International Prognostic Index Categories Research Articles

Aligning outcomes: DLBCL prognosis at a 4th Level University Hospital in Bogotá is comparable to high-income nations, identification of additional prognostic markers for overall survival and relapse.

Diffuse large B-cell lymphoma (DLBCL), a prevalent non-Hodgkin lymphoma subtype, displays diverse clinical outcomes with persistently high mortality and relapse rates, despite treatment advancements. Notably, the Hispanic demographic lacks consideration in existing prognostic indices for DLBCL. A retrospective cohort study encompassing 112 DLBCL patients diagnosed between 2010 and 2020 was conducted at our institution. Patient data, including overall survival (OS), treatment response, and relapse, were analysed. With a median age of 65 years and a predominant male population (60.7%), both the International Prognostic Index (IPI) and revised IPI correlated with OS. In multivariate analysis, patients with ki-67 ≥ 60% exhibited higher mortality risk (Hazard Ratio: 2.35, 95% confidence intervals (CI) 1.05-5.27, p = 0.039), even when controlled by IPI category and B2-microglobulin levels. The absence of B symptoms served as a protective factor for relapse (p < 0.01, OR: 0.147, 95% CI 0.058-0.376) when controlling for ki-67, CD5, and IPI. Our cohort demonstrated a 5-year OS rate comparable to high-income countries, highlighting the need for tailored prognostic models for Hispanic DLBCL patients. This study identifies easily accessible parameters aligning with regional resource constraints, providing insights into additional prognostic factors for DLBCL in the Hispanic population.

Red Cell Distribution Width-to-Albumin Ratio Is a Simple but Robust Prognostic Biomarker in Peripheral T-Cell Lymphoma

Background: Red cell distribution width (RDW) is the difference in the volume and size of erythrocytes. High RDW has been identified as a worse prognostic factor in various diseases, including sepsis, cerebrovascular accidents, and diverse cancers. More recently, RDW-to-albumin ratio (RAR) is a comprehensive biomarker combining inflammation and nutrition status that better reflects a patient's frailty. However, little is known about its prognostic relevance in peripheral T-cell lymphoma (PTCL), with only one publication focusing on RDW (Castro et al.). Methods: This retrospective analysis included consecutive patients with newly diagnosed PTCL between 2007 and 2023 at Kameda Medical Center. Extranodal NK/T-cell lymphoma, adult T-cell leukemia/lymphoma, and ALK-positive anaplastic large cell lymphoma were excluded due to distinct prognosis and treatment strategies. The RDW coefficient of variation (RDW-CV) was assessed prior to treatment and calculated using the following formula: 1 standard deviation of mean corpuscular volume (MCV) divided by MCV, multiplied by 100. Receiver operating curve (ROC) analysis was used to determine the optimal cutoff value of RDW-CV and RAR for 2-year outcomes. Survival analyses were conducted using Kaplan-Meier curves with log-rank tests, and Cox proportional hazard models were used for univariate and multivariate analyses. Results: In total, 115 patients were included in this analysis. The median age was 74 years (range 45-93), with male predominance (60.8%). Sixty-five patients (56.5%) were initially treated with the CHOP regimen, while 29 patients (25.2%) received more intensive chemotherapy. The most common disease subtype was PTCL-not otherwise specified (49.5%), followed by angioimmunoblastic lymphoma (40.0%). The median RDW-CV and RAR were 14.8 (range 12.2-21.5) and 4.61 (range 2.6-9.8), respectively. The RDW-CV was significantly correlated with levels of hemoglobin (R = -0.4), albumin (R = - 0.59), and lactate dehydrogenase (R = 0.27) (all P &amp;lt; 0.05). ROC curve analysis for 2-year survival revealed a higher area under the curve (AUC) for RAR (0.79) compared to RDW (0.74), with cutoff values of 4.4 and 14.1, respectively (Figure 1). Using this cutoff value, patients with high RAR had significantly worse overall survival (OS) and progression free survival (PFS) than those without (2-year OS rate: 82.5% vs. 35.1%, Figure 2; 2-year PFS rate: 54.8% vs. 27.9%, P &amp;lt;0.001). On multivariate analysis, high RAR was associated with a significantly worse PFS (hazard ratio [HR] =1.89 [95% confidence interval 1.15-3.11], P =0.01) and OS (HR=3.02 [1.66-5.50], P &amp;lt;0.001) independent of the international prognostic index (IPI), dose reduction of chemotherapy and lymphoma subtype. Conclusion: We demonstrated that RAR improved the prognostic stratification compared to RDW-CV alone. Additionally, baseline high RAR was identified as a simple but robust prognostic factor independently associated with IPI category and treatment intensity in PTCL patients.

