Double-hit lymphomas: current paradigms and novel treatment approaches

Dunleavy, Kieron

doi:10.1182/asheducation-2014.1.107

Cited by 43 publications

(36 citation statements)

References 41 publications

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“…42,45 They are usually secondary events that appear in the context of complex karyotypes and are more frequently detected in DLBCL with a germinal center B-cell (GCB) phenotype. 45,46 B-cell lymphoma unclassifiable (BCLU) with features intermediate between DLBCL and BL is a provisional entity described in the latest version of the WHO classification to designate those cases that share both clinical and biological characteristics between DLBCL and the BL, but that cannot be clearly assigned to any of those categories. 1 Those lymphomas frequently resemble BL, have been proven to be very aggressive, and show poor response to conventional treatments.…”

Section: Myc In Other Aggressive Mature B-cell Lymphomasmentioning

confidence: 99%

“…New therapeutic approaches using small molecule inhibitors that target MYC and BCL2 are currently under investigation. 46 MYC rearrangement predicted an inferior outcome in aggressive lymphomas in most studies, but it is not yet entirely clear if this is due to the MYC rearrangement itself or because 50%-80% of MYC-translocated DLBCL cases harbor dual or even triple translocations also targeting BCL2 and/or BCL6. [45][46][47] The prognostic implication of MYC in those patients is difficult to establish since the diagnostic, phenotypic, and cytogenetic criteria, together with therapeutic approaches are very heterogeneous in the different published series.…”

Section: Myc In Other Aggressive Mature B-cell Lymphomasmentioning

confidence: 99%

“…46 MYC rearrangement predicted an inferior outcome in aggressive lymphomas in most studies, but it is not yet entirely clear if this is due to the MYC rearrangement itself or because 50%-80% of MYC-translocated DLBCL cases harbor dual or even triple translocations also targeting BCL2 and/or BCL6. [45][46][47] The prognostic implication of MYC in those patients is difficult to establish since the diagnostic, phenotypic, and cytogenetic criteria, together with therapeutic approaches are very heterogeneous in the different published series. 47 An increasing interest on the "double-expressor" (DE) large B-cell lymphomas, defined by most groups to have approximately 40% MYC and 50%-70% BCL2 cells by immunohistochemistry has been recently described.…”

Section: Myc In Other Aggressive Mature B-cell Lymphomasmentioning

confidence: 99%

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MYC as therapeutic target in leukemia and lymphoma

Cortiguera¹,

Batlle-López²,

Albajar³

et al. 2015

BLCTT

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MYC is a transcription factor that is involved in the expression of many genes. Deregulated MYC is found in about half of human tumors, being more prevalent in hematological neoplasms. Deregulation mechanisms include chromosomal translocation (particularly in lymphoma), amplification, and hyperactivation of MYC transcription. Here we review MYC involvement in the major types of leukemia and lymphoma. MYC rearrangements appear in all Burkitt lymphomas and are common in other lymphoma types, whereas in acute lymphoblastic leukemia, acute myeloid leukemia, lymphoproliferative, and myeloproferative diseases, they are less frequent. However, MYC overexpression is present in all types of hematological malignancies and often correlates with a worse prognosis. Data in leukemia-derived cells and in animal models of lymphomagenesis and leukemogenesis suggest that MYC would be a good therapeutic target. Several MYC-directed therapies have been assayed in preclinical settings and even in clinical trials. First, peptides and small molecules that interrupt the MYC-MAX interaction impair MYCmediated tumorogenesis in several mouse models of solid tumors, although not yet in lymphoma and leukemia models. Second, there are a number of small molecules inhibiting the interaction of MYC-MAX heterodimers with DNA, still in the preclinical research phase. Third, inhibitors of MYC expression via the inhibition of BRD4 (a reader of acetylated histones) have been shown to control the growth of MYC-transformed leukemia and lymphoma cells and are being used in clinic trials. Finally, we review a number of promising MYC-mediated synthetic lethal approaches that are under study and have been tested in hematopoietic neoplasms.

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Section: Myc In Other Aggressive Mature B-cell Lymphomasmentioning

confidence: 99%

Section: Myc In Other Aggressive Mature B-cell Lymphomasmentioning

confidence: 99%

Section: Myc In Other Aggressive Mature B-cell Lymphomasmentioning

confidence: 99%

See 1 more Smart Citation

MYC as therapeutic target in leukemia and lymphoma

Cortiguera¹,

Batlle-López²,

Albajar³

et al. 2015

BLCTT

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“…One intriguing aspect in the CopieBergman et al study is the better-than-expected outcome of patients with MYC alterations, independent of the translocated partner or subtype of DH lesions, compared with the poor outcome reported in the majority of previous publications. [1][2][3][4] As the authors recognize, the selection of patients from clinical trials may represent a bias that excludes patients with a poor performance status from being eligible for the trials. In fact, virtually all cases in their study had DLBCL morphology and, upon review, only 4 cases qualified for BCLu.…”

mentioning

confidence: 99%

“…The failure of current immunochemotherapy protocols to control the disease in these patients has motivated the development of new therapies that may overcome the adverse clinical impact of this genetic alteration. 3 However, one of the major challenges in advancing this perspective is understanding the complex biological mechanisms underlying the relationship between MYC alterations and the behavior of the tumors. Although most studies highlight the adverse impact of MYC translocations in DLBCL, some reports have provided conflicting results questioning whether MYC translocation as a single hit (SH) or its frequent association with BCL2 or BCL6 (DH) alterations is responsible for the aggressive behavior.…”

