Ibrutinib resistance in mantle cell lymphoma: clinical, molecular and treatment aspects

Hershkovitz‐Rokah, Oshrat; Pulver, Dana; Lenz, Georg; Shpilberg, Ofer

doi:10.1111/bjh.15108

Cited by 80 publications

(79 citation statements)

References 94 publications

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“…As the advent of ibrutinib, studies have been conducted to unravel the mystery of ibrutinib resistance and clonal evolution in MCL. Some of these newer molecular alterations include: chromosomal complexity, NSD2 , NOTCH2 , UBR5 , BIRC3 , TRAF2 , MAP2K14 , KMT2D , CARD11 , SMARCA4 , and BTK . Activation of PI3K/AKT and the integrin‐β1 signaling pathway has been shown as another mechanism of acquired ibrutinib resistance. Microenvironmental impact —In addition to the pathogenic features described above, the tissue microenvironmental milieu is critical to support MCL cell growth and survival and promote drug resistance.…”

Section: Advances In the Pathogenesis Of MCLmentioning

confidence: 99%

“…Overall, the advent of ibrutinib is a “great leap forward” in the treatment of MCL; however, problems with ibrutinib discontinuation, management of ibrutinib‐refractory disease, and mechanisms of ibrutinib resistance pose new challenges. In contrast with SLL/CLL, where the C481S mutation is commonly associated with ibrutinib resistance, this mutation is infrequent in ibrutinib‐resistant MCL, and other mechanisms of ibrutinib resistance and ways to overcome ibrutinib resistance must be explored.…”

Section: Advances In the Treatment Of MCLmentioning

confidence: 99%

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Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

2019

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Unprecedented advances in our understanding of the pathobiology, prognostication, and therapeutic options in mantle cell lymphoma (MCL) have taken place in the last few years. Heterogeneity in the clinical course of MCL—indolent vs aggressive—is further delineated by a correlation with the mutational status of the variable region of immunoglobulin heavy chain, methylation status, and SOX‐11 expression. Cyclin‐D1 negative MCL, in situ MCL neoplasia, and impact of the karyotype on prognosis are distinguished. Apart from Ki‐67% and morphology pattern (classic vs blastoid/pleomorphic), the proliferation gene signature has helped to further refine prognostication. Studies focusing on mutational dynamics and clonal evolution on Bruton's tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib) and/or Bcl2 antagonists (venetoclax) have further clarified the prognostic impact of somatic mutations in TP53, BIRC3, CDKN2A, MAP3K14, NOTCH2, NSD2, and SMARCA4 genes. In therapy, long‐term follow‐up on chemo‐immunotherapy studies has demonstrated durable remissions in some patients; however, long‐term toxicities, especially from second cancers, are a serious concern with chemotherapy. The therapeutic options in MCL are constantly evolving, with dramatic responses from nonchemotherapeutic agents (ibrutinib, acalabrutinib, and venetoclax). Chimeric antigen receptor therapy and combinations of nonchemotherapeutic agents are actively being studied and our focus is shifting toward making the treatment of MCL chemotherapy‐free. Still, MCL remains incurable. The following aspects of MCL continue to pose a challenge: disease transformation, role of the cytokine‐microenvironmental milieu, incorporation of positron emission tomography‐computerized tomography imaging, minimal residual disease in the prognosis, circulating tumor DNA testing for clonal evolution, predicting resistance to BTK inhibitors, and optimal management of patients who progress on BTK/Bcl2 inhibitors. Next‐generation clinical trials should incorporate nonchemotherapeutic agents and personalize the treatment based upon the genomic profile of individual patient. Recent advances in the field of MCL are reviewed.