Tumor Mutational Burden As a Prognostic Factor in Diffuse Large B-Cell Lymphoma

Background: Tumor mutational burden (TMB), defined as the number of nonsynonymous mutations per megabase (Mb) in the coding regions of a tumor genome, has been associated with improved response to immune checkpoint blockade treatments and more broadly with overall survival (OS) in many cancers. Limited prior studies have found that TMB is higher in diffuse large B-cell lymphoma (DLBCL) compared to many other cancers. However, only two studies have evaluated TMB and prognosis in newly diagnosed DLBCL patients. The prognostic role of TMB in diffuse large B-cell lymphoma (DLBCL) remains unclear as prior studies have been limited to panel sequencing of cancer genes and/or lacked matched germline-tumor samples for filtering. Methods: We characterized TMB from whole exome sequencing (WES) in newly diagnosed DLBCL patients with matched diagnostic tumor-normal samples prior to treatment with standard immunochemotherapy (IC). Tumor DNA was extracted from formalin-fixed, paraffin embedded tissue sections and germline DNA from peripheral blood. We evaluated the association between TMB and event-free (EFS) and OS using Cox regression adjusted for the international prognostic index (IPI) and other factors including cell of origin (COO), MYC double hit (DH) with BLC2 or BCL6 by FISH, and TP53 mutation status. EFS and OS were defined as time from diagnosis to earliest of treatment failure (EFS only), death, or last follow-up; EFS at 24 months (EFS24) was also modeled as a marker of early aggressive DLBCL. An optimal high/low TMB cutpoint was determined based on EFS using maximally selected rank statistics; sensitivity analyses used an 20/80 percentile to define the threshold. We also evaluated the association of driver tumor mutational load (driverTML) with EFS and OS, defined as the total number of mutations in 292 DLBCL driver genes. Results: In the analysis cohort of 394 DLBCL patients, the median age at diagnosis was 65 years (interquartile range: 56-73), 43% were female, 62.2% had IPI 0-2, and 57.4% germinal center B-cell COO. MYC was DH in 7.5% and TP53 was mutated in 16.2% of patients. Through a median follow-up of 7.5 years, there were 141 events and 122 deaths. EFS24 was achieved in 75.1% of the cohort; 5-year EFS was 69% (95% CI 64-74%) and 5-year OS was 75% (95% CI 71-80%). Median TMB in our cohort of DLBCL patients was 3.6 mutations/Mb, which was the fifth highest compared with 32 cancers in The Cancer Genome Atlas. As a continuous variable, increasing TMB (mutation/Mb) was associated with superior EFS (HR=0.89, 95% CI 0.81-0.98) and OS (HR=0.89, 95% CI 0.81-0.99) after adjustment for IPI. Spline analyses confirmed linear associations of TMB with EFS and OS. The optimal modeled cutpoint based on EFS was 4.5 mutations/Mb, with 31% classified as high TMB (&amp;gt;4.5). No significant ( P &amp;gt;.05) differences were observed between high and low TMB patients with clinical (i.e., age, sex, IPI category) or molecular (cell of origin, MYC DH, TP53 mutated) factors. In Cox regression, high-TMB was significantly protective for EFS and for OS compared to low-TMB after adjustment for each clinical factor ( Figure 1), with simultaneous adjustment for all these factors associated with superior EFS (HR=0.52, 95% CI 0.33-0.84) and OS (HR=0.59, 95% CI 0.36-1.00). TMB (high/low) combined with IPI (0-2, 3-5) was significantly ( P =.001) associated with EFS in Kaplan-Meier analysis ( Figure 2). Among patients with IPI 3-5, high TMB was significantly associated with superior EFS (HR=0.47, 95% CI 0.27-0.81) and OS (HR=0.57, 95% CI 0.33-0.99). Among patients with IPI 0-2, we also observed longer EFS (HR=0.62, 95% CI 0.34-1.11) and OS (HR=0.62, 95% CI 0.32-1.20) in high TMB patients, although the associations were not statistically significant ( P &amp;gt;.05). In sensitivity analyses, a 20/80 percentile TMB threshold found similar results for EFS (HR=0.64, 95% CI 0.41-1.03) and OS (HR=0.69, 95% CI 0.42-1.12) as in our main analyses. TMB and driverTML were significantly correlated ( R=0.65, P &amp;lt;10 -16) and we found similar effect sizes for EFS (HR=0.45, 95% CI 0.22-0.91) and OS (HR=0.55, 95% 0.27-1.13) as in our main analyses. Conclusions: In a large and well-defined cohort of IC treated DLBCL patients, we found DLBCL patients with higher TMB had superior EFS and OS after adjustment for other clinical and molecular prognostic factors, and the prognostic association for TMB was robust to threshold and gene set.

Lower Prognostic Performance of the International Metabolic Prognostic Index Compared to the Conventional IPI and NCCN-IPI in a Real-World Cohort of Diffuse Large B-Cell Lymphoma

