rituximab to the regimen increased the cure rate to 60%. This is a major improvement, however, further advance is still needed to increase the cure rate. The extensive genetic testing performed recently revealed several important pathognomic mutations as potential targets in this disease. Routine diagnosis of patients now includes the use of 18 Fluor-deoxy-glucose positron emission computer tomography, according to the recent Lugano classification system. With all these data we can better predict the prognosis of patients, and we can select candidates for novel targeted therapies as well. Answering these questions, and utilizing novel therapies possibly will further increase the cure rate in the near future. This paper summarizes current diagnostic and therapeutic approaches and describes recent understanding in the mutations and pathognomic changes resulting in the disease. The authors also summarize the data available on experimental therapies possibly entering clinical pratice in the forthcoming years. Keywords: lymphoma, DLBCL, treatmentGergely, L., Illés, Á. [Recent advances in the understanding and treatment of diffuse large B-cell lymphoma]. Orv. Hetil., 2016, 157(31), 1232-1241. (Beérkezett: 2016 elfogadva: 2016. május Rövidítések 18 FDG = 18-fluoro-deoxi-glükóz; ABC = aktivált B-sejtes; ADCC = antitest-közvetített sejt mediálta citotoxicitás; antiHBc = hepatitis B-vírus-mag-antigén elleni ellenanyag; ...

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Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression

Cited by 252 publications

References 32 publications

Brentuximab vedotin in refractory or relapsed peripheral T-cell lymphomas: the French named patient program experience in 56 patients

Brentuximab vedotin in refractory or relapsed peripheral T-cell lymphomas: the French named patient program experience in 56 patients

Immuno-PET Imaging of CD30-Positive Lymphoma Using ⁸⁹Zr-Desferrioxamine–Labeled CD30-Specific AC-10 Antibody

A diffúz nagy B-sejtes lymphoma modern szemlélete és kezelése

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Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression

Cited by 252 publications

References 32 publications

Brentuximab vedotin in refractory or relapsed peripheral T-cell lymphomas: the French named patient program experience in 56 patients

Brentuximab vedotin in refractory or relapsed peripheral T-cell lymphomas: the French named patient program experience in 56 patients

Immuno-PET Imaging of CD30-Positive Lymphoma Using 89Zr-Desferrioxamine–Labeled CD30-Specific AC-10 Antibody

A diffúz nagy B-sejtes lymphoma modern szemlélete és kezelése

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Immuno-PET Imaging of CD30-Positive Lymphoma Using ⁸⁹Zr-Desferrioxamine–Labeled CD30-Specific AC-10 Antibody