International Prognostic Index Group Research Articles

A Real-World Data-Based Analysis of Prognostic Indices as Part of Trial Eligibility Criteria in Diffuse Large B-Cell Lymphoma Patients.

Recent front-line clinical trials used the International Prognostic Index (IPI) to identify trial-eligible patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). However, many IPI-like variants with improved accuracy have been developed over the years for rituximab-treated patients. We assessed the impact of International Prognostic Indices on patient enrolment in clinical trials, aiming to exclude low-risk IPI patients based on POLARIX/EPCORE DLBCL-2 trial criteria. We identified 2877 patients in the Danish Lymphoma Registry who would have been eligible for the POLARIX trial if patients with IPI 0-1 scores were included. IPI and NCCN-IPI assigned 33.3% and 11.9% of patients to the low-risk group, respectively. Shorter 5-year overall survival (91.4% vs. 97.5%), higher relapse rate (9.9% vs. 4.4%), and more deaths (16.1% vs. 4.4%) occurred in the low-risk IPI group compared with low-risk NCCN-IPI group. Analyzed models failed to identify true high-risk patients with poor prognosis. Similar results were found in the confirmatory cohort developed based on EPCORE DLBCL-2 trial eligibility criteria. True low-risk patients are more optimal identified by NCCN-IPI and should be excluded from front-line clinical trials due to their excellent prognosis. However, additional high-risk factors besides clinical prognostic models need to be considered when selecting trial-eligible patients.

External Validation Shows That Baseline PET Radiomics Outperform the IPI Risk Score for Prediction of Outcome in DLBCL

Introduction Up to one-third of newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients relapse or fail to achieve complete remission following first-line treatment. Adding PET radiomics features to currently used clinical predictors may improve the identification of poor prognosis patients. The objective of this study was to externally validate the radiomics model developed in the HOVON-84 trial (Eertink et al, EJNMMI 2021) using datasets from 6 other DLBCL research studies within the PETRA database. Methods 1195 newly diagnosed DLBCL patients with baseline 18F-FDG PET/CT scans with 2 years follow up in 7 studies in the PETRA database (https://petralymphoma.org) were included. 308 patients from the HOVON 84 were used as test set previously described. 887 patients from 6 studies in the PETRA database were used as external validation datasets. Primary outcome measures were 2-year progression free survival (PFS) and 2-year time to progression (TTP). Lesions were delineated using a fully automated preselection of 18F-FDG avid structures defined by a standardized Uptake Value (SUV) ≥ 4.0 and volume >3mL. Missed lesions were manually added and non-tumor regions were removed using the ACCURATE tool. Metabolic tumor volume (MTV), the maximum distance between the largest lesion and any other lesion (DmaxBulk) and the peak standardized uptake value (SUVpeak) were extracted for all patients. We tested the predictive value of the currently used international prognostic index (IPI) score and the radiomics model developed in the HOVON-84 trial, which included MTV, DmaxBulk, SUVpeak, WHO performance status and age. Model performance was assessed using the receiver-operator-characteristics area under the curve (AUC). To allow comparison of the continuous radiomics model with individual predicted probabilities per patient with the categorical IPI risk score, the high-risk group for the radiomics model was set as equal the size of the high-risk IPI group. Diagnostic performance was assessed using the positive predictive value (PPV). Differences between model performances of prediction models, expressed as AUC, were assessed with the two-sided DeLong test. Results Using 2-year PFS as outcome, the IPI model yielded an AUC of 0.62 using all 1195 patients (Table 1). Within the 6 external datasets, the AUC of the IPI model ranged from 0.51 for the SAKK study to 0.65 for the PETAL study. The radiomics model yielded an AUC of 0.71, which was significantly higher than the IPI model (p < 0.001). The AUC of the radiomics model ranged between 0.59 for the HOVON-130 study to 0.75 for the PETAL study. For all external datasets, the AUC of the radiomics model was higher than the AUC of the IPI model. Comparable results were found using 2-year TTP as outcome. The IPI model yielded an AUC of 0.62 and the radiomics model yielded an AUC of 0.71 when using all 1195 patients (p < 0.001). Again, the AUCs of the radiomics models were consistently higher than the AUCs of the IPI model for all individual studies. High-risk patients according to the IPI model had a 2-year PFS of 60.3% (95% confidence interval (CI): 54.4-67.0). High risk patients by the radiomics model had a 2-year PFS of 50.9% (95% CI: 44.8-57.7). The PPV increased from 35.5% for the IPI model to 49.1% for the radiomics model. For 2-year TTP as outcome, high-risk IPI patients had an overall survival rate of 66.4% (95%CI: 60.3-73.0). High-risk radiomics patients had a survival rate of 55.5% (95% CI: 49.1-62.6). The PPV increased from 33.7% to 44.6% for the radiomics model compared to the IPI model. Conclusion The radiomics model that was developed in the HOVON-84 dataset remained predictive of outcome in 6 independent first-line DLBCL studies, and had higher model performance than the currently used IPI risk score in all studies. Differences between IPI and radiomics model performance between individual studies are most likely caused by differences in patient characteristics between studies. Our radiomics model is able to select high-risk patients more accurately than the IPI model, with higher model performance and PPV. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk Stratification for Diffuse Large B-Cell Lymphoma by Integrating Interim Evaluation and International Prognostic Index: A Multicenter Retrospective Study.

