The Impact of Concurrent Expression of MYC and BCL2 on Outcomes of Localized Primary Gastric Diffuse Large B-Cell Lymphoma Undergoing Rituximab-Containing Chemotherapy with or without Radiotherapy

Abstract Introduction Although the Japanese multicenter phase II trial in localized primary gastric diffuse large B-cell lymphoma (PG-DLBCL), which evaluated three cycles of CHOP followed by radiotherapy (RT), showed good prognosis (Cancer Sci 2005; 96: 349), reports about outcomes and prognostic factors of localized PG-DLBCL patients in the rituximab era are limited. Recently, it has been reported that the concurrent expression of MYC and BCL2 predicts unfavorable outcome in DLBCL patients treated with R-CHOP (J Clin Oncol 2012; 30: 3460). However, the impact of the concurrent expression of MYC and BCL2 on outcomes of localized PG-DLBCL patients has never been reported. Patients and Methods We retrospectively analyzed 52 consecutive patients diagnosed as having localized (stage I or II according to the Lugano Staging System for Gastrointestinal Lymphomas) PG-DLBCL who were initially treated at our institution between 2003 and 2013. Positivity of MYC in immunohistochemistry was defined as labeling of tumor cells of more than 40% and positivity of BCL2 was defined as more than 70%. The lymphoma cells were assigned a GCB or non-GCB phenotype using the Hans algorithm for determining the cell-of-origin (COO) subtyping. Results Twenty-four (46%) patients were male and 28 (54%) female, with a median age of 62 years (range: 29-85). Thirty (58%) patients presented with stage I disease, 15 (29%) with stage II1, two (4%) with stage II2 and five (9%) patients with stage IIE. Most patients (47 patients; 90%) had low or low-intermediate risk based on the International Prognostic Index. Fifty (96%) patients received R-CHOP with or without RT, and one each received CHOP plus RT, and total gastrectomy followed by rituximab. The median number of CHOP cycles was three (range: 2-8). The majority (43 patients; 83%) of patients were treated with R-CHOP followed by RT. COO subtype could be determined in 48 of the 52 patients (63% GCB and 37% non-GCB). Both MYC and BCL2 expression could be assessed in 47 of the 52 patients, and the concurrent expression of MYC and BCL2 was confirmed in seven (15%) patients. In this analysis, no patients showed positivity for EBER-1 in situ hybridization, which was reported as an adverse prognostic factor of localized PG-DLBCL in the pre-rituximab era. Median follow-up duration was 76 months (range: 4-127 months). Fifty (96%) patients achieved complete responses, and the remaining two without concurrent expression of MYC and BCL2 had primary refractory disease. The estimated 5-year overall and progression-free survival rates of all 52 patients were 90% (95% CI, 75-96%) and 89% (95% CI, 75-95%), respectively (Fig. 1). The estimated 5-year overall survival rates of GCB phenotype and non-GCB phenotype cases were 86% (95% CI, 63-96%) and 93% (95% CI, 59-99%), respectively, with no statistically significant difference (p=0.96). The estimated 5-year overall survival rates of the patients with and without concurrent expression of MYC and BCL2 were 100% and 88% (95% CI, 72-96%), respectively (Fig. 2). There was no significant difference between the two cohorts (p=0.74). Conclusions The results of our analysis showed good prognosis, and revealed that COO subtype and concurrent expression of MYC and BCL2 did not influence the outcome in patients with localized PG-DLBCL treated with rituximab-containing chemotherapy with or without RT. Further investigations, especially a prospective cohort study, are needed to confirm our results. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Maruyama: Eisai Co., Ltd: Honoraria. Kobayashi:Otsuka Pharmaceutical Co., Ltd.: Research Funding; ARIAD Pharmaceuticals, Inc.: Research Funding; Boehringer Ingelheim GmbH: Research Funding. Tobinai:Zenyaku Kogyo: Research Funding; Chugai Pharmaceutical: Research Funding.

Download Full-text

Significance of c-myc Rearrangements in Diffuse Large B-Cell Lymphoma.