Introduction: The international metabolic prognostic index (IMPI) is a recently proposed model that shows improved outcome prediction for patients with diffuse large B-cell lymphoma (DLBCL) compared to the International Prognostic Index (IPI) (Mikhaeel et al.). IMPI combines total metabolic tumor volume (TMTV) as continuous variables with clinical factors, allowing individualized prognosis estimation. However, the applicability of IMPI to routine clinical practice remains uncertain since the model construction was based on data from clinical trials. Furthermore, the comparison of the model performance between IMPI and the National Comprehensive Cancer Network IPI (NCCN-IPI) is not reported so far. Methods: We performed retrospective analysis of consecutive patients with newly diagnosed DLBCL who were initially treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) at Kameda Medical Center between 2006 and 2020. Patients who had no fluorodeoxyglucose-avid lesions were excluded. TMTV was defined as the volume of lymphoma-associated lesions with a standardized uptake value of ≥4 as the absolute threshold (Metavol, Hokkaido University, Japan). According to the original study (Mikhaeel et al.), IMPI was calculated using the following formula: 0.003077330 × (MTV lower than the median of 307.9ml) - 0.002761985 × (MTV higher than the median of 307.9ml) + 0.008092449 × Age -0.114645415 × Stage 2 + 0.281141117 × Stage 3 + 0.322247142 × Stage 4. The receiver operating curve (ROC) for predicting 5-year survival was compared among IMPI-, IPI-, and NCCN-IPI-based classifications. The predictive performance of these three systems was evaluated using the Akaike information criterion (AIC) and Harrell's concordance index (c-index). Results: A total of 314 patients were included in the study. The median age was 72 years old (interquartile range [IQR] 64-79), which was younger than the original data (median 62, IQR 51-70). Regarding the distributions of IPI risk groups, this cohort had a lower number of low-risk patients (27.0% vs. 32.4%) and a higher number of high-risk patients (23.9% vs. 19.5%). The median TMTV was 168 (IQR 47-530), which was approximately two times lower than that in the original study (median 307, IQR 77-838). After calculating and ranking the individual IMPI scores, nearly half of the patients (n=147, 46.8%) were reclassified into different risk groups from the original IPI categories (Figure 1); 76 (51.7%) were upstaged, and 71 (48.3%) were downstaged. Of note, the reclassification resulted in a significantly better OS prediction only for the IPI high-risk group (5-year OS rate, IMPI high-risk vs. IMPI not high-risk, 41.9% vs. 59%, P =0.042), while it did not for the IPI low-, low-intermediate-, and high-intermediate-risk groups. The area under the curve (AUC) from the ROC curve predicting 5-year survival was not significantly different between IMPI- (AUC 0.65) and either IPI- (AUC 0.67, P =0.42) or NCCN-IPI-categories (AUC 0.68, P=0.25). Finally, the predictive performance and model fitness were compared among these three indices. IMPI had the highest AIC (1117.68) and the lowest c-index (0.643) for OS prediction, whereas NCCNIPI yielded the best performance (AIC 1097.66 and c-index 0.677) (Table 1). Conclusions: We demonstrated that the IMPI model did not outperform the conventional IPI and NCCN-IPI systems in a real-world cohort of DLBCL patients. The difference in age and tumor burden, which are the major components of IMPI, may lead to poorer prognostic performance. Further large-scale studies are warranted to validate the prognostic value of IMPI outside of clinical trials.

The Novel Prognostic Index Model of Combining Circulating Tumor DNA and PINK-E Predicts the Clinical Outcomes for Newly Diagnosed Extranodal NK/T-cell Lymphoma.

Extranodal NK/T-cell lymphoma (ENKTL) is a highly aggressive and heterogeneous disease with poor clinical outcome. Our previous work had demonstrated that circulating tumor DNA (ctDNA) analyses were feasible in ENKTL, and dynamic tracing of ctDNA could be used to monitor the disease status. However, the prognostic value of ctDNA in ENKTL has not been fully investigated. Patients with newly diagnosed ENKTL from February 2017 to December 2021 (n = 70) were enrolled. The pretreatment ctDNA concentration (hGE/mL) was measured. The prognostic value of ctDNA, international prognostic index (IPI), Korean prognostic index (KPI), PINK-E, and the combination of PINK-E and ctDNA (PINK-EC) were investigated in our cohort. The IPI and PINK-E risk categories had a significant difference in progression-free survival (PFS) and overall survival (OS) between the low-risk and intermediate-risk groups. The KPI risk category had a difference in PFS and OS between the intermediate-risk and high-risk groups. Furthermore, integrating ctDNA into the PINK-E model could overcome the shortcomings of other prognostic models, which could significantly distinguish the different-risk groups. Overall, our results demonstrated that PINK-EC showed a superior prognostic prediction value and stability compared with IPI, KPI, and PINK-E. The integration of molecular features of the tumor into classic risk categories might better characterize a high-risk group where novel treatment approaches are most needed.

Characterizing Diffuse Large B Cell Lymphoma (DLBCL) Disease Biology Features and Survival Outcomes By Patient Racial Groups Using Real World Data