The baseline International Prognostic Index (IPI) is not sufficient for the initial risk stratification of patients with diffuse large B-cell lymphoma (DLBCL) treated with R‐CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). The aims of this study were to evaluate the prognostic relevance of early risk stratification in DLBCL and develop a new stratification system that combines an interim evaluation and IPI. This multicenter retrospective study enrolled 314 newly diagnosed DLBCL patients with baseline and interim evaluations. All patients were treated with R-CHOP or R-CHOP-like regimens as the first-line therapy. Survival differences were evaluated for different risk stratification systems including the IPI, interim evaluation, and the combined system. When stratified by IPI, the high-intermediate and high-risk groups presented overlapping survival curves with no significant differences, and the high-risk group still had >50% of 3-year overall survival (OS). The interim evaluation can also stratify patients into three groups, as 3-year OS and progression-free survival (PFS) rates in patients with stable disease (SD) and progressive disease (PD) were not significantly different. The SD and PD patients had significantly lower 3-year OS and PFS rates than complete remission and partial response patients, but the percentage of these patients was only ~10%. The IPI and interim evaluation combined risk stratification system separated the patients into low-, intermediate-, high-, and very high-risk groups. The 3-year OS rates were 96.4%, 86.7%, 46.4%, and 40%, while the 3-year PFS rates were 87.1%, 71.5%, 42.5%, and 7.2%. The OS comparison between the high-risk group and very high-risk group was marginally significant, and OS and PFS comparisons between any other two groups were significantly different. This combined risk stratification system could be a useful tool for the prognostic prediction of DLBCL patients.

The Value of Prognostic Nutritional Index (PNI) on Newly Diagnosed Diffuse Large B-Cell Lymphoma Patients: A Multicenter Retrospective Study of HHLWG Based on Propensity Score Matched Analysis.