Blood ◽

10.1182/blood.v108.11.2030.2030 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2030-2030

Author(s):

Philip Bierman ◽

Fausto Loberiza ◽

Bhavana Dave ◽

Warren Sanger ◽

R. Gregory Bociek ◽

...

Keyword(s):

Overall Survival ◽

B Cell ◽

Cell Lymphoma ◽

Survival Rates ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Free Survival ◽

Large B Cell Lymphoma ◽

Large B Cell ◽

Overall Survival Rates

Abstract Rearrangements of the c-myc oncogene can be seen in 5–10% of patients with diffuse large B-cell lymphoma. However, studies examining the significance of this finding have yielded conflicting results. Therefore, we performed a retrospective analysis to determine the clinical significance of c-myc rearrangements in diffuse large B-cell lymphoma. The results of classical cytogenetic studies and FISH analyses were used to identify diffuse large B-cell lymphoma cases in the database of the Nebraska Lymphoma Study Group with or without c-myc rearrangements. Patients who were HIV positive and those with post-transplant lymphoproliferative disease were excluded. We identified 16 patients with diffuse large B-cell lymphoma and c-myc rearrangements. All patients were initially treated with doxorubicin- or mitoxantrone-containing chemotherapy regimens. The median age of these 16 patients was 61 years (range 40 to 80), and 5 (31%) were males. The International Prognostic Index (IPI) was 0–2 at diagnosis in 9 patients (56%), and 3–5 in 7 patients (44%). Eleven patients (69%) had bulky disease (≥ 5 cm) at diagnosis. No significant differences in outcome were identified when the 16 c-myc positive patients were compared with 97 c-myc negative diffuse large B-cell lymphoma patients in the same age range. The actuarial 5-year progression-free survival for the c-myc positive patients was 23% (95% CI 6% to 46%), as compared with 38% (95% CI 29% to 48%) for c-myc negative patients (p=0.17). The actuarial 5-year overall survival rates were 36% (95% CI 14% to 59%) and 47% (95% CI 36% to 56%), respectively (p=0.19). Classical cytogenetics and FISH analyses were also used to examine the 16 c-myc positive cases for bcl-2 rearrangements. Eight (50%) cases had rearrangements of bcl-2 in addition to c-myc rearrangements. These patients were similar to the c-myc positive/bcl-2 negative patients except for a higher likelihood of an elevated LDH level at diagnosis (88% vs. 25%; p=0.03). The actuarial 5-year progression-free survival for c-myc positive/bcl-2 positive patients was 0%, as compared to 33% (95% CI 6% to 66%) for patients with rearrangements of c-myc alone, and 37% (95% CI 28% to 47%) for c-myc negative patients. The actuarial 5-year overall survival rates were 12% (95% CI 1% to 42%), 47% (95% CI 12% to 76%), and 41% (95% CI 31% to 51%), respectively. A multivariate analysis, adjusting for IPI score, demonstrated that the relative risk (RR) of treatment failure was significantly worse for the c-myc positive/bcl-2 positive patients, as compared to the c-myc negative patients (RR 2.86, 95% CI 1.32–6.23; p=0.008). Similarly, mortality was also significantly worse for the c-myc positive/bcl-2 positive patients, as compared to the c-myc negative patients (RR 2.69, 95% CI 1.18–6.11; p=0.02). In contrast, no significant differences in treatment failure or overall survival were demonstrated when c-myc positive/bcl-2 negative patients were compared with c-myc negative patients. Our results demonstrate that the c-myc rearrangement is not associated with poorer survival in patients with diffuse large B-cell lymphoma. However, patients with rearrangements of bcl-2 in addition to c-myc had significantly worse progression-free survival and overall survival.

Download Full-text

Frequency of MYC Overexpression and MYC-BCL2 Double Expression (DEL) in Localized Diffuse Large B-Cell Lymphoma (DLBCL) at a Large Academic Cancer Center

Blood ◽

10.1182/blood-2018-99-111902 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4223-4223

Author(s):

Stephanie Ryanne Corder ◽

Ankit Agarwal ◽

Jonathan Galeotti ◽

Xianming Tan ◽

Natalie S Grover ◽

...

