Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE-TN): a randomised, controlled, phase 3 trial

Sharman, Jeff P.; Egyed, Miklós; Jurczak, Wojciech; Skarbnik, Alan P; Pagel, John M.; Flinn, Ian W.; Kamdar, Manali; Munir, Talha; Walewska, Renata; Corbett, Gillian; Fogliatto, Laura; Herishanu, Yair; Banerji, Versha; Coutre, Steven; Follows, George; Walker, Patricia; Karlsson, Karin; Ghia, Paolo; Janssens, Ann; Cymbalista, Florence; Woyach, Jennifer A.; Salles, Gilles; Wierda, William G.; Izumi, Raquel; Munugalavadla, Veerendra; Patel, Priti; Wang, Minhui; Wong, S. S.; Byrd, John C.

doi:10.1016/s0140-6736(20)30262-2

Cited by 457 publications

(507 citation statements)

References 28 publications

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“…112 Finally, the alternative BTK inhibitor acalabrutinib was recently approved by the FDA (not by the EMA yet) as frontline therapy in view of the results of a phase III trial comparing acalabrutinib versus ClbO. 114…”

Section: Frontline Therapymentioning

confidence: 99%

Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies

et al. 2020

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Chronic lymphocytic leukemia is a well-defined lymphoid neoplasm with very heterogeneous biological and clinical behavior. The last decade has been remarkably fruitful in novel findings elucidating multiple aspects of the pathogenesis of the disease including mechanisms of genetic susceptibility, insights into the relevance of immunogenetic factors driving the disease, profiling of genomic alterations, epigenetic subtypes, global epigenomic tumor cell reprogramming, modulation of tumor cell and microenvironment interactions, and dynamics of clonal evolution from early steps in monoclonal B cell lymphocytosis to progression and transformation into diffuse large B-cell lymphoma. All this knowledge has offered new perspectives that are being exploited therapeutically with novel target agents and management strategies. In this review we provide an overview of these novel advances and highlight questions and perspectives that need further progress to translate into the clinics the biological knowledge and improve the outcome of the patients.

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Section: Frontline Therapymentioning

confidence: 99%

Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies

et al. 2020

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“…Using second generation BTKis we did not observe a synergistic effect, although the combination of acalabrutinib and obinutuzumab was shown to improve progressionfree survival for patients with treatment-naive symptomatic CLL (39). Here, the high single-agent activity of each drug or ADCP-independent mechanisms of synergy are probably reflecting the superior clinical response in CLL.…”

Section: Discussionmentioning

confidence: 76%

Macrophage-mediated antibody dependent effector function in aggressive B-cell lymphoma treatment is enhanced by Ibrutinib via inhibition of JAK2

Barbarino

Henschke

Blakemore

et al. 2020

Preprint

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Targeted inhibition of Bruton's Tyrosine Kinase (BTK) with ibrutinib and other agents has become important treatment options in chronic lymphocytic leukemia, Waldenström´s Macroglobulinemia, Mantle cell lymphoma and non-GCB DLBCL. Clinical trials combining small molecule inhibitors with monoclonal antibodies have been initiated at rapid pace, with the biological understanding between their synergistic interactions lagging behind. Here, we have evaluated the synergy between BTK inhibitors and monoclonal antibody therapy via macrophage mediated antibody dependent cellular phagocytosis (ADCP). Initially, we observed increased ADCP with ibrutinib, whilst second generation BTK inhibitors failed to synergistically interact with monoclonal antibody treatment. Kinase activity profiling under BTK inhibition identified significant loss of Janus Kinase 2 (JAK2) only under ibrutinib treatment. We validated this potential off-target effect via JAK inhibition in vitro as well as with CRISPR/Cas9 JAK2 -/experiments in vivo, showing increased ADCP and prolonged survival, respectively. This data supports inhibition of the JAK-STAT signaling pathway in B-cell malignancies in combination with monoclonal antibody therapy to increase macrophage mediated immune responses.

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“…However, the real benefit of obinutuzumab still remains unclear as the control arm of the clinical trial was chlorambucil with obinutuzumab ( 185 ). In the ELEVATE clinical trial, acalabrutinib or acalabrutinib plus obinutuzumab were both superior to chlorambucil plus obinutuzumab ( 170 ). Even though it is not yet clear whether this combination reduces the occurrence of acquired BTK inhibition resistance, it is true that re-distributing malignant cells to the peripheral blood makes malignant cells more susceptible to monoclonal antibodies ( 145 , 186 ).…”

Section: Targeting Ibrutinib Resistancementioning

confidence: 99%

Genetic and Non-Genetic Mechanisms of Resistance to BCR Signaling Inhibitors in B Cell Malignancies

Ondrisova

Mráz

2020

Front. Oncol.

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The approval of BTK and PI3K inhibitors (ibrutinib, idelalisib) represents a revolution in the therapy of B cell malignancies such as chronic lymphocytic leukemia (CLL), mantle-cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), or Waldenström’s macroglobulinemia (WM). However, these “BCR inhibitors” function by interfering with B cell pathophysiology in a more complex way than anticipated, and resistance develops through multiple mechanisms. In ibrutinib treated patients, the most commonly described resistance-mechanism is a mutation in BTK itself, which prevents the covalent binding of ibrutinib, or a mutation in PLCG2, which acts to bypass the dependency on BTK at the BCR signalosome. However, additional genetic aberrations leading to resistance are being described (such as mutations in the CARD11 , CCND1 , BIRC3, TRAF2, TRAF3, TNFAIP3, loss of chromosomal region 6q or 8p, a gain of Toll-like receptor (TLR)/MYD88 signaling or gain of 2p chromosomal region). Furthermore, relative resistance to BTK inhibitors can be caused by non-genetic adaptive mechanisms leading to compensatory pro-survival pathway activation. For instance, PI3K/mTOR/Akt, NFkB and MAPK activation, BCL2, MYC, and XPO1 upregulation or PTEN downregulation lead to B cell survival despite BTK inhibition. Resistance could also arise from activating microenvironmental pathways such as chemokine or integrin signaling via CXCR4 or VLA4 upregulation, respectively. Defining these compensatory pro-survival mechanisms can help to develop novel therapeutic combinations of BTK inhibitors with other inhibitors (such as BH3-mimetic venetoclax, XPO1 inhibitor selinexor, mTOR, or MEK inhibitors). The mechanisms of resistance to PI3K inhibitors remain relatively unclear, but some studies point to MAPK signaling upregulation via both genetic and non-genetic changes, which could be co-targeted therapeutically. Alternatively, drugs mimicking the BTK/PI3K inhibition effect can be used to prevent adhesion and/or malignant B cell migration (chemokine and integrin inhibitors) or to block the pro-proliferative T cell signals in the microenvironment (such as IL4/STAT signaling inhibitors). Here we review the genetic and non-genetic mechanisms of resistance and adaptation to the first generation of BTK and PI3K inhibitors (ibrutinib and idelalisib, respectively), and discuss possible combinatorial therapeutic strategies to overcome resistance or to increase clinical efficacy.

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Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE-TN): a randomised, controlled, phase 3 trial

Cited by 457 publications

References 28 publications

Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies

Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies

Macrophage-mediated antibody dependent effector function in aggressive B-cell lymphoma treatment is enhanced by Ibrutinib via inhibition of JAK2

Genetic and Non-Genetic Mechanisms of Resistance to BCR Signaling Inhibitors in B Cell Malignancies

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