Background Various real world data (RWD) studies have highlighted differences in the survival outcomes of DLBCL patients of different ethnicities and racial groups. However, few studies have examined the differences in DLBCL biology features in patients of different racial groups. Using RWD, we evaluated both biology features and survival outcomes of DLBCL patients from different racial groups. Method Our retrospective analysis used de-identified, real-world patient data from the Flatiron Health electronic health record-derived database. Inclusion criteria were patients with an initial diagnosis of DLBCL (ICD 9: 200x, 202x; ICD 10: C82x, C83x, C84x, C85x, C86x, C88x, C96x) between 1 January 2011 to 31 May 2022 and who had at least two documented clinical visits. Patients’ racial groups were classified into Asian, Black or African American, White, Others and Unknown; the Others group were patients not included in the other racial groups. The DLBCL disease features included cell-of-origin (COO) subtypes, double hit status (MYC and BCL2 translocations), double expressor status (MYC and BCL2 expression by immunohistochemistry) and International Prognostic Index (IPI) scores. Differences among racial groups were examined using the chi-square test with p-value<0.05 considered significant. Differences in overall survival (OS) by patients racial groups were analyzed using Kaplan Meier survival analysis and an adjusted Cox regression model for multivariable analysis. Results In total there were 8289 evaluable patients. The racial group distribution of the cohort was as follows: White (n = 5659, 68.3%), Others (n =1084, 13.1%) Black or African American ( n = 509, 6.1%), Asian (n = 185, 2.2%) and Unknown (n = 852, 10.3%); Fig. 1a. Disease biology features among patients of different racial groups were evaluated. There was a significant difference in the racial distribution between the two COO subtypes (p=0.045). Higher proportion of White patients had the germinal-center B-cell-like (GCB) subtype (n=1888/3127, 60.4%) compared to Asian (n=58/119, 48.7%) and Others (n=351/626, 56.1%) patients. Asian patients had the highest proportion of activated B-cell-like (ABC) subtype (n=61/119, 51.3%) compared to the other racial groups. No significant difference in racial group distribution was seen in double hit status. In terms of double expressor status, there was a significant difference in racial distribution (p = 0.008). More Asian patients had positive double expressor status (n=30/185, 16.2%) compared to the other racial groups. Racial distribution was significantly different between IPI categories (p = 0.028). Higher proportion of White patients presented with higher IPI scores compared to Asian, Black or African American patients. The univariate analysis showed that White patients had worse overall survival (median OS 85.3 months) than Black or African American patients (median OS 111.2 months), Asian patients (median OS 102.6 months) or Others patients (median OS 107.0 months); Fig. 1b. However, multivariable analysis, adjusted for age, gender, IPI and COO, showed no significant difference in OS between White patients and Black or African American (HR 0.89, 95% CI 0.75 - 1.06, p = 0.18) or Asian patients (HR 0.86, 95% CI 0.65 - 1.16, p = 0.31); though was a difference with the Others patients (HR 0.87, 95% CI 0.77-0.98, p =0.024) . Conclusions Using a RWD cohort, we described the disease characteristics and OS between DLBCL patients of different racial groups. Although differences were seen in COO and IPI scores, OS was not significantly different between racial groups in multivariable analysis except between White and Others patients . As the Others patients were a heterogenous group, in-depth study is warranted in the future to delineate true differences. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Proposed New Dynamic Prognostic Index for Diffuse Large B-Cell Lymphoma: International Metabolic Prognostic Index.

PURPOSEBaseline metabolic tumor volume (MTV) is a promising biomarker in diffuse large B-cell lymphoma (DLBCL). Our aims were to determine the best statistical relationship between MTV and survival and to compare MTV with the International Prognostic Index (IPI) and its individual components to derive the best prognostic model.METHODSPET scans and clinical data were included from five published studies in newly diagnosed diffuse large B-cell lymphoma. Transformations of MTV were compared with the primary end points of 3-year progression-free survival (PFS) and overall survival (OS) to derive the best relationship for further analyses. MTV was compared with IPI categories and individual components to derive the best model. Patients were grouped into three groups for survival analysis using Kaplan-Meier analysis; 10% at highest risk, 30% intermediate risk, and 60% lowest risk, corresponding with expected clinical outcome. Validation of the best model was performed using four studies as a test set and the fifth study for validation and repeated five times.RESULTSThe best relationship for MTV and survival was a linear spline model with one knot located at the median MTV value of 307.9 cm3. MTV was a better predictor than IPI for PFS and OS. The best model combined MTV with age as continuous variables and individual stage as I-IV. The MTV-age-stage model performed better than IPI and was also better at defining a high-risk group (3-year PFS 46.3% v 58.0% and 3-year OS 51.5% v 66.4% for the new model and IPI, respectively). A regression formula was derived to estimate individual patient survival probabilities.CONCLUSIONA new prognostic index is proposed using MTV, age, and stage, which outperforms IPI and enables individualized estimates of patient outcome.

Prognostic impact of the controlling nutritional status score in patients with peripheral T-cell lymphoma

The controlling nutritional status (CONUT) score is a simplified nutritional index calculated from serum albumin, total cholesterol, and total lymphocyte count. This study evaluated the prognostic impact of the CONUT score on overall survival (OS) in patients with peripheral T-cell lymphoma (PTCL). A multicenter, retrospective cohort study including 99 patients with PTCL was conducted. The CONUT score was significantly higher in the non-survivor group (median 5, range 0-12) than in the survivor group (median 3, range 0-11; p = 0.026). The CONUT score was an independent prognostic factor in a multivariable Cox proportional hazards model (hazard ratio 1.119, 95% confidence interval 1.021-1.227, p = 0.017). No significant effect-modification by the International Prognostic Index (IPI) was observed, and the CONUT score affected the prognosis of PTCL regardless of the IPI (P for interaction = 0.208). In conclusion, the CONUT score is an independent prognostic factor for PTCL irrespective of IPI category.

