Prognostic impact of concordant and discordant bone marrow involvement and cell-of-origin in Korean patients with diffuse large B-cell lymphoma treated with R-CHOP

2015 ◽  
Vol 68 (9) ◽  
pp. 733-738 ◽  
Author(s):  
Mi-Jung Park ◽  
Soon-Ho Park ◽  
Pil-Whan Park ◽  
Yiel-Hea Seo ◽  
Kyung-Hee Kim ◽  
...  

AimsPrevious studies have suggested many prognostic factors in diffuse large B-cell lymphoma (DLBCL), but the prognostic importance of cell-of-origin and discordant bone marrow involvement remains unclear. The aim of this study was to evaluate the prognostic impact of bone marrow involvement histological subtype, cell-of-origin subtype and international prognostic index (IPI) scores in patients with DLBCL.MethodsPatients who were newly diagnosed with DLBCL and treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) were analysed. Clinical information was reviewed retrospectively. Patients were classified into negative, concordant and discordant bone marrow involvement by histological review. The cell-of-origin types were defined using immunohistochemical analysis.ResultsBoth concordant and discordant bone marrow involvement had a negative prognostic impact on progression-free survival, independent of the standard and National Comprehensive Cancer Network (NCCN) IPI scores and cell-of-origin. Patients with non-germinal centre B-cell type showed significantly shorter progression-free survival than those with germinal centre B-cell type. However, non-germinal centre B-cell type did not have a prognostic impact on progression-free survival or overall survival after controlling for the standard and NCCN-IPI and bone marrow involvement.ConclusionsBoth concordant and discordant bone marrow involvement had an adverse prognostic impact on progression-free survival and overall survival; this was independent of the standard and NCCN-IPI and cell-of-origin (non-germinal centre B-cell type). The NCCN-IPI had more powerful prognostic value than the standard IPI (sIPI). The non-germinal centre B-cell type lost significant prognostic impact on progression-free survival after adjustment for standard and NCCN-IPI and bone marrow involvement.

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-42
Author(s):  
Luis Alberto de Padua Covas Lage ◽  
Gisele Rodrigues Gouveia ◽  
Suzete Cleusa Ferreira ◽  
Sheila Aparecida Coelho de Siqueira ◽  
Abrahão Elias Hallack Neto ◽  
...  

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoid malignancy, representing 30-40% of all non-Hodgkin's lymphomas (NHLs). They comprise a group of aggressive and heterogeneous neoplasms in terms of clinical presentation, response to therapy and prognosis. The OCT-1 gene is a member of the homodomain-POU family of transcriptional regulators of B-lymphoid differentiation. OCT-1 acts by controlling the expression of specific B-cell genes, such as BCL-2, a potent inhibitor of apoptosis that is essential for the differentiation of B-cells in the germinal center. These genes can be expressed in DLBCL, but the role of BCL-2 in its prognosis has been contradictory and the prognostic impact of the OCT-1 gene has not yet been tested in this lymphoma. Methods: In this observational, retrospective, single-center study, we investigated the prognostic impact of BCL-2 and OCT-1 gene expression in Brazilian patients with DLCBL treated with immunopolychemotherapy R-CHOP in a real-world context. The BCL-2 and OCT-1 genes were assessed in 78.5% (77/98) DLBCL patients, and the RNA for quantitative real-time PCR (qRT-PCR) was isolated from formalin-fixed and paraffin-embedded (FFPE) samples. The values obtained for gene expression were transformed into categorical variables according to their medians (6.27 for BCL-2 and 24.5 for OCT-1). The association between clinical and laboratory variables and results of gene expression was verified by the Fischer test. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Univariate analysis was performed using Cox's bivariate regression method and multivariate analysis using Cox multiple regression methodology. Results: The median age of the cohort was 54.5 years (15-84), 50% (49/98) were male, 49.4% (38/77) and 51.4% (40/77) showed expression of OCT-1 and BCL- 2 ≥ median, respectively. The clinical characteristics of the 98 Brazilian patients with DLBCL that comprised our cohort are summarized in Table 1. The overall response rate (ORR) in all patients was 68.4% (67/98), 65.3% (64/98) showed a complete response (CR), and 3.1% (3/98) showed partial response (PR), while 6.1% (6/98) were primary refractory. With a median follow-up of 3.77 years (95% CI: 3.2-4.1), the median overall survival (OS) was 5.43 years (95% CI: 2.2-NR) and the median progression-free survival (PFS) was 5.15 years (95% CI: 2.9-NR). The 5-year OS and PFS was 54.2% (42.2% -64.8%) and 52.0% (40.1-62.6%), respectively. In the univariate analysis OCT-1 ≥ median was associated with shortened OS (HR: 2.45, 95% CI: 1.21-4.96, p = 0.013) and PFS (HR: 2.27, 95% CI: 1.14-4.51, p = 0.019). Overexpression of BCL-2 was associated with worse PFS (HR: 2.00, 95% CI: 1.02-3.95, p = 0.043). Subgroup analysis showed that OCT-1 overexpression predominated in elderly individuals (≥ 60 years) in a statistically significant mode (29/38 cases - 76.3%, p = 0.029). It was also observed that overexpression of OCT-1 was associated with worse OS in the high-risk adjusted International Prognostic Index (aIPI) subgroup (p = 0.048) - Figure 1, and worse PFS in patients ≥ 60 years old (p = 0.025) - Figure 2. In the multivariate analysis, overexpression of OCT-1 was associated with poor PFS (HR: 2.22, 95% CI: 1.06-4.76, p = 0.035). Conclusion: In this study, we demonstrated that overexpression of the OCT-1 gene was an independent prognostic factor associated with adverse outcomes in Brazilian patients with DLCBL. We also show that in patients with unfavorable risk, such as the elderly and those with intermediate-high and high-risk IPI, overexpression of OCT-1 contributed to the identification of a very high-risk clinical-molecular subgroup, where the results with standard R-CHOP therapy are unsatisfactory, and they may benefit from intensified therapeutic strategies. Our results are preliminary and need to be validated in subsequent studies of prospective nature and with an expanded sample. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4330-4330
Author(s):  
Christina Tsao ◽  
Kate Fisher ◽  
Ji-Hyun Lee ◽  
Julio C Chavez ◽  
Samir Dalia ◽  
...  

