Outcomes of patients with relapsed/refractory double-expressor B-cell lymphoma treated with ibrutinib monotherapy

Landsburg, Daniel J.; Hughes, Mitchell E.; Koike, Alexa; Bond, David A.; Maddocks, Kami J.; Guo, Ling; Winter, Allison M.; Hill, Brian T.; Ondrejka, Sarah L.; Hsi, Eric D.; Nasta, Sunita Dwivedy; Svoboda, Jakub; Schuster, Stephen J.; Bogusz, Agata M.

doi:10.1182/bloodadvances.2018026401

Cited by 17 publications

(8 citation statements)

References 15 publications

(15 reference statements)

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“…A retrospective analysis of 25 patients with R/R DLBCL DE that were treated with ibrutinib monotherapy showed an OS of 5.5 months similar to the OS of 5.1 months observed in patients with DE DLBCL treated with selinexor. 31 ORR for patients with R/R transformed DLBCL who were treated with ibrutinib monotherapy was 35% 32 compared to 38.7% in the current study. Monotherapy with loncastuximab…”

Section: Discussioncontrasting

confidence: 61%

Comparison of the Effectiveness and Safety of the Oral Selective Inhibitor of Nuclear Export, Selinexor, in Diffuse Large B Cell Lymphoma Subtypes

Casasnovas¹,

Follows²,

Zijlstra³

et al. 2022

Clinical Lymphoma Myeloma and Leukemia

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Section: Discussioncontrasting

confidence: 61%

Comparison of the Effectiveness and Safety of the Oral Selective Inhibitor of Nuclear Export, Selinexor, in Diffuse Large B Cell Lymphoma Subtypes

Casasnovas¹,

Follows²,

Zijlstra³

et al. 2022

Clinical Lymphoma Myeloma and Leukemia

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“…Salvage therapies can have an unacceptably high relapse rate of over 40%, and few patients achieve long-term remission [2,8]. Novel agents, including obinutuzumab, lenalidomide, or ibrutinib, barely demonstrate a significant OS benefit in this high-risk population [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Polatuzumab vedotin–based salvage immunochemotherapy as third-line or beyond treatment for patients with diffuse large B-cell lymphoma: a real-world experience

et al. 2021

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Polatuzumab vedotin (PoV) has recently shown promising activity when combined with rituximab-bendamustine (BR) in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, few studies have described the prognostic factors predicting response. Here, we aimed to evaluate the efficacy and safety profile of PoV-based chemotherapy, including regimens other than BR, as third-line or beyond treatment for patients with R/R DLBCL and to explore prognostic factors. Overall, 40 patients, including 37 with de novo and 3 with transformed DLBCL, were enrolled. The overall response rate was 52.5%, and 25% and 27.5% of patients showed a complete response and partial response, respectively. With a median follow-up of 18.8 months, the median overall survival (OS) of the total cohort was 8.5 months, and that of those receiving subsequent hematopoietic stem cell transplantation (HSCT) was 24 months. Low/intermediate risk according to the revised International Prognostic Index score at diagnosis and before PoV treatment predicted better OS. Furthermore, a normal lactate dehydrogenase level and an absolute lymphocyte count/absolute monocyte count ratio > 1.5 were favorable OS prognostic factors. The most common adverse event was cytopenia, with 42.5% of patients developing febrile neutropenia. Grade 1-3 peripheral neuropathy associated with PoV was reported in 25% of patients and resolved in most patients after the cessation of treatment. In summary, we demonstrated that PoV combined with either BR or other intensive chemotherapy is an effective and well-tolerated salvage option for patients with R/R DLBCL. Subsequent HSCT has the potential to further improve survival outcomes in this high-risk population. Clinicaltrials.gov number: NCT05006534.