Keyword(s):

Risk Factors ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Stage I ◽

Prognostic Impact ◽

Advanced Stage ◽

Large B Cell Lymphoma ◽

Significant Difference ◽

The Impact ◽

Large B Cell

Abstract Background: Genetic and functional drivers of diffuse large B-cell lymphoma (DLBCL) have increasingly been used to prognosticate and occasionally even guide treatment for patients with advanced stage DLBCL. In advanced disease, the non-germinal center (non-GC) phenotype, double hit lymphomas (DHLs), and double expression lymphomas (DELs) have poorer outcomes. However, the incidence and impact of these factors on patient outcomes in the limited stage setting is not as well described. In particular, the prevalence of MYC and BCL2 overexpression has not been previously described in the literature for early stage DLBCL. The purpose of our analysis was to determine the incidence of these high-risk factors and analyze if these have an impact on outcomes in patients with stage I-II DLBCL. Methods: We performed a single site retrospective study of patients newly diagnosed with stage I-II DLBCL as defined by the Ann-Arbor staging system. All patients were treated at our institution, between 2011 and 2017. Patients with stage III-IV disease, concomitant follicular lymphoma, primary mediastinal lymphoma, or CNS lymphomas were excluded. The stage-modified IPI was used to categorize patients into different risk categories. Cell of origin (COO) was determined by the Hans criteria. Double expression was defined as overexpression of both MYC (positive ≥50%) and BCL2 (positive ≥70%). Molecular rearrangements of MYC with either BCL2 or BCL6 were used to define DHLs. MYC overexpression, BCL2 overexpression, double (MYC and BCL2) expression, MYC rearrangement, and Ki67 were quantified. Whenever possible, original patient histologic tissue samples were examined if information was not available in the original pathology report. The study examined the impact of these clinical and pathologic factors on progression-free survival (PFS). The impact of prognostic factors was analyzed with the Wilcoxon rank-sum for continuous variables and chi-square tests for categorical variables. Results: A total of 35 patients were identified with stage I-II DLBCL. The median age was 60 years old (range 25-86). Twelve patients (34%) were female. Patient characteristics are summarized in Table 1. Fifteen patients (43%) were treated with chemotherapy alone, while 20 patients (57%) were treated with a combination of chemotherapy and radiation. There were 8 patients (23%) with MYC overexpression and 27 patients (77%) with BCL2 overexpression. Six patients (17%) had double expression. Of the 6 patients who were double expressers, 2 (33.3%) progressed after frontline therapy, while 4 of 25 non-double expressers progressed (16%), although this was not a statistically significant difference. The COO was the non-GC type in 16 patients (45.7%) by Hans criteria. There was 1 patient with MYC rearrangement, and this patient had progression at distant sites. We did not identify any DHLs. There was 1 patient with CNS relapse, but this patient did not have double expression or MYC rearrangement. There was no significant difference in PFS associated with any of our identified clinical and pathological factors. Conclusion: In this retrospective review, we identified the proportion of patients who have high risk genetic and pathologic risk factors. The prognostic impact of the COO in localized DLBCL has been described, and our data support the previously published studies showing no difference in localized DLBCL (Savage et al., Blood 2016 and Johnson et al., JCO 2012). The prognostic impact of DELs has been well described in advanced stage DLBCL; however, the prognostic impact of DELs in localized DLBCL is not well described. To our knowledge, this is the first study reporting the frequency of MYC and BCL2 overexpression in localized DLBCL. While it is difficult to compare rates across trials, the rate of patients with double expression at 17% is lower than the rate of approximately 30% described for advanced stage DLBCL (Johnson et al., JCO 2012 and Hu et al., Blood 2013). Additionally, there was not a significant difference in the risk of progression for DEL versus non-DEL, but this was limited by the small sample size. Disclosures Grover: Seattle Genetics: Consultancy. Dittus:Seattle Genetics: Consultancy.

