MYC protein expression and genetic alterations have prognostic impact in patients with diffuse large B-cell lymphoma treated with immunochemotherapy

Valera, Alexandra; López‐Guillermo, Armando; Cardesa-Salzmann, Teresa Marta; Climent, Fina; González‐Barca, Eva; Mercadal, Santiago; Espinosa, Íñigo; Novelli, Silvana; Briones, Javier; Mate, José-Luís; Salamero, O.; Sancho, Juan‐Manuel; Arenillas, Leonor; Serrano, Sergio; Erill, Nadina; Martı́nez, Daniel; Castillo, Paola; Rovira, Jordina; Martı́nez, Antonio; Campo, Elı́as; Colomo, Luís

doi:10.3324/haematol.2013.086173

Cited by 197 publications

(250 citation statements)

References 44 publications

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“…Extra BCL2 copies were more commonly seen in the non-GCB type of DLBCL 37,39 and usually associated with overexpression of BCL2, 40 which has been correlated with poorer prognosis in DLBCL in some studies. 31 Overall, these studies directly or indirectly support the hypothesis that extra copies of MYC and BCL2 likely result in MYC and BCL2 overexpression in most cases and confer a poorer prognosis.…”

Section: Discussionmentioning

confidence: 55%

“…MYC expression was observed in 14 of 20 (70%) cases by using a 40% cutoff, 28,30 or 17 of 20 (85%) cases by using 10% as cutoff as reported by a recent study. 31 On the basis of these results and by Survival of patients with atypical double-hit lymphoma.…”

Section: Resultsmentioning

confidence: 96%

“…Data showing that DLBCL patients with MYC and BCL2 coexpression shown by immunohistochemistry have a poor prognosis in the absence of concurrent MYC and BCL2 translocations indirectly supports this hypothesis. 28,30,[34][35][36] In this study, similar proportions of 31 However, this study included only three cases with MYC amplification (44 copies). Our results suggest that patients with atypical double-hit lymphoma that had three to four copies of MYC showed similar OS to patients with atypical DHL with more than four copies of MYC.…”

Section: Discussionmentioning

confidence: 99%

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B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas

Seegmiller

Lin

et al. 2015

Modern Pathology

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Large B-cell lymphomas with IGH@BCL2 and MYC rearrangement, known as double-hit lymphoma (DHL), are clinically aggressive neoplasms with a poor prognosis. Some large B-cell lymphomas have concurrent abnormalities of MYC and BCL2 other than coexistent translocations. Little is known about patients with these lymphomas designated here as atypical DHL. We studied 40 patients of atypical DHL including 21 men and 19 women, with a median age of 60 years. Nine (23%) patients had a history of B-cell non-Hodgkin lymphoma. There were 30 diffuse large B-cell lymphoma (DLBCL), 7 B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma, and 3 DLBCL with coexistent follicular lymphoma. CD10, BCL2, and MYC were expressed in 28/39 (72%), 33/35 (94%), and 14/20 (70%) cases, respectively. Patients were treated with standard (n ¼ 14) or more aggressive chemotherapy regimens (n ¼ 17). We compared the atypical DHL group with 76 patients with DHLand 35 patients with DLBCL lacking MYC and BCL2 abnormalities. The clinicopathologic features and therapies were similar between patients with atypical and typical DHL. The overall survival of patients with atypical double-hit lymphoma was similar to that of patients with double-hit lymphoma (P ¼ 0.47) and significantly worse than that of patients with DLBCL with normal MYC and BCL2 (P ¼ 0.02). There were some minor differences. Cases of atypical double-hit lymphoma more often have DLBCL morphology (Po0.01), less frequently expressed CD10 (Po0.01), and patients less often had an elevated serum lactate dehydrogenase level (P ¼ 0.01). In aggregate, these results support expanding the category of MYC/ BCL2 DHL to include large B-cell lymphomas with coexistent MYC and BCL2 abnormalities other than concurrent translocations.

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Section: Discussionmentioning

confidence: 55%

Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas

Seegmiller

Lin

et al. 2015

Modern Pathology

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“…5,13,[22][23][24] Furthermore, the poor prognosis associated with Myc overexpression was contributed by cases with Myc/Bcl-2 coexpression-'doublepositive lymphoma' (DPL)-which account for 18-44% of DLBCLs. 13,20,[23][24][25][26] However, one study showed that the prognostic value of double-positive lymphoma was lost in younger DLBCL patients with poor prognosis. 27 Inconsistent results have been reported regarding whether the prognostic significance of Myc or Myc/Bcl2 protein expression depends on MYC or MYC/BCL2 gene rearrangement status or not.…”

mentioning

confidence: 99%

“…27 Inconsistent results have been reported regarding whether the prognostic significance of Myc or Myc/Bcl2 protein expression depends on MYC or MYC/BCL2 gene rearrangement status or not. 8,13,20 Other issues include whether Myc/Bcl2 immunohistochemistry is robust and reproducible, 28 and that immunohistochemistry cutoff values have varied among different study groups, 13,20,[23][24][25][26] which may affect the specificity of this combined biomarker for poorer prognosis.…”

