Obinutuzumab and venetoclax induced complete remission in a patient with ibrutinib‐resistant non‐nodal leukemic mantle cell lymphoma

Zhou, Xiang; Steinhardt, Maximilian; Düll, Johannes; Krummenast, Franziska; Danhof, Sophia; Meckel, Katharina; Nickel, Katharina; Grathwohl, Denise; Leicht, Hans‐Benno; Rosenwald, Andreas; Einsele, Hermann; Rasche, Leo; Kortüm, Martin

doi:10.1111/ejh.13382

Cited by 6 publications

(3 citation statements)

References 18 publications

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“…Multiple clinical trials looking to evaluate the therapeutic efficacy for ibrutinib in combination with an immunotherapeutic such as anti-CD20 monoclonal antibodies has either been completed or currently underway. Successful therapeutic response was reported in a case study, where a 73-year-old ibrutinib-resistant MCL patient achieved complete remission after three cycles of combination treatment with obinutuzumab and venetoclax [181]. In a phase-3 clinical trial for WM patients, the combination of ibrutinib with rituximab resulted in significantly higher rates of 30 month PFS (82%) compared to rituximab alone (28%) [182].…”

Section: Ibrutinib In Combination With Cd20 Targeting Immunotherapymentioning

confidence: 97%

Ibrutinib Resistance Mechanisms and Treatment Strategies for B-Cell Lymphomas

George

Chowdhury

Hart

et al. 2020

Cancers

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Chronic activation of B-cell receptor (BCR) signaling via Bruton tyrosine kinase (BTK) is largely considered to be one of the primary mechanisms driving disease progression in B–Cell lymphomas. Although the BTK-targeting agent ibrutinib has shown promising clinical responses, the presence of primary or acquired resistance is common and often leads to dismal clinical outcomes. Resistance to ibrutinib therapy can be mediated through genetic mutations, up-regulation of alternative survival pathways, or other unknown factors that are not targeted by ibrutinib therapy. Understanding the key determinants, including tumor heterogeneity and rewiring of the molecular networks during disease progression and therapy, will assist exploration of alternative therapeutic strategies. Towards the goal of overcoming ibrutinib resistance, multiple alternative therapeutic agents, including second- and third-generation BTK inhibitors and immunomodulatory drugs, have been discovered and tested in both pre-clinical and clinical settings. Although these agents have shown high response rates alone or in combination with ibrutinib in ibrutinib-treated relapsed/refractory(R/R) lymphoma patients, overall clinical outcomes have not been satisfactory due to drug-associated toxicities and incomplete remission. In this review, we discuss the mechanisms of ibrutinib resistance development in B-cell lymphoma including complexities associated with genomic alterations, non-genetic acquired resistance, cancer stem cells, and the tumor microenvironment. Furthermore, we focus our discussion on more comprehensive views of recent developments in therapeutic strategies to overcome ibrutinib resistance, including novel BTK inhibitors, clinical therapeutic agents, proteolysis-targeting chimeras and immunotherapy regimens.

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Section: Ibrutinib In Combination With Cd20 Targeting Immunotherapymentioning

confidence: 97%

Ibrutinib Resistance Mechanisms and Treatment Strategies for B-Cell Lymphomas

George

Chowdhury

Hart

et al. 2020

Cancers

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“…In the same line, obinutuzumab-venetoclax combination has also recently been suggested as a possible salvage therapy in nnMCL. Of special interest, this combination was well-tolerated and induced a CR after only two cycles and in a patient with prior refractoriness to bendamustine and ibrutinib [152].…”

Section: New Therapeutics Antibodiesmentioning

confidence: 99%

Management of Drug Resistance in Mantle Cell Lymphoma

Roué

Sola

2020

Cancers

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Mantle cell lymphoma (MCL) is a rare but aggressive B-cell hemopathy characterized by the translocation t(11;14)(q13;q32) that leads to the overexpression of the cell cycle regulatory protein cyclin D1. This translocation is the initial event of the lymphomagenesis, but tumor cells can acquire additional alterations allowing the progression of the disease with a more aggressive phenotype and a tight dependency on microenvironment signaling. To date, the chemotherapeutic-based standard care is largely inefficient and despite the recent advent of different targeted therapies including proteasome inhibitors, immunomodulatory drugs, tyrosine kinase inhibitors, relapses are frequent and are generally related to a dismal prognosis. As a result, MCL remains an incurable disease. In this review, we will present the molecular mechanisms of drug resistance learned from both preclinical and clinical experiences in MCL, detailing the main tumor intrinsic processes and signaling pathways associated to therapeutic drug escape. We will also discuss the possibility to counteract the acquisition of drug refractoriness through the design of more efficient strategies, with an emphasis on the most recent combination approaches.

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“…This combination was well tolerated and showed CR of 67% in relapsed and 86.6% in untreated MCL patients [ 72 ]. This combination can be considered a possible salvage therapy for ibrutinib-resistant MCL patients [ 165 ]. However, despite high initial response rates in the OAsIs trial nearly 1/3 of patients relapsed [ 166 ].…”

Section: Combination Approaches With Monoclonal Antibodies For the Tr...mentioning

confidence: 99%

Beyond Bruton’s tyrosine kinase inhibitors in mantle cell lymphoma: bispecific antibodies, antibody–drug conjugates, CAR T-cells, and novel agents

Jain,

Mamgain,

Chowdhury

et al. 2023

J Hematol Oncol

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Mantle cell lymphoma is a B cell non-Hodgkin lymphoma (NHL), representing 2–6% of all NHLs and characterized by overexpression of cyclin D1. The last decade has seen the development of many novel treatment approaches in MCL, most notably the class of Bruton's tyrosine kinase inhibitors (BTKi). BTKi has shown excellent outcomes for patients with relapsed or refractory MCL and is now being studied in the first-line setting. However, patients eventually progress on BTKi due to the development of resistance. Additionally, there is an alteration in the tumor microenvironment in these patients with varying biological and therapeutic implications. Hence, it is necessary to explore novel therapeutic strategies that can be effective in those who progressed on BTKi or potentially circumvent resistance. In this review, we provide a brief overview of BTKi, then discuss the various mechanisms of BTK resistance including the role of genetic alteration, cancer stem cells, tumor microenvironment, and adaptive reprogramming bypassing the effect of BTK inhibition, and then provide a comprehensive review of current and emerging therapeutic options beyond BTKi including novel agents, CAR T cells, bispecific antibodies, and antibody–drug conjugates.

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Obinutuzumab and venetoclax induced complete remission in a patient with ibrutinib‐resistant non‐nodal leukemic mantle cell lymphoma

Cited by 6 publications

References 18 publications

Ibrutinib Resistance Mechanisms and Treatment Strategies for B-Cell Lymphomas

Ibrutinib Resistance Mechanisms and Treatment Strategies for B-Cell Lymphomas

Management of Drug Resistance in Mantle Cell Lymphoma

Beyond Bruton’s tyrosine kinase inhibitors in mantle cell lymphoma: bispecific antibodies, antibody–drug conjugates, CAR T-cells, and novel agents

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