Download Full-text

Therapeutic Comparision of Surgical Resection Followed by R-CHOP and R-CHOP Alone for Primary Localized Intestinal Diffuse Large B Cell Lymphoma

Blood ◽

10.1182/blood.v118.21.1627.1627 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1627-1627 ◽

Cited By ~ 1

Author(s):

Ho Sup Lee ◽

Lee Chun Park ◽

Eun Mi Lee ◽

Seong Hoon Shin ◽

Byeong Jin Ye ◽

...

Keyword(s):

Prognostic Factors ◽

Survival Rate ◽

B Cell ◽

Cell Lymphoma ◽

Survival Rates ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Surgery Group ◽

Significant Difference ◽

Large B Cell

Abstract Abstract 1627 Abstract Background: Gastrointestinal tract is the most commonly involved extranodal site and is represented 10–15% of all non-Hodgkin¡&hibar;s lymphoma (NHL) cases and 30–40% of all extranodal sites. In this retrospective studies, the purpose is finding appropriate treatment strategy according to comparing the efficacy of treatment in patients with primary intestinal diffuse large B cell lymphoma (DLBL) undergoing surgery followed chemotherapy or chemotherapy alone. Method: Seventy six patients were newly diagnosed with DLBL and received chemotherapy between March 2004 and June 2011. Primary intestinal lymphoma which had predominant intestinal lesions was diagnosed by specialized hemato-oncologist. All patients were treated with rituximab combined cyclophosphamide, adriamycin, vincristine, and prednisolone (R-CHOP). Patients were divided into two groups. One included patients who were undertaken surgery followed by R-CHOP (surgery group). The other included patients who were undertaken R-CHOP alone (CT group). Results: The characteristics of the patients were as follows: the median age was 56.5 years (range 15–85 years) with a female-to-male ratio of 45: 31. Patients characteristics had no significant difference between two groups. The estimated 3 years progrression free survival rates (PFS) and overall survival rates (OS) of surgery and CT group were 92.2% and 74.8%, (p=0.009) and 94.2% and 80.7%, (p=0.049) respectively. In univariate analysis, PFS and OS were estimated in Lugano stage I, II1 and II2, IIE (p=0.006 and p=0.036), Low, Low-intermediate, and high-intermediate risk (p=0.004 and p=0.000), and surgery and CT alone, (p=0.009 and p=0.049), respectively. In multivariate analysis, there was no independent predictive factors for survival. Conclusion: Patients treated with surgery followed by R-CHOP were seemed to have higher survival rate than R-CHOP alone although there was no significant differences for survival rate. There was no significant prognostic factors for survival but there were possible prognostic factors such as Lugano stage, IPI risk, and treatment modality for PFS and OS. Figure. The superior survival rates were shown in surgery group than those in R-CHOP chemotherapy group. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

The Impact on Survival of EBV Positive Diffuse Large B- Cell Lymphoma, Not Otherwise Specified in Young Adults

Blood ◽

10.1182/blood-2018-99-117662 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5407-5407

Author(s):

Brady E. Beltrán ◽

Denisse A. Castro ◽

Julio Vega ◽

Jose Manuel Malaga ◽

Mauricio Postigo ◽

...

Keyword(s):

Overall Survival ◽

Young Adults ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Not Otherwise Specified ◽