mentioning

confidence: 99%

MYC in DLBCL: partners matter

Campo

2015

Blood

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The biological effect of MYC translocation in DLBCL may be modulated by additional parameters that include the IG or non-IG partner gene involved in the translocation, the association with an additional translocation of the BCL2 or BCL6 genes in the so-called DH, the tumor cell context in which the alteration occurs such DLBCL, GCB or ABC, BCLu, and other factors such as the MYC or BCL2 protein levels. Additional studies are needed to explore other aspects such as the influence of somatic mutations in the tumor. Professional illustration by Patrick Lane, ScEYEnce Studios.BLOOD, 26 NOVEMBER 2015 x VOLUME 126, NUMBER 22 2439For personal use only. on May 12, 2018. by guest www.bloodjournal.org From subtypes of DLBCL, germinal center B-cell-like (GCB) or activated B-cell type (ABC), are not always considered. In addition, preliminary studies suggest that some biological aspects such as the partner gene in the MYC translocation or the levels of MYC or BCL2 protein expression may also influence tumor behavior. 2,4,6 The interplay of so many variables and the relative low frequency of aggressive lymphomas with MYC alterations make the development of appropriate studies challenging. However, this is exactly what Copie-Bergman and colleagues do in their study.1 The authors concentrated (in the evaluation of the MYC translocation partner, IG vs non-IG gene) on the outcome of 574 patients with DLBCL treated with immunochemotherapy in the context of clinical trials. They started using a MYC break-apart fluorescence in situ hybridization probe to detect any MYC translocation followed by IGH, IGK, and IGL fusion probes to confirm whether the partner was an IG or non-IG gene. MYC analysis was combined with the investigation of BCL2 and BCL6 translocations. MYC-Rs were found in 9% of the cases with a similar distribution of IG (48%) or non-IG (52%) as partner genes. Interestingly, only the rearrangement with IG had a negative effect on the outcome of the patients, and this impact was seen in cases with isolated MYC translocation and also in DH tumors. Concordant with previous messenger RNA studies, 7 the authors found significantly higher MYC protein expression in MYC-IG than in MYC-non-IG translocated cases, suggesting that MYC levels and its transcriptional regulator partner may be relevant in the behavior of the tumor. The study further clarifies other controversial issues. The prognostic impact of MYC-SH and MYC-DH was only observed in DLBCL with a GCB phenotype, suggesting that MYC activation may be more relevant in this subset of DLBCL. Intriguingly, MYC-SH translocations but not MYC-DH had an independent prognostic value from the International Prognostic Index or cell-of-origin classification. However, when MYC/BCL6-DH cases were excluded, then MYC/BCL2-DH also had an independent poor prognostic impact. The study included only 7 cases with MYC/ BCL6-DH but, interestingly, 6 of them were non-GCB and had a tendency to better prognosis than cases with MYC/BCL2-DH, which occurs almost exclusively in GCB tumors. Previous repo...

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Bright CD38 Expression by Flow Cytometric Analysis Is a Biomarker for Double/Triple Hit Lymphomas with a Moderate Sensitivity and High Specificity

Alsuwaidan

Pirruccello

Jaso

et al. 2019

Cytometry Part B Clinical

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BackgroundHigh‐grade B‐cell lymphomas (HGBCL) with MYC and BCL2 or/and BCL6 rearrangements (R), so‐called double/triple‐hit lymphomas (DH/THL), are uncommon, clinically aggressive lymphomas that require a prompt diagnosis. We aim to identify flow cytometric immunophenotypic (IP) features of DH/THL that may aid in triaging these cases followed by a timely confirmatory cytogenetic study.MethodsWe compared the IP features of 43 cases of DH/THL to those of 55 cases of single‐hit lymphoma (SHL) and 59 cases of diffuse large B‐cell lymphoma (DLBCL) without MYC‐R (MYCneg DLBCL). We analyzed the expression patterns of CD10, CD19, CD20, CD38, and surface immunoglobulin light chain in lymphoma cells.ResultsBright CD38 expression (CD38bright) analyzed either qualitatively or semi‐quantitatively was more common in DH/THL (56%) than in MYCneg DLBCL (17%) but less common compared to SHL (82%), indicating that CD38bright can serve as a biomarker for DH/THL. Additionally, CD38bright may be a better indicator for predicting DH/THL‐BCL2 than DHL‐BCL6, and very bright CD38 expression was exclusive to MYC rearranged lymphomas. The expression patterns of other markers were similar among these lymphoma groups.ConclusionsCD38bright is a biomarker associated with DH/THL with a moderate sensitivity (~50%) and high specificity (~90%). While this marker cannot be used as a screening tool, awareness of this correlation may aid in expediting the diagnosis and prioritizing FISH testing in resource limited settings or situations when samples are limited. Future studies to combine immunohistochemical markers are needed to further enhance the predictive power of CD38bright in diagnosing DH/THL. © 2019 International Clinical Cytometry Society

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Double-hit lymphomas: current paradigms and novel treatment approaches

Abstract: Learning Objectives• To understand the outcome with current standard treatment paradigms for "double-hit" and "double-expressor" lymphomas • To learn about novel treatment paradigms and promising targeted agents for these disease entities

Cited by 43 publications

References 41 publications

MYC as therapeutic target in leukemia and lymphoma

MYC as therapeutic target in leukemia and lymphoma

MYC in DLBCL: partners matter

Bright CD38 Expression by Flow Cytometric Analysis Is a Biomarker for Double/Triple Hit Lymphomas with a Moderate Sensitivity and High Specificity

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