Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study

Younes, Anas; Thiéblemont, Catherine; Morschhauser, Franck; Flinn, Ian W.; Friedberg, Jonathan W.; Amorim, Sandy; Hivert, Bénédicte; Westin, Jason R.; Vermeulen, Jessica; Bandyopadhyay, Nibedita; Vries, Ronald de; Balasubramanian, Sriram; Hellemans, Peter; Smit, Johan W.; Fourneau, Nele; Oki, Yasuhiro

doi:10.1016/s1470-2045(14)70311-0

Cited by 240 publications

(173 citation statements)

References 27 publications

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“…Identification and targeting of OxPhos-dependent survival mechanisms may have important clinical utility. First, although downstream inhibitors of BCR signaling, including small-molecule inhibitors of spleen tyrosine kinase and Bruton tyrosine kinase kinases, are being evaluated in DLBCL, 50,51 there are currently no clinically approved targeted therapeutic strategies for OxPhos-type DLBCLs. Second, select targeting of OxPhostype survival mechanisms may have broader implications for resistance mechanisms that enable tumors to escape inhibition of canonical growth factor signaling, including those initiated by BCR, RAS, and BRAF signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets

et al. 2016

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Diffuse large B-cell lymphomas (DLBCLs) are a highly heterogeneous group of tumors in which subsets share molecular features revealed by gene expression profiles and metabolic fingerprints. While B-cell receptor (BCR)-dependent DLBCLs are glycolytic, OxPhos-DLBCLs rely on mitochondrial energy transduction and nutrient utilization pathways that provide pro-survival benefits independent of BCR signaling. Integral to these metabolic distinctions is elevated mitochondrial electron transport chain (ETC) activity in OxPhos-DLBCLs compared with BCR-DLBCLs, which is linked to greater protein abundance of ETC components. To gain insights into molecular determinants of the selective increase in ETC activity and dependence on mitochondrial energy metabolism in OxPhos-DLBCLs, we examined the mitochondrial translation pathway in charge of the synthesis of mitochondrial DNA encoded ETC subunits. Quantitative mass spectrometry identified increased expression of mitochondrial translation factors in OxPhos-DLBCL as compared with the BCR subtype. Biochemical and functional assays indicate that the mitochondrial translation pathway is required for increased ETC activity and mitochondrial energy reserves in OxPhos-DLBCL. Importantly, molecular depletion of several mitochondrial translation proteins using RNA interference or pharmacological perturbation of the mitochondrial translation pathway with the FDA-approved inhibitor tigecycline (Tigecyl) is selectively toxic to OxPhos-DLBCL cell lines and primary tumors. These findings provide additional molecular insights into the metabolic characteristics of OxPhosDLBCLs, and mark the mitochondrial translation pathway as a potential therapeutic target in these tumors. Cells adapt their metabolism to satisfy changing biosynthetic and bioenergetic needs.1,2 Investigation of metabolic reprogramming in cancer has provided insights into the metabolic control of proliferation and survival.3-5 Although the initial focus of this field has been aerobic glycolysis (the Warburg effect), 6 increasing evidence points to a complex landscape of tumor metabolic circuitries beyond aerobic glycolysis, including varied contribution of mitochondria to tumor metabolism as well as heterogeneity in fuel utilization pathways. 7-12Diffuse large B-cell lymphomas (DLBCLs) are a genetically heterogeneous group of tumors that can be classified into distinct molecular subtypes based on gene expression profiles. The cell-of-origin (COO) classification defined DLBCL subsets that shared certain components of their RNA profiles with normal germinal center B cells (GCBs) or in vitroactivated B cells (ABCs), and a third undefined subset designated 'type 3'. 13 Using an independent approach, the consensus cluster classification (CCC) framework compared the transcriptional profiles of DLBCL groups with each other without referencing normal B cells. 14 CCC identified tumorintrinsic distinctions in three highly reproducible clusters; the B-cell receptor/proliferation cluster (BCR-DLBCL) showing increased expression of BCR signa...

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Section: Discussionmentioning

confidence: 99%

Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets

et al. 2016

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“…At best, given our small sample size, there were signals of activity of the immunomodulatory effects of RIT in GC and ABC patients. Targeted approaches to the underlying biology associated with cell of origin may be more effective, as demonstrated with early-phase trials with agents such as lenalidomide and ibrutinib, specifically for ABC-origin DLBCL (33,34).…”

Section: Discussionmentioning

confidence: 99%

Phase 2 study of CHOP-R-14 followed by 90Y-ibritumomab tiuxetan in patients with previously untreated diffuse large B-cell lymphoma

Karmali¹,

Larson²,

Shammo³

et al. 2017

Molecular and Clinical Oncology

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Abstract. The aim of this open-label, single-center, phase 2 study was to assess the efficacy and safety of dose-dense CHOP-R-14 followed by 90 Y-ibritumomab radioimmunotherapy (RIT) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). A total of 20 patients, the majority presenting with high-risk characteristics, were enrolled to receive dose-dense cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab every 14 days (CHOP-R-14), followed by 90 Y-ibritumomab tiuxetan consolidation. Sixteen patients completed RIT consolidation (rituximab 250 mg/m 2 on day 1 and day 7, 8, or 9, followed by a single injection of 90 Y-ibritumomab). Complete response (CR) rates of 75 and 95% were observed after treatment with CHOP-R-14 and RIT, respectively; 4 of the 5 patients who achieved a partial response after CHOP-R-14 converted to CR following treatment with RIT. With a median follow-up of 89.7 months, the progression-free and overall survival rates for the cohort were 75 and 85%, respectively. Hematological adverse events were common following CHOP-R-14 and RIT, but they were manageable with treatment interruption. Therefore, this regimen achieved promising survival outcomes in high-risk DLBCL on long term follow-up, with manageable toxicity.

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“…R‐CHOP therapy, the combination of CHOP therapy, which until now has been the standard treatment, and rituximab, a chimeric anti‐CD20 monoclonal immunoglobulin G antibody, has been successfully used to treat CD20‐positive B‐cell non‐Hodgkin's lymphoma 16, 17. This treatment protocol was selected for our two patients, and we observed tumor regression in one patient and eradication of the tumor in the other patient.…”

Section: Discussionmentioning

confidence: 99%

Two cases of uterine malignant lymphoma diagnosed by needle biopsy

Kasai

Ichimura

Murakami

et al. 2015

J of Obstet and Gynaecol

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The incidence of primary malignant lymphoma arising in the female genital tract is extremely rare and constitutes approximately 0.05% of malignant tumors. Uterine malignant lymphoma develops in the endometrial stroma, causing minimal necrosis. It is therefore difficult to diagnose malignant lymphoma, as it does not involve genital bleeding or epithelial defects. We have performed transcervical needle biopsies from deep in the myometrium, with the purpose of diagnosing uterine muscle layer lesions, such as leiomyosarcoma, but this is an unusual method. In this report, we suggest that transcervical needle biopsy is useful in the diagnosis of uterine malignant lymphoma.

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Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study

Cited by 240 publications

References 27 publications

Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets

Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets

Phase 2 study of CHOP-R-14 followed by 90Y-ibritumomab tiuxetan in patients with previously untreated diffuse large B-cell lymphoma

Two cases of uterine malignant lymphoma diagnosed by needle biopsy

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