Large B Cell Lymphoma ◽

Impact On Survival ◽

The Impact ◽

Large B Cell

Abstract Introduction: Epstein Barr virus-positive (EBV+) diffuse large B- cell lymphoma (DLBCL), not otherwise specified (NOS) is a new entity recognized by the WHO 2016. This entity was widely studied in older age patients, but in recent years there are few reports that show that EBV positive DLBCL, NOS can affect younger adults and there is a lack of evidence in this age group. The aim of this study is to evaluate the impact on survival in EBV+ DLBCL, NOS in young adults. Methods: The study was retrospective, reviewing clinical records of patients treated at Rebagliati Martins Hospital between years 2002 - 2013. Patients of both sexes ≥ 18 years old, but ≤ 50 years old, with the diagnosis of EBV+DLBCL, NOS were included. IRB approval was obtained prior to research. Pathological samples were reviewed by hematopathologists at our institution to confirm the diagnosis. Pertinent clinicopathological data were collected through chart review and are presented using descriptive statistics. Overall survival (OS) was determinate according to the Kaplan -Meier method, the comparison of the survival curves were made with the log-rank test. Univariate and multivariate Cox proportional-hazard regression models were fitted to evaluate hazard ratios (HR) for OS. Results: A total of 57 patients with a diagnosis of EBV+DLBCL, NOS were included in this analysis. The median age at diagnosis was 43 years (range 25-50 years), 61 % of patients were older than 40 years old and there was a slight female predominance (51%). Clinically, 55% presented ECOG >1, 57% had B symptoms, 68% had an extranodal disease as a primary tumor, 50% had stage III/IV and 26% had ≥ 1 extranodal site involved. EBV positivity was present in 16% of patients (9 patients). PDL-1 expression was present in 12% of patients. 92% received first-line treatment, but 7% of patients did not for progressive disease and death at diagnosis. During the treatment, 92% of patients received R-CHOP and 8% received other regimens. The overall response rate was 71%; 63% had a complete response and 7% had a partial response. The 5-year OS rate was 59%. In the univariate analysis, EBV positivity (<0.001) and ≥ 1 extranodal site involved (p=0.011) were associated with a poor prognosis. In the multivariate analysis, patients with EBV positive had a worse outcome (HR 7.8, 95% 2.2-25.9.2; p=0.001). Conclusions: The prevalence of EBV in young adults with DLBCL is high compared with other series and there is an adverse impact on overall survival in this group of patients. Figure. Figure. Disclosures Castillo: Genentech: Consultancy; Abbvie: Consultancy, Research Funding; Millennium: Research Funding; Beigene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding.

Download Full-text

High Microvascular Density Correlates with Poor Outcome in Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Treated with Rituximab Plus Chemotherapy (R-CT).

Blood ◽

10.1182/blood.v114.22.1948.1948 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1948-1948

Author(s):

Teresa M Cardesa-Salzmann ◽

Luis Colomo ◽

Fina Climent ◽

Eva Gonzalez-Barca ◽

Armando López-Guillermo ◽

...

Keyword(s):