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confidence: 99%

Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP

et al. 2015

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MYC dysregulation, including MYC gene rearrangement and Myc protein overexpression, is of increasing clinical importance in diffuse large B-cell lymphoma (DLBCL). However, the roles of MYC and the relative importance of rearrangement vs overexpression remain to be refined. Gaining knowledge about the tumor biology associated with MYC dysregulation is important to understand the roles of MYC and MYC-associated biology in lymphomagenesis. In this study, we determined MYC rearrangement status (n = 344) and Myc expression (n = 535) in a well-characterized DLBCL cohort, individually assessed the clinical and pathobiological features of patients with MYC rearrangement and Myc protein overexpression, and analyzed the prognosis and gene expression profiling signatures associated with these MYC abnormalities in germinal center B-cell-like and activated B-cell-like DLBCL. Our results showed that the prognostic importance of MYC rearrangement vs Myc overexpression is significantly different in germinal center B-cell-like vs activated B-cell-like DLBCL. In germinal center B-cell-like DLBCL, MYC-rearranged germinal center B-cell-like DLBCL patients with Myc overexpression significantly contributed to the clinical, biological, and prognostic characteristics of the overall

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The role of autologous stem cell transplantation in diffuse large B‐cell lymphoma

Nikolaenko

Herrera

2019

Adv Cell Gene Ther

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Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma (NHL) and is the most common lymphoid malignancy, accounting for more than 30% of newly diagnosed cases of NHL. 1,2 Diagnosis of DLBCL is made primarily by morphologic and immunohistochemical evaluation of the affected lymphoid tissue. Standard treatment of newly diagnosed DLBCL is anthracycline-based combination chemotherapy plus rituximab (eg, R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), which produces long-term remission in the majority of patients, including older patients and patients with advanced stage disease. 3-5 DLBCL can be classified into subgroups based on gene expression profiling (GEP) of tumor tissue (or using immunohistochemistry stains as a proxy for GEP), including the germinal center B-cell (GCB) and activated B-cell (ABC) subtypes, with latter exhibiting an inferior outcome with standard therapy. 6-8 In addition, double-hit lymphomas (DHL)-DLBCL with concurrent rearrangement of MYC and BCL2 and/or BCL6 identified by FISH-and double-expressor lymphoma (DEL)-DLBCL with concurrent expression of the MYC and BCL2 proteins by immunohistochemistry-are subtypes of DLBCL that are associated with poor outcomes after standard therapy. 9-26 Standard treatment for patients with relapsed or refractory DLBCL is non-cross-resistant salvage chemotherapy plus rituximab, followed by high-dose therapy and autologous stem cell transplantation for patients demonstrating chemotherapy-sensitive disease. 27,28 1 | What is considered de novo DLBCL? De novo DLBCL arises in lymphoid tissue without prior history of lymphoma. On the other hand, patients with transformed DLBCL have a prior history of indolent NHL, such as follicular, marginal zone, lymphoplasmacytic lymphoma. Transformed DLBCL has historically been associated with a poor prognosis, though newer data in the rituximab era suggests that outcomes may be improving. Patients with de novo or transformed DLBCL typically present with constitutional symptoms, rapid growth of lymph nodes, elevated lactate dehydrogenase, and can often have involvement of non-nodal sites. Positron emission tomography (PET) scan typically demonstrates increased FDG uptake at sites of involvement by DLBCL (in de novo or transformed disease) as compared to sites of involvement by low-grade lymphoma that tend to have less FDG-avidity. 29 Standard treatment of transformed DLBCL is anthracycline-based chemotherapy plus rituximab, similar to induction regimens for DLBCL. If a patient has had prior exposure to anthracycline-containing chemotherapy as part of treatment for their indolent lymphoma, alternative chemoimmunotherapy should be utilized. Rituximab-containing regimen followed by high-dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT) in patients with transformed lymphoma (TL) showed 3-year overall survival (OS) of over 50%. 30,31 | What are the indications for ASCT in DLBCL?The primary indication for HDT/ASCT in patients with DLBCL is for patients with relapse...

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MYC protein expression and genetic alterations have prognostic impact in patients with diffuse large B-cell lymphoma treated with immunochemotherapy

Cited by 197 publications

References 44 publications

B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas

B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas

Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP

The role of autologous stem cell transplantation in diffuse large B‐cell lymphoma

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