Abstract Background Diffuse large b-cell lymphoma (DLBCL) with CNS relapse or progression has a poor prognosis. Prior studies noted certain factors which increased the risk of CNS relapse: bone marrow involvement, type as well as number (1+) of extra-nodal sites, age over 60, and increasing International Prognostic Index (IPI) score. However, these were prior to the advent of rituximab (R), which has been suggested to lower CNS relapse when used in combination with CHOP therapy. To our knowledge, no one has looked at the incidence of CNS relapse with regards to extranodal disease in the rituximab era. Methods Retrospective chart review of patients with DLBCL treated with multiagent induction therapy including rituximab from July‘08 to Jan’12 at Moffitt Cancer Center. Age, stage, IPI score, extra-nodal site, number of nodal sites, and use of intrathecal prophylaxis (IT), were evaluated for their impact on the risk of developing CNS relapse. For those who had complete response to initial therapy, time to progression(TTP) for CNS relapse was measured from completion date of first set of chemo cycles to date of CNS relapse (those who did not CNS relapse were censored at last follow up). TTP was censored at 6 years. Progression free survival(PFS) was measured from date of diagnosis to date of CNS or systemic relapse or death (those who were alive without relapse were censored at last follow up). Overall survival (OS) was measure from date of diagnosis to date of death. Stratified Kaplan Meier curves(with log rank p-values) and Cox PH models(with Wald p-values) were used to explore potential risk factors associated with relapse. Results Sixty-four patients with DLBCL who received induction therapy were evaluated: median age (range) = 65 (24-93) years; male =56%; IPI scores at diagnosis: 1 (43.8%), 2(21.9%), 3(15.6%); median length of follow up from time of diagnosis = 32 months. All the patients received a regimen containing rituximab, and 92% of patients received R-Chop as treatment. IT prophylaxis with methotrexate was used in 28% of the patients. Incidence of CNS relapse in our study population= 17.3% (n=9) The risk of CNS relapse varied depending on the extranodal site. Those with bone marrow and/or musculoskeletal involvement had an increased risk, with 78% of the CNS relapses occurring in patients with one or both of these sites of involvement. The hazard ratio (HR) for CNS relapse for patients with bone marrow and musculoskeletal involvement was 2.53 and 2.74, respectively (p=0.20 and p=0.13). Other extranodal sites of disease such as visceral organs, genital urinary tract, nasopharynx, or skin did not seem to significantly contribute to the risk of CNS relapse. Patients with bone marrow involvement also had an inferior overall survival (HR=3.05, Wald p=0.02) (see figure 1). Though not statistically significant (log rank p=0.126), those receiving IT methotrexate prophylaxis appear to have longer PFS than those who did not, with 83% alive without relapse at 6 years compared to 43% (see figure 2). Conclusions Despite the addition of rituximab to multiagent chemotherapy, those with bone marrow and musculoskeletal involvement still had a significantly higher risk of CNS relapse. There is a trend which suggests intrathecal prophylaxis with methotrexate can improve progression free survival and is still possibly beneficial in high risk DLBCL patients even in the rituximab era. Larger prospective studies are needed to determine the true benefit of prophylactic IT therapy in this population. Disclosures: No relevant conflicts of interest to declare.