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Section: Advances In the Pathogenesis Of MCLmentioning

confidence: 99%

Section: Advances In the Treatment Of MCLmentioning

confidence: 99%

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

2019

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“…The mechanisms of ibrutinib resistance and the relevance of clonal evolution are being studied in B cell lymphoid malignancies (Burger et al , ; Jayappa et al , ; Landau et al , ; Zhao et al , ; Hershkovitz‐Rokah et al , ). In contrast to SLL/CLL, where the primary mode of ibrutinib resistance is considered to be via BTK C481S and PLCG2 gene mutations (Ahn et al , ; Woyach et al , ), studies in MCL (Chiron et al , ; Martin et al , ) and in follicular lymphoma (FL) (Jain et al , ) indicate that these mutations were uncommon in ibrutinib‐resistant patients.…”

mentioning

confidence: 99%

Long‐term outcomes and mutation profiling of patients with mantle cell lymphoma (MCL) who discontinued ibrutinib

et al. 2018

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Long term outcomes and mutations in patients with mantle cell lymphoma (MCL) who discontinued ibrutinib have not been described. Using deep targeted next generation sequencing, we performed somatic mutation profiling from 15 MCL patients (including 5 patients with paired samples; before and after progression on ibrutinib). We identified 80 patients with MCL who discontinued ibrutinib therapy for various reasons. Median follow-up after ibrutinib discontinuation was 38 months. The median duration on ibrutinib was 7·6 months. Forty-one (51%) patients discontinued ibrutinib due to disease progression/transformation, 20 (25%) for intolerance, 7 (9%) due to patient choice, 5 (6%) for stem cell transplant, 4 (5%) due to second cancers and 3 (4%) other causes. The median survival after ibrutinib was 10 and 6 months for disease progression and transformation, respectively, and 25 months for patients with ibrutinib intolerance. Overall, BTK mutations were observed in 17% patients after progression on ibrutinib. Notably, TP53 alterations were observed after progression in 75% patients. Among the 4 patients with blastoid transformation, 3 (75%) had NSD2 mutations (co-existing with TP53). Ibrutinib-refractory MCL patients had a short survival. Demonstration of TP53 and NSD2 mutations in patients who developed blastoid transformation and ATM and TP53 mutations in patients who progressed, opens the door for future investigations in ibrutinib-refractory MCL.

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“…30,58 However, some MCL and CLL patients are refractory to Ibrutinib treatment. 12,59 Here, we showed that JeKo-1 but not REC-1 MCL cells require BCR signaling for their migration and adhesion to stromal cells, suggesting that Although there is no obvious explanation for the apparent clustering of the MCL patient samples into two separate groups, it is interesting to note that clustering of differentially expressed microenvironment/ adhesion related genes led to separation of MCL patient samples into two groups.…”

Section: Discussionmentioning

confidence: 87%

Differential B-cell receptor signaling requirement for adhesion of mantle cell lymphoma cells to stromal cells

Sadeghi

Arvidsson

Merrien

et al. 2020

Preprint

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AbstractInteractions between lymphoma cells and stromal cells play a key role in promoting tumor survival and development of drug resistance. We identified differences in key signaling pathways between the JeKo-1 and REC-1 mantle cell lymphoma (MCL) cell lines, which exhibited different patterns of stromal cell adhesion and chemotactic migration towards stroma-conditioned medium. The identified adhesion-regulated genes reciprocated important aspects of microenvironment-mediated gene modulation in MCL patients. 590 genes were differently regulated between the cell lines upon adhesion to stromal cells, while 32 genes were similarly regulated in both cell lines. Regulation of B-cell Receptor (BCR) signature genes in adherent cells was specific for JeKo-1. Inhibition of BCR signaling by siRNA or clinically approved inhibitors, Ibrutinib and Acalabrutinib, decreased adhesion of JeKo-1 but not REC-1 cells to stromal cells. Cell surface levels of CXCR4 were higher in JeKo-1 cells and CXCR4 was important for migration and adhesion of JeKo-1 but not REC-1 cells. Surface levels of ICAM1 adhesion protein differ for REC-1 and JeKo-1. While ICAM1 plays a positive role in adherence of both cell lines to stromal cells, S1PR1 had an inhibitory effect. The results presented here provide a model framework for further investigation of mechanistic differences in patient-response to new pathway-specific drugs.

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Ibrutinib resistance in mantle cell lymphoma: clinical, molecular and treatment aspects

Cited by 80 publications

References 94 publications

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

Long‐term outcomes and mutation profiling of patients with mantle cell lymphoma (MCL) who discontinued ibrutinib

Differential B-cell receptor signaling requirement for adhesion of mantle cell lymphoma cells to stromal cells

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