Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study

Stilgenbauer, Stephan; Eichhorst, Barbara; Schetelig, Johannes; Coutre, Steven; Seymour, John F.; Munir, Talha; Puvvada, Soham D.; Wendtner, Clemens; Roberts, Andrew W.; Jurczak, Wojciech; Mulligan, Stephen P.; Böttcher, Sebastian; Mobasher, Mehrdad; Zhu, Ming; Desai, Monali; Chyla, Brenda; Verdugo, Maria; Enschede, Sari H.; Cerri, Elisa; Humerickhouse, Rod; Gordon, Gary; Hallek, Michael; Wierda, William G.

doi:10.1016/s1470-2045(16)30019-5

Cited by 690 publications

(631 citation statements)

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“…Venetoclax is a promising new molecular therapy that is currently being evaluated in clinical trials for different hematological malignancies (14,15,36). However, the limited number of complete remissions (14) and the emergence of resistance with venetoclax as single agent prompts for a systematic evaluation of combinations with rationally-designed small molecules to assess its true therapeutic potential.…”

Section: Discussionmentioning

confidence: 99%

“…Venetoclax has recently also been approved by the FDA for the treatment of chronic lymphocytic leukemia (CLL). Indeed, clinical trials demonstrated progress-free survival in more than two thirds of relapsed CLL patients (14), including poor prognostic CLL patients that carry a 17p deletion (15). Nevertheless, complete remission remained uncommon (14), further reinforcing the need for the evaluation of combined therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

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Targeting BET proteins improves the therapeutic efficacy of BCL-2 inhibition in T-cell acute lymphoblastic leukemia

et al. 2017

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Inhibition of anti-apoptotic BCL-2 has recently emerged as a promising new therapeutic strategy for the treatment of a variety of human cancers, including leukemia. Here, we used T-cell acute lymphoblastic leukemia as a model system to identify novel synergistic drug combinations with the BH3 mimetic venetoclax . In vitro drug screening in primary leukemia specimens that were derived from patients with high risk of relapse or relapse and cell lines revealed synergistic activity between venetoclax and the BET bromodomain inhibitor JQ1. Notably, this drug synergism was confirmed in vivo using T-ALL cell line and patient-derived xenograft models. Moreover, the therapeutic benefit of this drug combination might, at least in part, be mediated by an acute induction of the pro-apoptotic factor BCL2L11 and concomitant loss of BCL-2 upon BET bromodomain inhibition, ultimately resulting in an enhanced binding of BIM (encoded by BCL2L11) to BCL-2. Altogether, our work provides a rationale to develop a new type of targeted combination therapy for selected subgroups of high-risk leukemia patients.Leukemia accepted article preview online, 11 January 2017. doi:10.1038/leu.2017.10. This is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication. NPG are providing this early version of the manuscript as a service to our customers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply. Conflict of interestThe authors declare no conflict of interest.© 2017 Macmillan Publishers Limited. All rights reserved.3 AbstractInhibition of anti-apoptotic BCL-2 has recently emerged as a promising new therapeutic strategy for the treatment of a variety of human cancers, including leukemia. Here, we used T-cell acute lymphoblastic leukemia as a model system to identify novel synergistic drug combinations with the BH3 mimetic venetoclax . In vitro drug screening in primary leukemia specimens that were derived from patients with high risk of relapse or relapse and cell lines revealed synergistic activity between venetoclax and the BET bromodomain inhibitor JQ1. Notably, this drug synergism was confirmed in vivo using T-ALL cell line and patient-derived xenograft models. Moreover, the therapeutic benefit of this drug combination might, at least in part, be mediated by an acute induction of the pro-apoptotic factor BCL2L11 and concomitant loss of BCL-2 upon BET bromodomain inhibition, ultimately resulting in an enhanced binding of BIM (encoded by BCL2L11) to BCL-2.Altogether, our work provides a rationale to develop a new type of targeted combination therapy for selected subgroups of high-risk leukemia patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting BET proteins improves the therapeutic efficacy of BCL-2 inhibition in T-cell acute lymphoblastic leukemia

et al. 2017

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“…Overall response rate (ORR) determined by an independent review was achieved in 85 (79.4%) patients with a median follow-up of 12.1 months. 38 Response rates were similar regardless of whether the patients were refractory to prior fludarabine-based therapy. The clinical responses of CLL patients were also independent of del17p, TP53 mutation, and TP53 function.…”

Section: The Development Of Venetoclax As Monochemotherapymentioning

confidence: 93%

Development of venetoclax for therapy of lymphoid malignancies

Zhu

Almasan

2017

DDDT

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B-cell lymphoma-2 (BCL-2) family dysfunction and impairment of apoptosis are common in most B-cell lymphoid malignancies. Venetoclax (Venclexta™, formerly ABT-199, GDC-0199) is a highly selective BCL-2 inhibitor, which mimics its BCL-2 homology 3-domain to induce apoptosis. It was approved for treatment of previously treated chronic lymphocytic leukemia (CLL) patients with 17p deletion early in 2016. It has also been in clinical trials for other B-cell lymphoid malignancies. Unlike the other recently approved targeted agents idelalisib and ibrutinib, so far there has been no relapse reported in some patients. Also, unlike the other targeted agents, it is effective against tumor cells that reside in the blood marrow. Despite its promising outcome in CLL, preclinical data have already uncovered mechanistic insights underlying venetoclax resistance, such as upregulation of MCL-1 or BCL-xL expression and protective signaling from the microenvironment. In this review, we describe the role of the BCL-2 family in the pathogenesis of B-cell lymphoid malignancies, the development of venetoclax, and its current clinical outcome in CLL and other B-cell malignancies. We also discuss the resistance mechanisms that develop following venetoclax therapy, potential strategies to overcome them, and how this knowledge can be translated into clinical applications.