2011 ◽  
Vol 29 (15_suppl) ◽  
pp. e18514-e18514
Author(s):  
B. W. Kang ◽  
Y. J. Lee ◽  
Y. S. Chae ◽  
J. H. Moon ◽  
J. G. Kim ◽  
...  

2017 ◽  
Vol 6 (11) ◽  
pp. 2507-2514 ◽  
Author(s):  
Tzu-Hua Chen-Liang ◽  
Taida Martín-Santos ◽  
Andrés Jerez ◽  
Guillermo Rodríguez-García ◽  
Leonor Senent ◽  
...  

2011 ◽  
Vol 29 (11) ◽  
pp. 1452-1457 ◽  
Author(s):  
Laurie H. Sehn ◽  
David W. Scott ◽  
Mukesh Chhanabhai ◽  
Brian Berry ◽  
Anna Ruskova ◽  
...  

Purpose In diffuse large B-cell lymphoma (DLBCL), prior studies suggest that concordant bone marrow involvement with DLBCL portends a poorer prognosis, whereas discordant bone marrow involvement with small B-cell lymphoma does not. We examined the significance of bone marrow involvement in patients treated in the current era of therapy including rituximab. Patients and Methods We performed a retrospective analysis of the prognostic impact of bone marrow involvement in an unselected population of patients with newly diagnosed DLBCL treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in British Columbia and Auckland, New Zealand, with complete clinical information and evaluable staging bone marrow biopsies. Results In total, 795 patients were identified. Six hundred seventy (84.3%) of 795 had a negative bone marrow, 67 patients (8.4%) had concordant and 58 (7.3%) had discordant involvement. Median follow-up was 41 months (range, 1 to 115). Progression-free survival (PFS) was inferior in those with concordant (P < .001) and discordant (P = .019) involvement while overall survival (OS) was inferior in those with concordant involvement (P < .001) only. In a multivariate analysis controlling for the International Prognostic Index (IPI) score, concordant involvement remained an independent predictor of PFS (P < .001) and OS (P = .007). Discordant involvement was associated with older age, elevated lactate dehydrogenase, advanced stage, and increased number of extranodal sites and was not a negative prognostic factor independent of the IPI score. Conclusion The negative prognostic impact of discordant involvement is adequately represented by the IPI score, while the risk with concordant involvement is greater than that encompassed by this predictor. The results emphasize the need for accurate staging assessment of bone marrow involvement in DLBCL.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 950-950 ◽  
Author(s):  
Brian T. Hill ◽  
Angela M.B. Collie ◽  
Tomas Radivoyevitch ◽  
Eric D. Hsi ◽  
John Sweetenham