IntroductionImmunonutritional status is associated with the survival of DLBCL. This multicenter retrospective study aimed to explore the prognostic value of Prognostic Nutrition Index (PNI) in DLBCL patients by using propensity score matched analysis (PSM).MethodsA total of 990 DLBCL cases were recruited from 5 centers of Huaihai Lymphoma Working Group (HHLWG). A 1:1 PSM analysis was performed using the nearest-neighbor method, with a caliper size of 0.02. Cox regression analysis was used to examine factors associated with survival.ResultsThe median age at diagnosis was 62 years and 52.5% were males, with the 3-y overall survival of 65.1%. According to the MaxStat analysis, 44 was the optimal cut-off point of PNI. After PSM analysis, a total of 282 patients in PNI < 44 group could be propensity matched to PNI ≥ 44 patients, creating a group of 564 patients. Multivariable analysis revealed that PNI, age, central nervous system involvement and International Prognostic Index (IPI) were independent prognostic factors for DLBCL. Kaplan–Meier analysis indicated that patients with low PNI in Ann Arbor Stage (III/VI), ECOG (<2), IPI (LR+LIR), GCB, and BCL-2 negative groups had a poor prognosis.DiscussionPNI could accurately stratify the prognosis of DLBCL after PSM analysis.

Prognostic value of international prognostic index, revised international prognostic index, enhanced international prognostic index and Grupo Español de Linfomas/trasplante autólogo de médula ósea-international prognostic index for diffuse large B-cell lymphoma

Objective: To compare the prognostic values of international prognostic index (IPI), revised international prognostic index (R-IPI), enhanced international prognostic index (NCCN-IPI) and Grupo Español de Linfomas/trasplante autólogo de médula ósea-international prognostic index (GELTAMO-IPI) for diffuse large B-cell lymphoma (DLBCL). Methods: The clinical data of 238 DLBCL patients who were initially treated in Shanxi Cancer Hospital from September 2011 to March 2016 were collected retrospectively, the risk stratification and prognostic evaluation were conducted according to the IPI, R-IPI, NCCN-IPI and GELTAMO-IPI. Survival analysis was performed by the Kaplan-Meier method, COX regression analysis was used to compare the risks of death and progress in each group. Harrell's C statistics was used to compare the prediction accuracy of each hazard stratification model. Results: The 3-years progression-free survival rates of low risk, middle-low risk, middle-high risk and high risk group stratified according to IPI were 90.9%, 67.5%, 54.0% and 52.4%, respectively. The 3-years overall survival rates of each group were 93.9%, 72.5%, 58.0% and 53.7%, respectively. The 3-years progression-free survival rates of patients with very good prognosis, good prognosis and poor prognosis were 90.9%, 79.8% and 53.0%, respectively, the 3-years overall survival rates were 95.5%, 83.3% and 55.3%, respectively. The 3-years of progression-free survival of low risk group, middle-low risk group, middle-high risk group and high risk group stratified according to NCCN-IPI were 91.7%, 76.5%, 66.7% and 41.1%, respectively. The 3-years overall survival rates of each group were 95.8%, 79.4%, 70.0% and 42.9%, respectively. The 3-years progression-free survival rates of low risk, middle-low risk, middle-high risk and high risk group stratified according to GELTAMO-IPI were 91.3%, 76.3%, 67.4% and 32.7%, respectively. The 3-years overall survival rates of each group were 95.7%, 80.7%, 67.4% and 34.5%, respectively. Cox regression analysis showed that the risks of progression and death were significantly different between the middle-low risk group and low risk group of IPI (HR=4.144 and 5.085). The risks of progression and death were significantly different between the poor prognosis group and good prognosis group of R-IPI (HR=2.752 and 3.171), but both of which were significantly lower than the IPI groups. The risk stratification showed that the risks of progression and death were significantly different between the high risk group and middle-high risk group of NCCN-IPI and GELTAMO-IPI. However, the screening ability of high risk patients in GELTAMO-IPI group was better than that of NCCN-IPI group (NCCN-IPI HR=2.290 and 2.309, GELTAMO-IPI HR=3.084 and 2.966). Harrell's C-index analysis showed that the C-indexes of 3-years progression-free survival prediction in IPI, R-IPI, NCCN-IPI and GELTAM0-IPI were 0.672, 0.641, 0.664 and 0.700, respectively (P<0.001). The C-indexes of 3-years overall survival prediction were 0.687, 0.653, 0.671 and 0.721, respectively (P<0.001). The C-index of GETAMO-IPI was highest, superior to other prediction models. Conclusions: The screening abilities of GELTAMO-IPI and NCCN-IPI for high-risk DLBCL patients are better than those of IPI and R-IPI. The prediction accuracy of GELTAMO-IPI is significantly better than other prognostic stratified models.

