<i>MYC</i>gene rearrangement in diffuse large B-cell lymphoma does not confer a worse prognosis following dose-adjusted EPOCH-R

Lai, Catherine; Roschewski, Mark; Melani, Christopher; Pittaluga, Stefania; Shovlin, Margaret; Steinberg, Seth M.; Dunleavy, Kieron; Pack, Svetlana D.; Jaffe, Elaine S.; Wilson, Wyndham H.

doi:10.1080/10428194.2017.1339882

Cited by 14 publications

(10 citation statements)

References 20 publications

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“…As there are no prospective studies in untreated MYC -R aggressive B-cell lymphomas, there is an unmet medical need to evaluate dose-intense treatment in these patients. DA-EPOCH-R is a dose-intense immuno-chemotherapy platform in which the continuous infusion of 3 of its components and pharmacodynamic dose-adjustments may be particularly important for highly proliferative lymphomas such as MYC-R aggressive B-cell and Burkitt lymphoma(18, 19). We hypothesized that DA-EPOCH-R would overcome the negative prognostic impact of MYC- R alone and in double-hit aggressive B-cell lymphomas and conducted a prospective multicenter study.…”

Section: Introductionmentioning

confidence: 99%

Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in untreated aggressive diffuse large B-cell lymphoma with MYC rearrangement: a prospective, multicentre, single-arm phase 2 study

Dunleavy

Fanale

Abramson

et al. 2018

The Lancet Haematology

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175

128

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SUMMARY Background MYC gene rearrangement (MYC-R) is present in approximately 10% of aggressive B-cell lymphomas with approximately half harboring a BCL2 gene rearrangement (BCL2-R). Multiple retrospective studies of R-CHOP show an inferior outcome in patients with MYC-R, both alone and with BCL2-R and/or BCL6-R, and suggest better outcomes with more aggressive treatment. In the current study, we aimed to determine the outcome of DA-EPOCH-R, an aggressive infusional treatment regimen, in untreated MYC-R aggressive B-cell lymphomas. Methods Final analysis of a prospective multi-center study of DA-EPOCH-R (dose-adjusted treatment: etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituxiomab) in 53 patients with untreated MYC-R aggressive B-cell lymphomas. DAEPOCH-R was scheduled to be administered with central nervous system prophylaxis for 6 cycles. Primary endpoints included event-free and overall survival. The study was registered at ClinicalTrials.gov (NCT01092182). Findings Patient characteristics included median age 61 (range 29–80) years, stage III/IV disease in 43 (81%), and high-intermediate/high international prognostic score (IPI) in 26 (49%) patients. Characteristics were similar among patients with confirmed MYC-R single-hit (n=19) versus those with a BCL2-R and/or BCL6-R, termed double-hit, (n=24) lymphomas. With a median follow up of 55.6 (Interquartile range: 50.5–61.1) months, the 48-month EFS and OS for all patients was 71% and 77%, respectively, with no differences among patients with single versus double-hit tumors or age < versus ≥ 60 years. The EFS at 48-months for low/low-intermediate (0–2) versus high-intermediate/high (3–5) IPI was 89% versus 50%, respectively, for all patients, and 92% versus 55% for double-hit patients. Toxicity included grade 4 neutropenia and thrombocytopenia on 53% and 13% of cycles, respectively, and fever with neutropenia occurred on 19% of cycles. There were 3 treatment related deaths. Interpretation In this study, DA-EPOCH-R produced durable remissions in MYC-R aggressive B-cell lymphomas and should be considered for the treatment of these diseases. Funding Cancer Trials Support Unit and Center for Cancer Research, National Cancer Institute, USA, and Genentech Inc.

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Section: Introductionmentioning

confidence: 99%

Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in untreated aggressive diffuse large B-cell lymphoma with MYC rearrangement: a prospective, multicentre, single-arm phase 2 study

Dunleavy

Fanale

Abramson

et al. 2018

The Lancet Haematology

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175

128

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“…Different cell experiments had confirmed that CUL4B activates the expression of mRNA and protein levels of c-Myc, promoting Wnt/β-catenin signaling activation and tumor progression ultimately [40,41]. Investigation of DLBCL consistently illustrated the connection between Ki-67, c-Myc and aggressive clinical behavior [42][43][44]. Ki-67 and c-Myc were regarded as proliferative markers but also poor prognostic markers in DLBCL [45].…”

