Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma

Wang, Michael L.; Jurczak, Wojciech; Jerkeman, Mats; Trotman, Judith; Zinzani, Pier Luigi; Belada, David; Boccomini, Carola; Flinn, Ian W.; Giri, Pratyush; Goy, André; Hamlin, Paul A.; Hermine, Olivier; Hernández‐Rivas, José‐Ángel; Hong, Xin; Kim, Seok Jin; Lewis, David; Mishima, Yuko; Özcan, Muhıt; Perini, Guilherme Fleury; Pocock, Christopher; Song, Yuqin; Spurgeon, Stephen E.; Storring, John M.; Walewski, Jan; Zhu, Jun; Qin, Rui; Henninger, T.; Deshpande, Sanjay; Howes, Angela; Gouill, Steven Le; Dreyling, Martin

doi:10.1056/nejmoa2201817

Cited by 105 publications

(92 citation statements)

References 23 publications

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“…We analyzed protein phosphorylation and found, as expected, that KAN0441571C prevented phosphorylation of ROR1 in a dose-dependent manner in all MCL cell lines ( Figure S2B ). Previous studies of ROR1 inhibitors in tumor cells from other hematological malignancies have indicated the involvement of both WNT non-canonical (PI3K/AKT/mTOR) and WNT canonical (beta-catenin) signaling pathways, as well as downregulation of the intrinsic apoptotic pathway, including cleavage of caspase 3 [ 12 , 27 , 28 ]. When primary MCL cells were analyzed, we also found that in addition to the prevention of ROR1 phosphorylation, PI3K, AKT, and mTOR were also subsequently dephosphorylated ( Figure 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…In the present study, the expression of ROR1 in MCL cells was characterized and the apoptotic effects of a novel ROR1 inhibitor, KAN0441571C, were evaluated in in vitro and ex vivo preclinical models as well as in combination with therapeutics with other MOAs of clinical relevance (ibrutinib, idelalisib, bendamustine, everolimus, and venetoclax) that are currently used for the treatment of patients with MCL [ 28 ] or have shown promising results in clinical trials. The results indicate that a small molecule ROR1 inhibitor might be a promising new drug candidate that warrants further evaluation in preclinical models and clinical trials in difficult-to-treat MCL patients.…”

Section: Introductionmentioning

confidence: 99%

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A ROR1 Small Molecule Inhibitor (KAN0441571C) Induced Significant Apoptosis of Mantle Cell Lymphoma (MCL) Cells

et al. 2022

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The receptor tyrosine kinase orphan receptor 1 (ROR1) is absent in most normal adult tissues but overexpressed in various malignancies and is of importance for tumor cell survival, proliferation, and metastasis. In this study, we evaluated the apoptotic effects of a novel small molecule inhibitor of ROR1 (KAN0441571C) as well as venetoclax (BCL-2 inhibitor), bendamustine, idelalisib (PI3Kδ inhibitor), everolimus (mTOR inhibitor), and ibrutinib (BTK inhibitor) alone or in combination in human MCL primary cells and cell lines. ROR1 expression was evaluated by flow cytometry and Western blot (WB). Cytotoxicity was analyzed by MTT and apoptosis by Annexin V/PI staining as well as signaling and apoptotic proteins (WB). ROR1 was expressed both in patient-derived MCL cells and human MCL cell lines. KAN0441571C alone induced significant time- and dose-dependent apoptosis of MCL cells. Apoptosis was accompanied by decreased expression of MCL-1 and BCL-2 and cleavage of PARP and caspase 3. ROR1 was dephosphorylated as well as ROR1-associated signaling pathway molecules, including the non-canonical WNT signaling pathway (PI3Kδ/AKT/mTOR). The combination of KAN0441571C and ibrutinib, venetoclax, idelalisib, everolimus, or bendamustine had a synergistic apoptotic effect and significantly prevented phosphorylation of ROR1-associated signaling molecules as compared to KAN0441571C alone. Our results suggest that targeting ROR1 by a small molecule inhibitor, KAN0441571C, should be further evaluated particularly in combination with other targeting drugs as a new therapeutic approach for MCL.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A ROR1 Small Molecule Inhibitor (KAN0441571C) Induced Significant Apoptosis of Mantle Cell Lymphoma (MCL) Cells

et al. 2022

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“…As resistance to ibrutinib therapy in MCL is common, its combination with other agents may reduce the risk for relapse [38]. Recently, multiple trials tested the efficacy of ibrutinib in combination with anti-CD20 monoclonal antibodies rituximab or obinutuzumab, and the small molecules venetoclax, bendamustine, and lenalidomide [39][40][41]. Although their anti-tumor activity is complementary to ibrutinib, a drug that overcomes specifically acquired ibrutinib resistance may be a superior partner.…”