The Echelon-2 Trial: 5-Year Exploratory Subgroup Analyses of a Randomized, Double-Blind, Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Vs CHOP in Frontline Treatment of Pts with CD30-Positive Peripheral T-Cell Lymphoma

The Echelon-2 Trial: 5-Year Exploratory Subgroup Analyses of a Randomized, Double-Blind, Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Vs CHOP in Frontline Treatment of Pts with CD30-Positive Peripheral T-Cell Lymphoma

Automated Baseline Fluorodeoxyglucose-Positron Emission Tomography Imaging and High BCL2 Expression Provide Orthogonal Prognostic Value in Predicting High-Risk De Novo Diffuse Large B-Cell Lymphoma Patients

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, accounting for 30─40% of cases (Li, et al. Pathology 2017). Although rituximab (R) plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) cures approximately 50─60% of patients, clinical outcomes remain poor for those with relapsed or refractory (R/R) disease (Liu and Barta. Am J Hematol 2019). Current prognostic models such as the International Prognostic Index (IPI) have suboptimal sensitivity and specificity to identify these patients at diagnosis. Models that combine biological, clinical and imaging markers may improve prognostication in DLBCL. Methods: We evaluated fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging features alongside clinical and biomarker data in modeling disease prognosis with a primary endpoint of investigator-assessed progression-free survival (PFS) for de novo DLBCL patients from the randomized phase III GOYA study (NCT01287741) comparing R-CHOP versus obinutuzumab (G)-CHOP. Imaging features were derived using a computer-vision modeling algorithm (Jemaa, et al. J Digit Imaging 2020), and included total and by-organ number and volume of lesions. The evaluable population (n=1286) was split into pre-defined training (n=964; PFS events=307) and holdout populations (n=322; PFS events=96). Baseline clinical and imaging features were dichotomized by median or a clinically relevant threshold, and screened with univariate Cox proportional hazard (PH) models (Figure A). Screened variables were further selected to construct a multivariate Cox PH model for risk prognosis utilizing a regularized LASSO Cox regression (Simon, et al. J Statistical Software 2011). Model performance was evaluated by area under the receiver operating characteristic curve (AUC) and C-index on the holdout population. Additional biomarker features were evaluated, including, BCL2 protein expression as determined by Ventana investigational-use only immunohistochemistry (IHC) assay, gene expression quantified by TruSeq® (Illumina) RNAseq, next generation sequencing-based genomic profiling using the FoundationOne HemeTM platform (F1H, Foundation Medicine Inc. [FMI]) and cell of origin (COO) by the Nanostring assay. Results: Total metabolic tumor volume (TMTV), total number of lesions, longest diameter of any lesion, number of kidney lesions, and number of liver lesions were selected as prognostic imaging factors for PFS in de novo DLBCL patients. Strong correlation was observed between corresponding volume and lesion number features, as expected, though collinearity appeared to otherwise be minimal (Figure B). Performance of the resulting model composed of these imaging variables alongside standard clinical features and treatment (AUC=0.66; C-Index=0.64) improved upon a model composed of IPI categories (AUC=0.60; C-Index=0.60). High risk, defined by log-hazard &amp;gt;0 was associated with reduced PFS (Figure C). High BCL2 expression by IHC (score &amp;gt;1) was prognostic for PFS independent of clinical and imaging features (HR, 2.02; CI: 1.36─2.98). High BCL2 was predictive of PFS in patients treated with G-CHOP over R-CHOP in de novo DLBCL patients (HR, 0.55; CI: 0.32─0.97) (Figure D). This trend held when adjusting for COO separate to imaging features. Mutational analysis using the FMI panel also indicated the additional prognostic value of BCL2 and TP53 single-nucleotide variants through selection by LASSO. Conclusions: Automated baseline imaging features and high BCL2 expression demonstrated prognostic value orthogonal to standard clinical features in predicting high-risk de novo DLBCL despite limitations imposed by sample size and multicollinearity among features. These findings support the integration of imaging, genomic and clinical factors in prognostic models to improve the identification of high-risk de novo DLBCL patients. Disclosures Jemaa: F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Tracy:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Bottos:F. Hoffmann-La Roche: Current Employment, Current equity holder in private company. de Crespigny:Genentech, Inc.: Current Employment; F Hoffmann-La Roche: Current equity holder in publicly-traded company. Bengtsson:Genentech, Inc.: Current Employment; F Hoffmann-La Roche: Current equity holder in publicly-traded company. Nielsen:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Paulson:Genentech, Inc.: Current Employment; F. Hoffmann-Roche: Current equity holder in private company, Current equity holder in publicly-traded company.

Diffuse large B-cell lymphoma: 10 years' real-world clinical experience with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone.

Treatment with rituximab plus a regimen of cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) for patients with diffuse large B-cell lymphoma (DLBCL) has proven efficacy in clinical trials. The present study investigated its application in clinical practice. This single-center, retrospective database analysis included patients with DLBCL treated at the Slovenian Institute of Oncology Ljubljana between 2004 and 2013. Overall survival (OS) and progression-free survival (PFS) were assessed according to International Prognostic Index (IPI) and revised IPI (R-IPI) categories. Overall, 573 patients with DLBCL were included in the study (median follow-up, 45.3 months; range, 0.1–143.0). Patients were categorized as IPI ‘low’ (n=170; 30%), ‘low-intermediate’ (n=134; 23%), ‘high-intermediate’ (n=129; 23%) and ‘high’ (n=140; 24%) risk. R-IPI groups were indicated with ‘very good’ (n=59; 10%), ‘good’ (n=245; 43%) and ‘poor’ (n=269; 47%) prognosis. Ten-year OS and PFS rates were 51 and 72%, respectively; median OS was 124 months and median PFS was not reached. Ten-year OS rates were 80 and 87% in low-risk and ‘very good’ prognosis groups, respectively, and 30 and 37% in high-risk and poor prognosis patients, respectively. This analysis of patients with DLBCL indicated that many patients treated with R-CHOP and R-CHOP-like regimens in the real-world setting have excellent outcomes.