Prognostic Validation of Diffuse Large B Cell Lymphoma International Prognostic Index for High Grade B Cell Lymphoma with and without MYC and BCL2 or BCL6 Rearrangements: An Institutional Review

Background: Diffuse large B cell lymphoma (DLBCL) NOS is the most common histologic subtype of non-Hodgkin lymphoma (NHL). Double hit lymphoma is re-classified as high-grade B cell lymphoma, with and without MYC and BCL2 or BCL6 rearrangements (HGBCL) in 2016. The International Prognostic Index (IPI) is the main prognostic tool for DLBCL NOS. We aimed to identify if IPI index scores can accurately predict the prognosis in patients with HGBCL. Methods: We observed the outcome of a cohort of patients (pts) with DLBCL NOS and HGBCL diagnosed and treated from 2008-2019 at SUNY Upstate Medical University. Fisher's exact test was used for the 2X2 comparison analysis. Results: 24 pts (82.8%) had DLBCL NOS and 5 (17.2%) pts had HGBCL. The median age was 58 yrs (13-81 yrs). 65.5% were males and 79.3% were caucasians. 8 pts had bone marrow involvement, 1 pt had brain metastasis and 12 pts had bulky disease. 15 DLBCL NOS pts (68.2%) and 4 HGBCL pts (80%) had low-intermediate IPI (&lt;/=3). 7 DLBCL NOS pts (31.8%) and 1 HGBCL pt (20%) had high IPI (&gt;/=4). 2 DLBCL NOS pts (13.33%) vs 1 HGBCL pt (25%) died in the low-intermediate IPI group. None of the DLBCL NOS pts (0%) vs 1 HGBCL pt (100%) died in the high risk group. Conclusion: Our study sample size is very small to identify prognostic relation of IPI score to predict the outcome for HGBCL. Our observation raises the hypothesis that patient with HGBCL might have a worse prognosis despite low IPI score which needs to be validated in a larger study population. Disclosures No relevant conflicts of interest to declare.

Interim PET/CT in diffuse large B-cell lymphoma may facilitate identification of good-prognosis patients among IPI-stratified patients

Treating patients with DLBCL remains a challenge, as the response to first-line immunochemotherapy is somewhat unpredictable. The International Prognostic Index (IPI) is one of the most widely used methods for assessing prognosis. Interim PET/CT (iPET/CT) can play an important role in the early identification of 'non-responder' patients before the end of treatment examination. In this study, we retrospectively analyzed 104 newly diagnosed DLBCL patients treated with R-CHOP-like regimens who underwent iPET/CT imaging during therapy. There was a significant difference in 2-year OS between patients with negative iPET/CT and those with positive iPET/CT. Patients who had positive iPET/CT showed inferior 2-year PFS compared to those with negative iPET/CT. According to IPI, there was a statistically significant difference in 2-year OS and PFS between patients in the lower and higher risk groups. However, these patients can be further subdivided according to iPET/CT. The iPET/CT results in the present study clearly separate good- and poor-prognosis patients according to differences in 2-year OS, both in the lower and higher IPI risk groups. These results are in agreement with those of previous studies that demonstrated that iPET/CT has high negative predictive value, clearly identifying good-prognosis patients even within the poor-prognosis IPI group.

Comparison of clinical scoring systems in aggressive B-cell lymphomas (BCL): An individual patient-level analysis across international trials (SEAL).