Relative Risk ◽

B Cell ◽

Research Funding ◽

Cell Lymphoma ◽

Cox Model ◽

B Cell Lymphoma ◽

Tissue Sections ◽

Large B Cell Lymphoma ◽

The Impact ◽

Large B Cell

Abstract Abstract 1948 Poster Board I-971 Survival after treatment of diffuse large B-cell lymphoma (DLBCL) is influenced by differences in the tumor microenvironment. Gene expression profiling (GEP) studies have shown that the angiogenesis-related signature (stromal-2 signature) is prognostically unfavorable. However, the clinical and biological significance of angiogenesis quantified in tumor tissue sections of DLBCL from patients treated with rituximab plus chemotherapy (R-CT) is not yet fully explored. CD31, the platelet adhesion molecule PECAM1, is one of the genes included in the “stromal-2 signature” reported in the GEP studies. The objective of this study was to determine whether the microvessel density (MVD) and microvessel number (MVN) in DLBCL patients treated with R-CT were associated with the clinicopathological features of the tumors and related to the outcome of the patients. The MVD and MVN were assessed in a series of 160 patients with DLBCL from the Leukemia Lymphoma Molecular Profiling Project consortium (LLMPP) 86M /74F; median age 64 yrs. The GEP was investigated in 116 of these including 50 germinal center B (GCB), 55 activated B-cell (ABC) and 11 unclassifiable cases. An independent series of 129 patients from the Catalan Lymphoma-Study Group (GELCAB) (67M/62F; median age 64 yrs) was used to validate the results. Front-line treatment was R-CT in all cases of both series. Tissue Microarrays (TMA) were constructed from pretreatment biopsy specimens of de novo DLBCL. High grade B cell lymphoma otherwise unclassifiable, primary mediastinal B cell lymphoma, T-cell-rich B cell lymphoma, and tumors associated with immunodeficiency were excluded. All cases were stained in an automated immunostainer with an antibody against CD31 (DAKO). The MVD and MVN were quantified using digitalized images of the tumor using Olympus Cell B Basic Imaging Software. Microvessel areas were defined as vascular areas delineated by CD31+ staining. The MVD was calculated as the sum of all microvessel areas divided by the total area analyzed. The MVN was the sum of all identified individual vessels, divided by the total area analyzed. TMAs were independently scored by two observers and discrepancies were resolved over a double-headed microscope. To determine whether the angiogenic values scored using the TMA were representative of the tumor sample, whole tissue sections and TMA cores from the same tumor were evaluated in 40 cases and compared by a linear regression analysis. MVD and MVN were grouped in quartiles when necessary and considered high or low when above or below the 50th percentile, respectively. Linear correlation analysis between the CD31 (+) MVD results on TMA cores and on the corresponding whole tissue sections in 40 cases showed a good correlation (R2=0.81). In the LLMPP cohort, DLBCL with an ABC profile showed higher MVD than those with GCB profile (p=0.05). In addition, higher MVD was observed in patients with advanced stage (p<0.01), but there was no significant correlation with other clinical features. 5-yr overall survival (OS) according to CD31(+) MVD was 74% vs. 47% for patients with low and high MVD respectively (p=0.0015). Both the International prognostic index (IPI) (relative risk 3.3; p=0.001) and MVD (relative risk 2.2; p<0.001) showed independent prognostic value for OS in a Cox model. In addition, MVD and GEP type (GCB vs. ABC) were also independent predictors of OS. MVN showed no meaningful relation with initial features or with OS. In the validation cohort from the GELCAB, all the above mentioned results were confirmed, including the influence of MVD on OS (5-yr OS 78% vs. 50% for low and high MVD, respectively; p=0.02) that was also independent of IPI in a Cox model. In conclusion, increased MVD is able to discriminate poor-risk patients in DLBCL treated with R-CT independently of the IPI risk groups. This finding highlights the relevance of angiogenesis in the behavior of these tumors and suggests that it may be an important parameter when assessing the impact of new therapies, particularly anti-angiogenic drugs. Disclosures: Gascoyne: Roche Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Connors:Roche Canada: Research Funding. Rimsza:High Throughput Genomics: .

Download Full-text

Effects of Concurrent Expression of Myc and Bcl-2 on the Treatment and Prognosis in Extranodal Diffuse Large B Cell Lymphoma

Journal of Global Oncology ◽

10.1200/jgo.18.16300 ◽

2018 ◽

Vol 4 (Supplement 2) ◽

pp. 34s-34s

Author(s):

M. Sonmez ◽

C. Konca

Keyword(s):

Overall Survival ◽

B Cell ◽

Cell Lymphoma ◽

Survival Rates ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Free Survival ◽

Large B Cell Lymphoma ◽

Large B Cell ◽

Overall Survival Rates

Aim: We aimed to investigate the effects of immunohistochemical and molecular presence of double-hit lymphomas (DHL) (combined expression of myc and bcl-2) on overall and progression-free survival rates of patients with extranodal diffuse large B-cell lymphoma (DLBCL). Methods: A total of 31 patients (17 female, 14 male; mean age 57 years) with diagnosis of extranodal DLBCL were included into the study. Patients transforming from low grade B cell lymphoma, and patients with HIV positivity were not included. In a retrospective manner, patient characteristics were noted (age at diagnosis, sex, sites of extranodal involvement, stage, high-risk group, histopathological diagnosis, IPI score, LDH level at diagnosis, bone marrow involvement, and treatment modalities). Histopathological specimens underwent immunohistochemical (bcl-6, bcl-2, myc, CD10, Mum-1) and molecular (bcl-2 and myc, by means of PCR) analysis. All patients was treatment with R-CHOP protocol. Results: DHL was observed immunohistochemically in only one patient, while molecular studies found 6 cases. Three-month overall survival rates were 50% and 88% in DHL positive and negative groups, respectively. Six-month overall survival rates were 16% and 76% in DHL positive and negative groups, respectively. Progression-free 3-month survival rates were 51% and 88% in DHL positive and negative groups, respectively. Progression-free 6-month survival rates were 33% and 76% in DHL positive and negative groups, respectively. No relation with histopathological type of the disease was noted. Conclusion: We conclude that DHL presence in patients with extranodal DLBCL was an independent factor leading to shortened overall or progression-free survival.