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“…However, ibrutinib also binds to other homologous cysteine-containing kinases, such as ITK, EGFR, TEC, and BMX, which result in toxic off-target side-effects, eventually leading to discontinuation of ibrutinib [6][7][8]. The clinical activity of ibrutinib as a single agent in DLBCL has a preferential benefit for patients with ABC-DLBCL but its utility is limited [9][10][11][12]. Despite the efficacy of ibrutinib, clinical responses are variable/partial, often leading to drug resistance and aggressive relapse of the disease.…”

Section: Introductionmentioning

confidence: 99%

Cooperative miRNA-dependent PTEN regulation drives resistance to BTK inhibition in B-cell lymphoid malignancies

Kapoor

Bodo²,

Hill³

et al. 2021

Cell Death Dis

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Aberrant microRNA (miR) expression plays an important role in pathogenesis of different types of cancers, including B-cell lymphoid malignancies and in the development of chemo-sensitivity or -resistance in chronic lymphocytic leukemia (CLL) as well as diffuse large B-cell lymphoma (DLBCL). Ibrutinib is a first-in class, oral, covalent Bruton’s tyrosine kinase (BTK) inhibitor (BTKi) that has shown impressive clinical activity, yet many ibrutinib-treated patients relapse or develop resistance over time. We have reported that acquired resistance to ibrutinib is associated with downregulation of tumor suppressor protein PTEN and activation of the PI3K/AKT pathway. Yet how PTEN mediates chemoresistance in B-cell malignancies is not clear. We now show that the BTKi ibrutinib and a second-generation compound, acalabrutinib downregulate miRNAs located in the 14q32 miRNA cluster region, including miR-494, miR-495, and miR-543. BTKi-resistant CLL and DLBCL cells had striking overexpression of miR-494, miR-495, miR-543, and reduced PTEN expression, indicating further regulation of the PI3K/AKT/mTOR pathway in acquired BTKi resistance. Additionally, unlike ibrutinib-sensitive CLL patient samples, those with resistance to ibrutinib treatment, demonstrated upregulation of 14q32 cluster miRNAs, including miR-494, miR-495, and miR-543 and decreased pten mRNA expression. Luciferase reporter gene assay showed that miR-494 directly targeted and suppressed PTEN expression by recognizing two conserved binding sites in the PTEN 3′-UTR, and subsequently activated AKTSer473. Importantly, overexpression of a miR-494 mimic abrogated both PTEN mRNA and protein levels, further indicating regulation of apoptosis by PTEN/AKT/mTOR. Conversely, overexpression of a miR-494 inhibitor in BTKi-resistant cells restored PTEN mRNA and protein levels, thereby sensitizing cells to BTKi-induced apoptosis. Inhibition of miR-494 and miR-495 sensitized cells by cooperative targeting of pten, with additional miRNAs in the 14q32 cluster that target pten able to contribute to its regulation. Therefore, targeting 14q32 cluster miRNAs may have therapeutic value in acquired BTK-resistant patients via regulation of the PTEN/AKT/mTOR signaling axis.

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Outcomes of patients with relapsed/refractory double-expressor B-cell lymphoma treated with ibrutinib monotherapy

Abstract: Key Points The B-cell receptor signaling pathway is active in diffuse large B-cell lymphomas, with increased expression of MYC and BCL2 protein. The overall response rate was 60% for relapsed/refractory non–germinal center double-expressor lymphoma patients treated with ibrutinib.

Cited by 17 publications

References 15 publications

Comparison of the Effectiveness and Safety of the Oral Selective Inhibitor of Nuclear Export, Selinexor, in Diffuse Large B Cell Lymphoma Subtypes

Comparison of the Effectiveness and Safety of the Oral Selective Inhibitor of Nuclear Export, Selinexor, in Diffuse Large B Cell Lymphoma Subtypes

Polatuzumab vedotin–based salvage immunochemotherapy as third-line or beyond treatment for patients with diffuse large B-cell lymphoma: a real-world experience

Cooperative miRNA-dependent PTEN regulation drives resistance to BTK inhibition in B-cell lymphoid malignancies

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