Section: Discussionmentioning

confidence: 99%

CD52 and OXPHOS—potential targets in ibrutinib-treated mantle cell lymphoma

et al. 2022

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Altered features of tumor cells acquired across therapy can result in the survival of treatment-resistant clones that may cause minimal residual disease (MRD). Despite the efficacy of ibrutinib in treating relapsed/refractory mantle cell lymphoma, the obstacle of residual cells contributes to relapses of this mature B-cell neoplasm, and the disease remains incurable. RNA-seq analysis of an ibrutinib-sensitive mantle cell lymphoma cell line following ibrutinib incubation of up to 4 d, corroborated our previously postulated resistance mechanism of a metabolic switch to reliance on oxidative phosphorylation (OXPHOS) in surviving cells. Besides, we had shown that treatment-persisting cells were characterized by increased CD52 expression. Therefore, we hypothesized that combining ibrutinib with another agent targeting these potential escape mechanisms could minimize the risk of survival of ibrutinib-resistant cells. Concomitant use of ibrutinib with OXPHOS-inhibitor IACS-010759 increased toxicity compared to ibrutinib alone. Targeting CD52 was even more efficient, as addition of CD52 mAb in combination with human serum following ibrutinib pretreatment led to rapid complement-dependent-cytotoxicity in an ibrutinib-sensitive cell line. In primary mantle cell lymphoma cells, a higher toxic effect with CD52 mAb was obtained, when cells were pretreated with ibrutinib, but only in an ibrutinib-sensitive cohort. Given the challenge of treating multi-resistant mantle cell lymphoma patients, this work highlights the potential use of anti-CD52 therapy as consolidation after ibrutinib treatment in patients who responded to the BTK inhibitor to achieve MRD negativity and prolong progression-free survival.

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“…The addition of bendamustine [ 238 ] or lenalidomide [ 175 ] into the ibrutinib–rituximab regime showed promising activity and tolerability. In the phase 3 SHINE study, ibrutinib plus the BR regime resulted in a drastic prolongation of 2.3 years in the median PFS in TN older MCL patients (≥ 65 years old) after a median follow-up of 7 years compared with patients treated with only BR [ 173 ]. These results strongly supported the addition of ibrutinib to the standard first-line BR treatment regime for an increased opportunity of durable disease control to inhibit or delay relapse in older MCL patients who are unsuitable for autologous stem cell transplantation.…”

Section: Btk Inhibitors In Hematological Malignanciesmentioning

confidence: 99%

BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies

Alu

Han

et al. 2022

J Hematol Oncol

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Bruton’s tyrosine kinase (BTK) is an essential component of multiple signaling pathways that regulate B cell and myeloid cell proliferation, survival, and functions, making it a promising therapeutic target for various B cell malignancies and inflammatory diseases. Five small molecule inhibitors have shown remarkable efficacy and have been approved to treat different types of hematological cancers, including ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, and orelabrutinib. The first-in-class agent, ibrutinib, has created a new era of chemotherapy-free treatment of B cell malignancies. Ibrutinib is so popular and became the fourth top-selling cancer drug worldwide in 2021. To reduce the off-target effects and overcome the acquired resistance of ibrutinib, significant efforts have been made in developing highly selective second- and third-generation BTK inhibitors and various combination approaches. Over the past few years, BTK inhibitors have also been repurposed for the treatment of inflammatory diseases. Promising data have been obtained from preclinical and early-phase clinical studies. In this review, we summarized current progress in applying BTK inhibitors in the treatment of hematological malignancies and inflammatory disorders, highlighting available results from clinical studies.

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Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma

Cited by 105 publications

References 23 publications

A ROR1 Small Molecule Inhibitor (KAN0441571C) Induced Significant Apoptosis of Mantle Cell Lymphoma (MCL) Cells

A ROR1 Small Molecule Inhibitor (KAN0441571C) Induced Significant Apoptosis of Mantle Cell Lymphoma (MCL) Cells

CD52 and OXPHOS—potential targets in ibrutinib-treated mantle cell lymphoma

BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies

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