Download Full-text

Risk Stratification Combining MYC Immunohistochemistry with Standard IPI Has Utility in Patients with Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v126.23.2656.2656 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2656-2656

Author(s):

David Simon Kliman ◽

Louise Imlay-Gillespie ◽

Kirsten McIlroy ◽

Anthony Gill ◽

Christopher Arthur ◽

...

Keyword(s):

High Risk ◽

Risk Stratification ◽

B Cell ◽

Research Funding ◽

Cell Lymphoma ◽

Prognostic Significance ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Significant Difference ◽

Large B Cell

Abstract Background Though the majority of patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL) are curable with R-CHOP chemotherapy, a significant proportion will relapse or have refractory disease. The most commonly used clinical tool is the international prognostic index (IPI), though this cannot fully capture the heterogeneity of cases seen in practice. In recent years biomarkers such as MYC are entering clinical use. Pts with lymphomas demonstrating dual abnormalities of MYC in association with BCL2 and/or BCL6-known as 'double-hit' lymphomas are consistently shown to have poorer disease free and overall survival. While Fluorescence in-situ hybridization (FISH) for MYC translocation is the gold-standard, immunohistochemistry (IHC) is faster and significantly cheaper. Studies in recent years have confirmed the prognostic significance of increased MYC expression by IHC. Due to significant inter-laboratory variability however, internal validation is required. Methods Tissue samples of pts treated at Royal North Shore Hospital in Sydney, Australia between 2003-2012 were retrospectively assessed. Pts were included if they were transplant eligible (age <70 years), and had been treated for de novo DLBCL with a rituximab containing regimen. Samples were scored for MYC IHC as well as BCL2 and BCL6. Clinical data including IPI score, treatment and outcomes were also collected. Treatments were stratified into standard R-CHOP-like versus more intensive regimens including R-Hyper-CVAD and dose-adjusted R-EPOCH. A significant cut-off for MYC staining was determined using X-Tile (Rimmlab, New Haven, CT) and confirmed with the log-rank test. Estimation of OS and EFS was performed using the Kaplan-Meier method. Pt characteristics were compared using Chi-squared test. Statistical analysis was performed using MedCalc 15.4 (MedCalc software, Ostend, Belgium). Ethics approval was received for a retrospective study. Results 105 patients met study criteria. The 5 year OS and EFS was 86% and 77% respectively (Figure 1 and 2). The optimal cut-off for positive MYC IHC was >70%. This was seen in 23% of samples. From the 13 cases with MYC FISH results, the positive and negative predictive values of positive MYC IHC were 50% and 92% respectively. There was no significant difference between the MYC positive and negative groups with respect to demographics or IPI score (Table 1). Significantly more patients with MYC positivity received intensive treatment (37% versus 16%, p=0.047). Despite this, 5 year OS was significantly poorer at 51% versus 87% at median follow-up of 40 months (P=0.0025, Figure 3). There was a trend towards worse EFS at 61% versus 75% though this did not reach statistical significance (P=0.242). On multivariate analysis, MYC IHC and IPI score were the only independent prognostic factors. Based on the relative odds ratio, a combined scoring system was designed, attributing 1 point for positive MYC IHC and/ or IPI intermediate-high risk, and 2 points for IPI high risk. This resulted in 4 risk groups with significantly different 5 year OS of 94%, 78%, 45% and 0% (P<0.0001). Discussion MYC IHC is of independent prognostic significance. Due to significant variability between laboratories, local validation is required. A composite score combining IPI and MYC IHC is simple to calculate and may provide better prognostic utility than either factor alone. Ongoing prospective studies investigating the role of clinical risk stratification and newer biomarkers are required to identify patients likely to need more intensive or novel therapies. Figure 1. Figure 1. Disclosures Imlay-Gillespie: Novartis: Honoraria. Arthur:Amgen: Honoraria; Novartis: Honoraria; BMS: Honoraria. Mackinlay:Roche: Research Funding; Sanofi Aventis: Research Funding. Mulligan:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi Aventis: Research Funding.