Clinical and Prognostic Significance of Epstein-Barr Virus in Diffuse Large B-Cell Lymphoma

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the largest subtype of lymphoma, but consists of heterogeneous groups with different prognosis. Many studies conducted to determine prognosis factors of DLBCL. Recently, several studies have been reported that the elderly Epstein-Barr virus (EBV)-positive DLBCL patients showed worse prognosis than the elderly EBV-negative DLBCL. (Oyama T et al. Clin Cancer Res 2007;13:5024-5032). On the other hand, other studies reported that EBV-positivity is not a prognosis factor in young-adult DLBCL patients (Hong JY et al. Annals of Oncology 2015;26:548-555, Nicolae A et al. BLOOD 2015;126:863-872). In the present study, retrospective analyses were carried out for patients with DLBCL diagnosed between 1990 and 2007 to analyze the clinical and prognostic significance of EBV.Patients: Those who met the following criteria were included in the study: (i) pathology confirmed de novo DLBCL, according to the WHO classification; (ii) adequate amount and quality of paraffin-embedded biopsy specimens or unstained slides for EBV-encoded RNA in situ hybridization.Statistical methods: Intergroup comparisons were carried out with Fisher's exact test for categorical variables and the Mann-Whitney test for age. For survival analysis, we carried out Kaplan-Meier and multivariate proportional hazard (Cox) analyses. Statistical analyses were carried out using the software Stata SE version 14.0.Results: A total of 456 patients were included. The median follow up duration of survivor was 100 months (range, 1.9-363). There were 236 male (51.75%) and 220 female patients (48.25%) with a median age of 67 (range, 22-94) years. 246 patients (54.0%) were in advanced (III/IV) stage, 134 (29.4%) presented with poor Eastern Cooperative Oncology Group Performance Status (ECOG-PS), 275 (60.3%) with elevated lactate dehydrogenase (LDH) level, 263 (57.7%) with extranodal involvement of 1 or more sites, and 64 (14.0%) with bulky mass. As a consequence, 211 patients (46.3%) were in high/high-intermediate International Prognostic Index (IPI) categories. 5 years overall survival (OS) was 66.2%, in total. EBV was detected in samples from 47 patients (10.3 %). The positivity was 10.6% (15 / 142) in patients of 60 years or younger, and 10.2 % (32 / 314) in those older than 60 years (p = 0.51). No differences in back ground date were found between EBV - positive and negative DLBCLs regarding age (median 66.5 vs. 64.8, P = 0.17), male sex (88.1% vs. 11.9%, P = 0.16), advanced stage (88.2% vs. 11.8%, P = 0.17), poor ECOG-PS (90.3% vs. 9.7%, P = 0.47), elevated LDH (89.5% vs. 10.6%, P = 0.48), extranodal sites of one or more (90.5% vs. 9.5%, P = 0.31), bulky mass (92.2% vs. 7.8%, P = 0.33), and higher IPI categories (88.6% vs. 11.4%, P = 0.29).The prognosis was also not different between EBV-positive and negative DLBCLs. The 5 years OS was 42.6% for EBV-positive DLBCLs, and 56.4% for EBV-negative DLBCLs (P = 0.11). The same results were found for the younger (53.3% vs. 66.9%, P = 0.30) and the elderly patients (42.9% vs. 51.8%, P = 0.18).Conclusion: In this practice based, uncontrolled study, EBV-positively wad not different in younger and elderly DLBCLs. Although EBV-positive DLBCL showed worse trend of prognosis, the difference was not statistically significant. The significance of EBV in DLBCL should be reconsidered in unbiased, large-scale patient date. [Display omitted] [Display omitted] [Display omitted] DisclosuresSuzuki:Chugai: Honoraria; Bristol-Myers Squibb: Honoraria; Kyowa Hakko kirin: Honoraria. Suzumiya:Chugai: Research Funding, Speakers Bureau; Astellas: Research Funding; Toyama Chemical: Research Funding; Eizai: Research Funding; Takeda: Speakers Bureau; Kyowa Hakko Kirin: Research Funding.

CD43 expression in diffuse large B-cell lymphoma, not otherwise specified: CD43 is a marker of adverse prognosis.

CD43 (leukosialin) is a transmembrane glycoprotein expressed in a variety of hematopoietic cells, including B lymphocytes, and a variety of malignancies including lymphoma, leukemia, and solid tumors. CD43 plays an important role in the development of many diseases, and coexpression of CD43 and CD20 on peripheral B cells is a predictive factor of hematopoietic malignancy. Although CD43 is expressed in approximately 25% of diffuse large B-cell lymphomas (DLBCLs), its prognostic significance remains unclear. To analyze CD43 expression in DLBCL, not otherwise specified (DLBCL, NOS), and assess its prognostic value, we analyzed clinical data from 160 patients with DLBCL, NOS. We observed that CD43 expression was detected in 47 (29.4%) of 160 cases. CD43 expression was positively correlated with old age (>60 years), high serum lactate dehydrogenase level, B symptoms, non-germinal center type, and DLBCL, NOS, mortality. Patients with CD43-positive DLBCL, NOS, had poorer overall survival (P < .001, log-rank test) and event-free survival (P < .001, log-rank test) than CD43-negative patients. Univariate analysis showed that CD43 expression, age, sex, Ann Arbor stage, International Prognostic Index category, and germinal center phenotype were prognostic factors for DLBCL, NOS, patient survival. Multivariate analysis showed that CD43 expression was an independent significant prognostic factor for event-free survival (P < .001) and overall survival (P < .001). Based on these data, we conclude that CD43 expression is a novel adverse prognostic factor for patients with DLBCL, NOS.