7544 Background: Great heterogeneity in survival exists for patients (pts) newly diagnosed with aggressive BCL. Three scoring systems based on simple clinical parameters (age, lactate dehydrogenase, number/sites of involvement, stage, performance status) are widely used: the international prognostic index (IPI), revised-IPI (R-IPI), and National Comprehensive Cancer Network IPI (NCCN-IPI). We studied BCL pts treated with R-CHOP to determine which scoring systems best identifies subgroups with poor outcomes that might benefit from new approaches. Methods: Individual pt data from 7 multicenter trials (1998-2009) of pts with BCL (86% DLBCL) treated front-line with R-CHOP (or variant) were analyzed to determine whether IPI, R-IPI, or NCCN-IPI best discriminated overall survival (OS). The concordance index (c-index) from a proportional hazards model, stratifying on trial and induction therapy, quantified predictive accuracy of each scoring system. Results: 2561 pts (median age 63 yrs, 56% male) were classified into IPI, R-IPI, and NCCN-IPI risk groups (Table). With a median follow-up of 5 yrs, NCCN-IPI had the greatest absolute difference in OS estimates between the highest and lowest risk groups at 1, 3, and 5 yrs, and best discriminated OS (c-index = 0.631, Table). Conclusions: In an independent and large cohort of pts, NCCN-IPI performs best in risk-stratifying pts with aggressive BCL, readily distinguishing pts at high and low risk for treatment failure using clinical parameters (5-yr OS between 48 and 92%). Improvement over the simpler IPI appears incremental, and IPI may remain a valuable alternative. Work integrating molecular features of the tumor into the (NCCN-) IPI is in progress to define high risk groups where targeted novel approaches are needed most. [Table: see text]

Peripheral Blood Lymphocyte-to-Monocyte Ratio at Relapse Predicts Outcome for Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma in the Rituximab Era.

Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) have a poor prognosis, even in the rituximab era. Several studies have reported the clinical importance of the peripheral blood lymphocyte-to-monocyte ratio (LMR) in various malignancies, including lymphoma. However, the prognostic value of the LMR in relapsed/refractory DLBCL has not been well evaluated. The purpose of the present study was to investigate whether the LMR at relapse can predict clinical outcomes for relapsed/refractory DLBCL patients treated with rituximab. We analyzed data on 74 patients with relapsed/refractory DLBCL, who were initially treated with R-CHOP (rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone) or an R-CHOP-like regimen. There was a significant association between a low LMR (≤ 2.6) and shorter overall survival (OS; P<.001) and progression-free survival (PFS; P< .001) compared with the high LMR group (> 2.6). Multivariate analysis showed that LMR was an independent prognostic factor for OS (P< .001) and PFS (P< .001), as was the international prognostic index (IPI) at relapse for OS. In addition, the LMR had an incremental value for OS and PFS compared with the IPI at relapse. The LMR predicts OS and PFS outcomes in relapsed/refractory DLBCL patients treated with rituximab, and might facilitate better stratification among patients in low- and intermediate-risk IPI groups.

Low Level of Blood CD4+ T Cells Is an Independent Predictor of Inferior Progression-free Survival in Diffuse Large B-cell Lymphoma.

Tumor-infiltrating immune cells influence diffuse large B-cell lymphoma (DLBCL) outcomes. Relatively little, however, is known about the significance of peripheral blood immune cell numbers on DLBCL behavior. In the present study, 43 patients with newly diagnosed DLBCL had pretreatment multiparameter peripheral blood flow cytometry performed to assess the immune cell numbers. These cell numbers were correlated with the outcomes of progression-free survival (PFS) and overall survival. After follow-up period of 0.8 to 152 months (median, 73), 25 patients (56%) were still alive. As continuous variables on univariate analysis, the predictors of PFS were patient age and absolute CD4 cell count (ACD4C), with the International Prognostic Index (IPI) marginally significant. Age was also a significant predictor of overall survival, and the IPI and ACD4C were marginally significant (P= .08). The 17 patients with a greater ACD4C (≥ 450/mm3) had better 5-year PFS than the 26 with a low ACD4C (88% vs. 50%; P= .02). Multivariable analysis, including age as a continuous variable, IPI group, and ACD4C of 450/mm3 showed that age and ACD4C were significant for PFS (P= .01 and P= .02, respectively). Our data, although from a small series, suggest that the blood ACD4C might be a predictor of PFS for patients with DLBCL, independent of age and the IPI.