Download Full-text

OCT1 gene Expression Is an Independent Prognostic Factor in Diffuse Large B Cell Lymphoma

Blood ◽

10.1182/blood.v124.21.5185.5185 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5185-5185

Author(s):

Gisele Rodrigues Gouveia ◽

Suzete Cleusa Ferreira ◽

Sheila Siqueira ◽

Juliana Pereira

Keyword(s):

Gene Expression ◽

B Cell ◽

Cell Lymphoma ◽

International Prognostic Index ◽

B Cell Lymphoma ◽

Prognostic Impact ◽

Large B Cell Lymphoma ◽

Significant Difference ◽

The Impact ◽

Large B Cell

Abstract Background: Transcription factors associated with the POU domain modulate the expression of several genes of B lymphoid differentiation, including the IgH. The study of these factors allowed to better understand the pathogenesis of lymphomas and to establish the lineage and the differentiation stage of the malignant cell. The silencing of OCT1 in tumor cell lines reduced its malignant transformation, but its ectopic expression enhanced the tumorigenesis ability. However, few studies has been evaluated the role of the OCT1 gene expression in lymphoma. In this study we assessed the impact of the OCT1 gene expression in the survival of patients with Diffuse Large B Cell Lymphoma (DLBCL). Methods: From January 2006 to January 2011 were evaluated 77 patients with DLBCL treated with R-CHOP at Clinical Hospital and Cancer Institute of Sao Paulo University. The RNA was extracted from the paraffin block at lymphoma diagnosis and gene expression analysis was performed by relative quantification method by Real-Time PCR (qRT-PCR). After the data normalization using two different reference genes, the median expression of OCT1 was obtained. The overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. The relative risks were obtained by Cox regression bivariate intervals with 95% of confidence. The significance level of 5% was accepted and the IBM SPSS Statistics software version 20.0 was used. Results: Patients showing OCT1 expression < the median presented higher OS (p = 0.010) and PFS (p = 0.016) than patients with OCT1 expression ≥ median with a hazard rate (HR) for OS and PFS of 2.45 and 1.14, respectively. In multivariate analysis the PFS was also higher in patients with OCT1 expression < the median (p = 0.035). The stratification by the international prognostic index (IPI) and age showed that the expression of OCT1 < median showed a statistically significant difference in the OS (p = 0.048) in IPI intermediate-high (HI) and high (HR) patients (p = 0.048), with a HR of 2.32 in HI plus HR group. The PFS (p = 0.025) and OS (p = 0.025) were lower in patients ≥ 60 years and OCT1 expression ≥ the median. Conclusion: Our data suggest that the expression of OCT1 showed a predictive prognostic impact in DLBCL independently of IPI. Patients with lower expression of OCT1 presented a better OS and PFS. Figure 1 SG curve for the OCT1 gene expression. Figure 1. SG curve for the OCT1 gene expression. Figure 2 SLP curve for the OCT1 gene expression. Figure 2. SLP curve for the OCT1 gene expression. Figure 3 SG curve for to expression of OCT1 gene for subgroup IPI intermediate-high and high. Figure 3. SG curve for to expression of OCT1 gene for subgroup IPI intermediate-high and high. Disclosures No relevant conflicts of interest to declare.

Download Full-text