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“…Ezen eltérések prognosztikailag egyenrangúak, így a nemzetközi irodalomban együtt, TP53-defektus néven szerepelnek, amely a legrosszabb prognózisú, nagy rizikójú betegcsoportot definiáló genetikai eltérés [19][20][21]. A TP53-deficiens betegek kemoimmuno-terápiára nem vagy alig reagálnak, így ennek a betegcsoportnak az azonosítása kiemelt jelentőségű, mivel az újonnan megjelenő célzott terápiáknak (ibrutinib, idelalisib, venetoclax) köszönhetően több, ebben a csoportban is hatékony kezelési lehetőség áll rendelkezésre [22][23][24]. A két laesio előfordulhat külön-külön vagy együtt is, utóbbi esetben az egyik allélon mutáció, a má-sikon deletio jelentkezik.…”

Section: A Tp53-státuszunclassified

“…A Bcl-2 fehérjecsalád (Bcl-2, Bcl-xL és Mcl-1) feladata az apoptó-zisindukció (proapoptotic) vagy -gátlás (antiapoptotic) szabályozása, így a Bcl-2 fehérje egy nélkülözhetetlen apoptózist gátló molekula [40]. Egy multicentrikus fázis 2 klinikai vizsgálat eredményeire alapozva törzskönyvez-ték relabált 17p-CLL-es betegek kezelésére [22]. Egyéves medián utánkövetésnél az átlagos reagálás (overall response rate -ORR) 79,4% volt.…”

Section: úJ Típusú Molekulák: Kinázgátlók Bcl-2-gátlásunclassified

A krónikus lymphocytás leukaemia korszerű molekuláris diagnosztikája és kezelése az új célzott terápiák korszakában

et al. 2017

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A krónikus lymphocytás leukaemia (CLL) heterogén klinikai lefolyású lymphoproliferativ betegség, amelyben számos klinikai és molekuláris prognosztikai marker nyújt segítséget a leghatékonyabb terápia megválasztásában. Eddig a TP53-defektus bizonyult kulcsfontosságú prognosztikai és prediktív faktornak, amely befolyásolja a terápiás döntést, különösen az új célzott kezelések érájában. A tünetmentes, korai stádiumú betegek nem igényelnek kezelést, követé-sük javasolt (úgynevezett "watch and wait"). Első vonalban a standard rizikójú CLL-es betegek többségében a standard kezelés továbbra is a kemo-immuno terápia. Az új orálisan alkalmazható kis molekulájú gyógyszereknek, mint a kinázinhibitorok (KI) és a Bcl-2-gátlók (ibrutinib, idelalisib és venetoclax), elsősorban relabáló/refrakter CLL kezelésében van helyük, ez alól kivétel az ibrutinib-monoterápia, amely a nagy rizikójú (TP53-defektust hordozó) betegek első vonalbeli kezelésére is javasolt. A nem túl távoli jövőben az új generációs szekvenálás diagnosztikába történő integrálása támogathatja majd a CLL-es betegek személyre szabott ellátását és az optimális kezelési stratégia megvá-lasztását. Orv Hetil. 2017; 158(41): 1620-1629.Kulcsszavak: krónikus lymphocytás leukaemia, prognosztikai marker, TP53-defektus, kemo-immuno terápia, célzott kezelés, ibrutinib, venetoclax State of the art molecular diagnostics and therapy of chronic lymphocytic leukaemia in the era of new targeted therapiesChronic lymphoid leukaemia (CLL) has a heterogeneous clinical course depending on many clinical and molecular prognostic markers, which play an important role in the selection of the best treatment option. So far, TP53 disruption is the key prognostic and predictive factor assisting treatment decisions, especially in the era of novel therapies. Asymptomatic patients in early stages of the disease will still benefit from watchful waiting. In the frontline setting, chemoimmunotherapy is still the standard care in the majority of standard risk CLL patients. New classes of drugs like kinase inhibitors and BCL-2 inhibitors (ibrutinib, idelalisib and venetoclax) are the treatment of choice in CLL patients with relapsed/refractory disease, with the exception of high risk disease, where the optimal treatment is frontline ibrutinib monotherapy. In the near future, integrating next generation sequencing into the routine diagnostics would help the development of individual CLL patient management and to choose an optimal treatment strategy.

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Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study

Cited by 690 publications

References 28 publications

Targeting BET proteins improves the therapeutic efficacy of BCL-2 inhibition in T-cell acute lymphoblastic leukemia

Targeting BET proteins improves the therapeutic efficacy of BCL-2 inhibition in T-cell acute lymphoblastic leukemia

Development of venetoclax for therapy of lymphoid malignancies

A krónikus lymphocytás leukaemia korszerű molekuláris diagnosztikája és kezelése az új célzott terápiák korszakában

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