Abstract Abstract 950 INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) can be categorized by its cell of origin (CoO) as either being derived from a germinal center B-cell (GCB) or activated B-cell (ABC). Primary mediastinal DLBCL represents a third, distinct entity. This classification was initially defined by gene expression profiling (GEP), which remains the gold standard for such determination. Determination of CoO will likely become the basis for patient selection for clinical trials of targeted therapies. Several algorithms and methods have been developed that use immunohistochemistry (IHC) to differentiate GCB-DLBCL from non-GCB DLBCL. These include the Hans algorithm (utilizes staining for CD10, Bcl-6 and Mum1), the Choi algorithm (utilizes additional staining for GCET1 and FoxP1) as well as the Tally method (does not use Bcl-6 and utilizes LMO2 as a tie-breaker stain for otherwise equivocal cases). Recently, it has been recognized that IHC approaches to assign CoO may not be reproducible even at highly experienced laboratories. We sought to determine the performance of these IHC assays in our laboratory as a necessary step in developing trials based on CoO stratification. METHODS: We reviewed 108 adult (age ≥18) cases of de novo DLBCL, the majority of which were treated with chemoimmunotherapy (R-CHOP or R-CVP) at the Cleveland Clinic from 2000–2010. Diagnostic biopsies were available for all cases. IHC staining was performed on tissue microarrays (TMAs), and published algorithms (Hans, Choi and Tally) were applied to categorize cases as GCB or non-GCB. In addition, gene expression profiling was completed in a subset of these cases, for which frozen tissue was available. A linear predictor score for gene expression profiling (GEP) was used to assign cases in 31 of 33 cases with 2 technical failures at the array stage (overall success rate 84.8%). Clinical details including age, sex, International Prognostic Index (IPI) stage at diagnosis, treatment, progression free survival (PFS) and overall survival (OS) were captured for 69 of the 108 patients. Actuarial survival analysis was performed according to the Kaplan and Meier method, and the curves compared by the log-rank test. RESULTS: For the 69 patients with adequate clinical follow-up, the median age was 64 years old (range 18–88). There were 49% males and 51% females. The distribution of patients with stage I, II, III, and IV disease at the time of diagnosis was 20%, 14%, 20%, and 32% (14% had unknown stage). The 5-year overall survival of patients was 88%. Results of the Hans algorithm, Choi algorithm and Tally method were interpretable in 98 (90.7%), 95 (87.9%) and 88 (81.5%) of 108 cases, respectively. Inability to assign subtypes was due to suboptimal staining of the TMA (tissue loss or poor staining of an individual core). Using GEP to assign CoO, 42% of cases were classified as GCB, 42% as ABC and 14% were unclassifiable. The sensitivities of the Hans, Choi and Tally approaches to identify the CoO predicted by GEP were 0.83, 0.83, and 0.58 for correctly identifying GCB cases, respectively, and were 0.70, 0.70 and 0.80 for identifying non-GCB cases, respectively. The positive predictive values of the Hans, Choi and Tally approaches were 0.83, 0.83, and 1.0 for GCB and 0.78, 0.78, and 0.89 for non-GCB. As shown in the figure, 5-year overall survival was significantly superior for GCB relative to ABC cases using GEP (100% vs. 58.9%, P < 0.001) and for GCB vs. non-GCB cases for the algorithms of Hans (100% vs. 82.3%, P = 0.0197) and Choi (95.6% vs. 78.0%, P = 0.0482). The Tally method was not predictive of outcome, possibly due to insufficient power (5-year OS 94.4% for GCB vs. 80.7% for non-GCB, P = 0.1725). Similar findings were observed for progression-free survival. CONCLUSIONS: The Hans and Choi algorithms are reasonable methods for identifying PFS and OS differences based on CoO for de novo DLBCL treated with chemoimmunotherapy. The positive predictive value is universally high for all algorithms tested, but the sensitivity of IHC for identifying CoO was fair, particularly for the Tally method. IHC represents a valid biomarker to identify non-GCB cases. Clinical trials of DLBCL that stratify patients by IHC are feasible provided the performance characteristics of the algorithms are taken into consideration during study design. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5081-5081
Author(s):  
Muath Dawod ◽  
Juan Gomez-Gelvez ◽  
Ahmad Mattour ◽  
Kedar V. Inamdar ◽  
Nalini Janakiraman

Abstract Abstract 5081 Background: Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease that has been divided into three different prognostic subgroups: Germinal Center B cell-like (GC), Activated B cell-like (ABC) and type 3 according to gene expression profile using cDNA. Immunohistochemistry (IHC) has been used as surrogate to identify these cell-of-origin subgroups. Data about the prognostic value of IHC has been conflicting. Patients and methods: In this retrospective study, we reviewed the charts of 252 patients diagnosed with DLBCL at Henry Ford Hospital from 1999 to 2012. We excluded patients with HIV, transformed lymphomas and unavailable samples. Data was collected on a total of 157 patients. The following data was gathered: age, sex, race, IPI score, disease stage, hemoglobin, white blood and platelet counts, best response achieved and dates of treatment start, relapse, death or last follow up. Tissue microarray slides with the following IHC stains (CD10, MUM1, Bcl6) were prepared and reviewed when needed. Using Hans Algorithm, samples were divided into two major groups (GC-like and non-GC-like). 3-year progression free and overall survivals were compared between all subgroups using a log-rank test. Continuous variables were reported as median and range, and compared using Wilcoxon rank-sum tests. Categorical variables were reported as median and range, and compared using Chi-square tests. Statistical significance was set at p<0. 05. Results: Eighty patients (51%) were classified as GC-like, and 77 patients (49%) as non-GC-like. GC-like subgroup had a significantly longer 3-year progression free survival (90% vs 74%, P=0. 024), as compared with the non-GC-like subgroup. There was a trend toward longer overall survival but it didn't reach statistical significance (74% vs 67%, P=0. 161). For all patients, IPI stands as a strong prognostic index with 3-year overall survival of (85% and 46%, P=<. 001) in patients with low IPI (0 to 2) and high IPI (3 to 5) respectively. Interestingly, in patients with low IPI, cell of origin stands as a prognostic factor with 3-year progression free survival of (96% and 81%, P=0. 032) in GC-like and non-GC-like groups respectively. While in patients with high IPI, there was no significant difference in progression free survival in cell-of-origin subgroups. Conclusion: Cell of origin subclassification as determined by IHC surrogate markers predict for better progression free survival in GC-like subgroup but not for overall survival. While this prognostic value was maintained in patients with low IPI, there was no prognostic significance in patients with high IPI. IPI is still a valuable prognostic tool in patients with DLBCL. Disclosures: No relevant conflicts of interest to declare.


Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 474 ◽  
Author(s):  
Sara Alonso-Álvarez ◽  
Miguel Alcoceba ◽  
María García-Álvarez ◽  
Oscar Blanco ◽  
Marta Rodríguez ◽  
...  

The biology and clinical impact of bone marrow (BM) infiltration in patients with diffuse large B-cell lymphoma (DLBCL) remains unclear in the rituximab era. We retrospectively analyzed 232 patients diagnosed with DLBCL at our center between 1999 and 2014. Concordant-presence of large cells similar to those of the lymph node biopsy- and discordant-infiltration by small cells forming lymphoid aggregates, lacking cytological atypia-BM infiltration was defined by histological criteria and further characterized by flow cytometry (FCM). Cell of origin (COO) was determined using Hans’ algorithm. For the clonal relationship between tumor and discordant BM, the VDJH rearrangement was analyzed. Survival analyses were restricted to 189 patients treated with rituximab and chemotherapy. Thirty-six (16%) had concordant, and 37 (16%) discordant BM infiltration. FCM described different indolent lymphomas among discordant cases, clonally related with DLBCL in 10/13 available samples. Median follow-up was 58 months. 5-year-progression-free survival (PFS) for non-infiltrated, discordant and concordant groups was 68%, 65% and 30%, respectively (p < 0.001). Combining COO and BM infiltration, patients with discordant BM and non-germinal center B-cell COO also had decreased 5-year-PFS (41.9%). In multivariate analysis, concordant BM had an independent effect on PFS (HR 2.5, p = 0.01). Five-year cumulative incidence of central nervous system (CNS) relapse was 21%, 4% and 1% in concordant, discordant and non-infiltrated groups, respectively (p < 0.001). In conclusion, concordant BM infiltration represents a subset with poor prognosis, whereas the prognostic impact of discordant BM infiltration could be limited to non-CGB cases.


2019 ◽  
Vol 3 (13) ◽  
pp. 2013-2021 ◽  
Author(s):  
Allison Barraclough ◽  
Musa Alzahrani ◽  
Marianne Schmidt Ettrup ◽  
Mark Bishton ◽  
Chris van Vliet ◽  
...  

Abstract In advanced-stage diffuse large B-cell lymphoma (DLBCL), the presence of an activated B-cell phenotype or a non–germinal center (GCB) phenotype, coexpression of MYC and BCL2 by immunohistochemistry, and the cooccurrence of MYC and BCL2 or BCL6 rearrangements are associated with inferior outcomes. It is unclear whether these variables remain prognostic in stage I/II patients. In this retrospective study, we evaluated the prognostic impact of cell of origin (COO), as well as dual-expressor (DE) status and molecular double-hit (DH) status, in stage I/II DLBCL by positron emission tomography with computed tomography (PET-CT). A total of 211 patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)–like regimens, with or without radiotherapy, was included. The median follow-up in the entire cohort was 4 years (range, 0.4-9.4), with estimated 4-year progression-free survival (PFS) and overall survival (OS) rates of 85% (95% confidence interval [CI], 79-89) and 88% (95% CI, 83-92), respectively. By univariable analysis, DE (PFS: hazard ratio [HR], 1.27; 95% CI, 0.58-2.81, P = .55 and OS: HR, 1.40; 95% CI, 0.60-3.30; P = .44), DH (PFS: HR, 1.21; 95% CI, 0.27-5.31; P = .80 and OS: HR, 0.61; 95% CI, 0.08-4.73; P = .64), and non-GCB status (PFS: HR, 1.59; 95% CI, 0.83-3.03; P = .16 and OS: HR, 1.80; 95% CI, 0.89-3.67; P = .10) were associated with poorer outcomes. In patients with PET-CT–defined stage I/II DLBCL treated with R-CHOP–like therapy, with or without radiation, COO and DE and DH status were not significantly associated with inferior PFS or OS.


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