The NCCN-IPI Helps to Identify Very High-Risk Patients with DLBCL and Can be Improved By Other Independent Clinical Factors Including Bulky Disease and beta2-Microglobulin

The International Prognostic Index (IPI) has been the basis for predicting the outcome of diffuse large B cell lymphoma (DLBCL). With the improvement in prognosis with immunochemotherapy the predictive power of the IPI has been questioned.Recently, the enhanced NCCN-IPI has been proposed to provide a better discrimination of risk groups. Additionally, other patient- and disease-specific factors not incorporated in the prognostic algorithms and easily assessed at diagnosis have been shown to impact on the clinical course. The prognostic value of the NCCN-IPI together with other clinical characteristics remains to be widely validated.We aimed to assess the power of NCCN-IPI in risk group discrimination and compare it with IPI, as well as to investigate if the Body Mass Index (BMI), gender, diameter of the largest mass and levels of β2-microglobulin have independent prognostic impact when controlling for NCCN-IPI risk.We conducted a retrospective analysis of consecutive R-CHOP treated de novo DLBCL cases diagnosed between January 2002 and December 2013 in a single center.Kaplan-Meier method was used to estimate the overall (OS) and progression-free survival (PFS) distributions for risk groups. Logrank test with p-value adjustment by Hochberg method was used for pairwise comparisons between risk groups within each index. Independent prognostic impact of BMI, gender, bulky disease and β2-microglobulin was assessed by multivariate analysis using Cox model.410 patients were included in the analysis, with a median age of 64 (16-89) years; 51% were male. The distribution according to age, stage, extranodal (EN) sites, performance status, β2-microglobulin, BMI and bulky disease (Table 1) were similar to published data.With a median follow-up of 59 months, 5-yr OS and PFS were 69% and 65%, respectively. The distribution of patients according to IPI and NCCN-IPI risk groups is detailed in Table 1. Both scores adequately stratified patients according to risk of progression and death. In our cohort OS and PFS of low and low-intermediate risk groups using the NCCN-IPI were not significantly different. We documented a migration of patients from low (62%) and high (48%) to intermediate risk groups using the NCCN-IPI compared to the IPI. This score allowed a better discrimination between high-intermediate and high-risk disease (pairwise comparison of OS and PFS within NCCN and IPI risk scores of p=0.0087 vs p=0.044 and p=0.032 vs p=0.096, respectively). Only 12 patients classified as intermediate-risk IPI migrated to high NCCN risk group. Of these, 5 relapsed and 6 died (4 of lymphoma).Multivariate analysis showed that bulky disease and β2-microglobulin are independent prognostic factors for OS and PFS when controlling for NCCN-IPI.Using a large series of unselected R-CHOP treated patients, we pursued the validation of the NCCN-IPI as a better prognostic tool for DLBCL. In contrast to the original series, the NCCN-IPI showed limited discrimination capacity for OS and PFS between low- and low-intermediate risk groups. However, the new prognostic index helps to identify particularly poor prognosis patients that might benefit from alternative therapies. We also identified bulky disease and β2-microglobulin as independent prognostic factors in addition to NCCN-IPI and that could be incorporated in future prognostic scores. Additional studies are needed to evaluate the ability of biomarkers to improve the clinical risk stratification systems. Table 1CharacteristicsValue, n (%)AgeMedian (range), yr64 (16-89)≥60 years241 (59%)Male208 (51%)Performance status (ECOG) ≥2a66 (16%)Stage ≥ III221 (54%)BMIbUnderweight (<18.5)15 (4%)Normal (18.5-24.9)170 (43%)Overweight (25.0-29.9)139 (35%)Obese (>29.9)73 (18%)Bulky disease (>7 cm)c157 (40%)β2 microglobulin >ULNd154 (45%)≥2 EN sites92(23%)BM, CNS, liver/GI or lung involvement136 (33%)IPIe vs NCCN-IPIe (%)Low12 vs 34Low-Int38 vs 26High-Int35 vs 20High18 vs 125-yr OS (%)IPI (low, low-int, high-int, high)87, 70, 59, 50p= 8x10-12NCCN-IPI (low, low-int, high-int, high)88, 82, 59, 47p= 2x10-125-yr PFS (%)IPI (low, low-int, high-int, high)86, 66, 51, 48p= 2x10-11NCCN-IPI (low, low-int, high-int, high)84, 78, 54, 45p= 7x10-10BM: bone marrow, CNS: central nervous system, GI: gastrointestinal, int: intermediate.a: 405 pts, b: 397 pts, c: 391 pts, d: 341 pts, e: 403 pts. DisclosuresNo relevant conflicts of interest to declare.