Section: Discussionmentioning

confidence: 99%

CUL4B regulates autophagy via JNK signaling in diffuse large B-cell lymphoma

Zhou

Zhang

et al. 2019

Cell Cycle

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Aberrant expression of CUL4B was identified in various types of solid cancers. Cumulative evidences support the oncogenic role of CUL4B in cancers, including regulation of cell proliferation and signal transduction. However, its clinical value and potential pathogenic mechanism in diffuse large B-cell lymphoma (DLBCL) have not been described previously. Therefore, we hypothesize that overexpressed CUL4B may contribute to the pathogenesis of DLBCL. The aim of this study is to assess the expression and the biological function of CUL4B in DLBCL progression. In our study, CUL4B overexpression was observed in DLBCL tissues, and its upregulation was closely associated with poor prognosis in patients. Furthermore, the functional roles of CUL4B was detected both in vitro and in vivo. We demonstrated that silencing CUL4B could not only induce cell proliferation inhibition, cell cycle arrest, and motility attenuation of DLBCL cells in vitro, but also decrease tumor growth in DLBCL xenografts mice. In addition, we identified that CUL4B may act as a potent inductor of JNK phosphorylation in regulation of autophagy. Our findings demonstrated a significant role of CUL4B in the development and progression of DLBCL. CUL4B may act as a useful biomarker and a novel therapeutic target in DLBCL. ARTICLE HISTORY

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“…Although double-hit or triple-hit B-cell lymphomas are well-known with worse prognosis, previous studies concerning the prognostic impact of a c-MYC rearrangement alone have been controversial. Some studies demonstrated that a c-MYC rearrangement leads to poor prognosis even without BCL2 or BCL6 rearrangements [22,23], while a c-MYC rearrangement alone did not show significant prognostic impact in other studies [24,25]. The rearrangement of BCL2, BCL6, or PAX5 alone has not been associated with worse outcome in DLBCL patients [26,27], while the prognostic impact of CCND1 rearrangement in DLBCL has been controversial [28].…”

Section: Discussionmentioning

confidence: 99%

Chromosomal abnormality variation detected by G‐banding is associated with prognosis of diffuse large B‐cell lymphoma treated by R‐CHOP‐based therapy

et al. 2018

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Diffuse large B‐cell lymphoma (DLBCL), which is the most prevalent disease subtype of non‐Hodgkin lymphoma, is highly heterogeneous in terms of cytogenetic and molecular features. This study retrospectively investigated the clinical impact of G‐banding‐defined chromosomal abnormality on treatment outcomes of DLBCL in the era of rituximab‐containing immunochemotherapy. Of 181 patients who were diagnosed with DLBCL and treated with R‐CHOP or an R‐CHOP‐like regimen between January 2006 and April 2014, metaphase spreads were evaluable for G‐banding in 120. In these 120 patients, 40 were found to harbor a single chromosomal aberration type; 63 showed chromosomal abnormality variations (CAVs), which are defined by the presence of different types of chromosomal abnormalities in G‐banding, including 19 with two CAVs and 44 with ≥3 CAVs; and 17 had normal karyotypes. No specific chromosomal break point or numerical abnormality was associated with overall survival (OS) or progression‐free survival (PFS), but the presence of ≥3 CAVs was significantly associated with inferior OS rates (hazard ratio (HR): 2.222, 95% confidence interval (CI): 1.056–4.677, P = 0.031) and tended to be associated with shorter PFS (HR: 1.796, 95% CI: 0.965–3.344, P = 0.061). In addition, ≥3 CAVs more frequently accumulated in high‐risk patients, as defined by several conventional prognostic indices, such as the revised International Prognostic Index. In conclusion, our results suggest that the emergence of more CAVs, especially ≥3, based on chromosomal instability underlies the development of high‐risk disease features and a poor prognosis in DLBCL.

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MYCgene rearrangement in diffuse large B-cell lymphoma does not confer a worse prognosis following dose-adjusted EPOCH-R

Cited by 14 publications

References 20 publications

Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in untreated aggressive diffuse large B-cell lymphoma with MYC rearrangement: a prospective, multicentre, single-arm phase 2 study

Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in untreated aggressive diffuse large B-cell lymphoma with MYC rearrangement: a prospective, multicentre, single-arm phase 2 study

CUL4B regulates autophagy via JNK signaling in diffuse large B-cell lymphoma

Chromosomal abnormality variation detected by G‐banding is associated with prognosis of diffuse large B‐cell lymphoma treated by R‐CHOP‐based therapy

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