A Comparison of THP- Cop and CHOP for Peripheral T-Cell Lymphoma, Not Otherwise Specified

▪ BACKGROUNDPeripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), is relatively rare, accounting for only 10% to 15% of non–Hodgkin’s lymphomas, and is characterized by disseminated disease, with systemic symptoms, bone marrow involvement, and extranodal disease. There is no general consensus regarding the preferred induction chemotherapy for PTCL-NOS. CHOP regimen consisting of cyclophosphamide (CPA), doxorubicin (DOX), vincristine (VCR) and prednisone (PSL) has been the most frequently employed regimen for PTCL-NOS, but the overall survival in each IPI category appears lower in patients with most PTCL-NOS than seen in diffuse large B-cell lymphoma. Pirarubicin (tetrahydropyranyladriamycin: THP), a derivative of DOX, is reportedly an anthracyclin with less cardiotoxicity than DOX, because the cardiac sympathetic dysfunction and cardiac mitochondrial damage were less common with THP than those with doxorubicin. We previously reported THP-COP regimen consisting of THP, CPA, VCR, and PSL produced resulted equivalent to CHOP regimen regarding efficacy and safety in patients with aggressive non-Hodgkin’s lymphoma (Tsurumi H et al. JCRCO 2004). In addition The Japanese Clinical Study Group of THP Lymphomas in the Elderly reported that T-cell lymphomas had a significantly better response to THP-COP than CHOP, and no such difference was observed in B-cell lymphoma. Therefore, we conducted a retrospective analysis to confirm the efficacy of THP-COP in the treatment of PTCL-NOS. PATIENTS AND METHODSThe study protocol employed a retrospective, consecutive entry design. We retrospectively analyzed 61 patients with PTCL-NOS who had received THP-COP or CHOP in 5 institutes of Gifu Hematology Study Group between December 1995 and March 2013. A diagnosis of PTCL-NOS was confirmed histrogically according to the World Health Organization classification. We exclude patients who had previously treated with any chemotherapy for lymphoma, and were diagnosed as Adult T-cell leukemia/lymphoma or angioimmunoblastic T-cell lymphoma. CHOP regimen composed CPA (750 mg/m2), DOX (50 mg/m2), VCR (1.4 mg/m2, maximal dose 2.0 mg) and PSL (100mg/body, administered for 5 days). In THP-COP regimen, THP (50 mg/m2) was used instead of DOX. These regimens were performed every 14 to 21 days. Thirty patients received THP-COP, 31 received CHOP. There were no significant differences in known prognostic factors include the international prognostic index (IPI) and prognostic index for T-cell lymphoma (PIT) between two groups. The median cycles of treatment were 6 in both groups. The median follow-up times were 25 and 19 months, respectively. RESULTComplete remission (CR) rates in the patients with THP-COP and CHOP were 53% and 55% (P=0.906), 3-yr overall survival (OS) rate 68% and 51% (P=0.096), and 3-yr progression free survival (PFS) rate 46% and 27% (P=0.078), respectively. Although there were no significant differences between two groups, THP-COP regimen had a tendency of better prognosis. In patients with low IPI (Low or Low-intermediate), THP-COP had significantly better 3yr-OS (100% vs 63%, P=0.002) and 3yr-PFS (69% vs 34%, P=0.002). Same difference was observed in patients with low PIT (group1 or 2), but was not observed in patients with high IPI (High-intermediate or High) or PIT (Group3 or 4). Fatal non-hematological adverse event did not occur in both groups. CONCLUSIONOur study showed THP-COP produced resulted equivalent to CHOP regarding efficacy and safety in patients with PTCL-NOS. Moreover, THP-COP had a tendency of better prognosis compared with CHOP. In patients with low IPI or PIT, THP-COP had significantly better prognosis. This result indicates that THP-COP is an effective and well tolerated regimen for patients with PTCL-NOS, and might be translated into improving survival in comparison with CHOP. Further large study is needed to clarify the difference between the two regimens. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prognostic significance of peripheral monocyte count in patients with extranodal natural killer/T-cell lymphoma

BackgroundExtranodal natural killer/T-cell lymphoma (ENKL) has heterogeneous clinical manifestations and prognosis. This study aims to evaluate the prognostic impact of absolute monocyte count (AMC) in ENKL, and provide some immunologically relevant information for better risk stratification in patients with ENKL.MethodsRetrospective data from 163 patients newly diagnosed with ENKL were analyzed. The absolute monocyte count (AMC) at diagnosis was analyzed as continuous and dichotomized variables. Independent prognostic factors of survival were determined by Cox regression analysis.ResultsThe AMC at diagnosis were related to overall survival (OS) and progression-free survival (PFS) in patients with ENKL. Multivariate analysis identified AMC as independent prognostic factors of survival, independent of International Prognostic Index (IPI) and Korean prognostic index (KPI). The prognostic index incorporating AMC and absolute lymphocyte count (ALC), another surrogate factor of immune status, could be used to stratify all 163 patients with ENKL into different prognostic groups. For patients who received chemotherapy followed by radiotherapy (102 cases), the three AMC/ALC index categories identified patients with significantly different survivals. When superimposed on IPI or KPI categories, the AMC/ALC index was better able to identify high-risk patients in the low-risk IPI or KPI category.ConclusionThe baseline peripheral monocyte count is shown to be an effective prognostic indicator of survival in ENKL patients. The prognostic index related to tumor microenvironment might be helpful to identify high-risk patients with ENKL.

Similar outcomes in Asian and Western patients with diffuse large B-cell lymphoma treated with R-CHOP

BackgroundLittle is known on racial differences in patients with diffuse large B-cell lymphoma (DLBCL). The aim of this retrospective study is to compare characteristics, prognostic factors and outcomes of Asian and Western patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). MethodsPatient-level data was collected from 8 centers. All patients were diagnosed with DLBCL and treated with R-CHOP. Patients were divided into Asian and Western, according to the country of report. Comparisons and univariate/multivariate survival analyses were performed. Results712 patients, 455 Asian and 257 Western patients were included. Westerners were more likely to present with elevated LDH (64% vs. 48%, p<0.01) and advanced stage (58% vs. 49%, p<0.01). After a median follow-up of 36 months, there was no difference in progression-free (PFS; p=0.33) or overall survival (OS; p=0.69). There were no PFS or OS differences between races when evaluating separately each age-adjusted International Prognostic Index category. In the multivariate analyses, performance status and stage were associated with PFS and OS in both races. ConclusionsThere are no differences in prognostic factors, PFS and OS between Asian and Western patients with DLBCL treated with R-CHOP.

High expression of tumor-infiltrating macrophages correlates with poor prognosis in patients with diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is characterized by its clinical and biological heterogeneity. Although the International Prognostic Index (IPI) provides a clinical model for risk stratification of patients with DLBCL, notable variability in outcome is still observed within the same IPI category. Tumor-infiltrating macrophages (also called Tumor-associated macrophages) are the major component in the microenvironment of DLBCL. Their correlation with the prognosis of DLBCL remains controversial. Using a CD68 antibody in immunohistochemical analysis, we studied the expression of CD68 in 112 Chinese patients with DLBCL, with 65 patients (58%) categorized as low CD68 expression and 47 patients (42%) as high CD68 expression. The complete response (CR) rate of patients with low CD68 expression was higher than that with high CD68 expression (66.1% vs. 51.6%), but there was no statistical significance (P=0.060). The median survival time of patients with low CD68 expression was not achieved and that of high expression was 41 months (P=0.029). The results suggest that higher expression of CD68 tended to yield poor treatment outcome of DLBCL.

Relapsed Diffuse Large B-Cell Lymphoma: Clinical Utility of Cell of Origin

Relapsed Diffuse Large B-Cell Lymphoma: Clinical Utility of Cell of Origin

Phase II Study of Risk-Adapted Therapy of Newly Diagnosed, Aggressive Non-Hodgkin Lymphoma Based on Midtreatment FDG-PET Scanning

In newly diagnosed aggressive non-Hodgkin lymphoma (NHL), a positive midtreatment fluorine-18 fluorodeoxyglucose positron emission tomography (PET) scan often carries a poor prognosis, with reported 2-year event-free survival (EFS) rates of 0% to 30% after standard therapy. To determine the outcome of early treatment intensification for midtreatment PET-positive disease, a phase II trial of risk-adapted therapy was conducted. Fifty-nine newly diagnosed patients, 98% with B cell lymphoma, had PET/CT performed after 2 or 3 cycles of first-line chemotherapy. Those with negative PET on semiquantitative visual interpretation completed standard therapy. Those with positive PET received platinum-based salvage chemotherapy, high-dose therapy, and autologous stem cell transplantation (ASCT). Midtreatment PET was positive in 33 (56%); 28 received ASCT with an actuarial 2-year EFS of 75% (95% confidence interval, 60%-93%). On intention-to-treat analysis, 2-year EFS was 67% (53%-86%) in all PET-positive patients and 89% (77%-100%) in PET-negative patients. No association was found between the International Prognostic Index category and the midtreatment PET result. The favorable outcome achieved here in historically poor-risk patients warrants further, more definitive investigation of treatment modification based on early PET scanning.

Prognostic Biomarkers in Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma. Although it represents a curable disease, less than half of the patients are cured with conventional chemotherapy. The highly variable outcome reflects a heterogeneous group of tumors, with different genetic abnormalities and response to therapy. The International Prognostic Index (IPI) is useful in predicting the outcome of DLBCL patients. However, patients with identical IPI still exhibit marked variability in survival, suggesting the presence of significant residual heterogeneity within each IPI category. The discovery of specific genetic alterations and the assessment of protein expression led to the identification of multiple novel single molecular markers capable of predicting the outcome of DLBCL patients independently of clinical variables. The recent application of DNA microarrays and tissue array technologies allowed a better understanding of the biology of lymphoma and the development of novel diagnostic tools capable of improving the current models for outcome prediction. However, much confusion exists in the literature regarding the importance of different prognostic biomarkers and their applicability in routine practice. This review summarizes the recent advances in our understanding of prognostic biomarkers in DLBCL and discusses whether this is the right time for biomarkers-guided risk-adjusted therapy.