Validation of German High-Grade Non-Hodgkin's Lymphoma (DSHNHL) Prognostic Model and the Impact of Treatment on Secondary Central Nervous System (CNS) Relapse in Diffuse Large B-Cell Lymphoma (DLBCL) in a Developing Country: Report from the Nationwide Multi-Institutional Registry of Thai Lymphoma Study Group (TLSG)

Introduction: Despite improved treatment outcome of DLBCL in the immunochemotherapy era, secondary CNS relapse remains a serious and fatal complication. Several prognostic models were reported in order to define high-risk patients for CNS relapse and provide proper prophylactic strategies. There is no standard approach for CNS prophylaxis in DLBCL with more data suggesting lack of efficacy of intrathecal chemoprophylaxis. In 2013, the DSHNHL introduced a prognostic model including each international prognostic index (IPI) factor (age, lactate dehydrogenase (LDH), stage, performance status (PS), extranodal involvement (EN) and kidney/adrenal involvement) to stratify patients into 3 groups. Herein, we applied and validated DSHNHL model to DLBCL patients treated at nationwide University hospitals in Thailand including analyzing an impact of rituximab and intrathecal chemoprophylaxis on CNS relapse.Method: From the nationwide multicenter registry of 4,371 newly diagnosed lymphoma patients in Thailand between 2007 and 2014, there were a total of 2,399 DLBCL patients. We looked at the incidence and clinical predictors of CNS relapse, the effect of immunotherapy and intrathecal chemoprophylaxis on CNS relapse in DLBCL who were treated with at least one cycle of CHOP-like or intensive chemotherapy regimens.Result: After excluding patients with CNS/ocular involvement at diagnosis, 2,034 DLBCL patients were included in the analysis. Table 1 summarizes baseline characteristics of DLBCL patients. The median follow up time for living patients was 51 months (interquartile range, 22-75 months). A total of 565 patients (27.8%) progressed or relapsed after first-line induction therapy and 61 patients (3.0%) developed CNS relapse. Median time to CNS relapse was relatively shorter than non-CNS relapse (8.4 vs 10.5 months, P =0.07). A total of 729 (35.8%), 1,024 (50.3%) and 281 (13.8%) patients were classified as low-, intermediate- and high-risk groups based on DSHNHL risk model for CNS relapse. Of high DSHNHL risk group, 45 patients (16%) received intrathecal chemotherapy for CNS prophylaxis along with induction treatments. Using the competing risk regression analysis, 2-year cumulative incidence of CNS relapse was 2.7% (1.5%, 3.1%, and 4.6% for low-, intermediate- and high-risk DSHNHL group respectively). Univariate analysis showed elevated LDH, poor PS, stage III/IV, presence of B symptoms, higher risk IPI and DSHNHL risk group as risk factors of CNS relapse (Table 2). Presence of concurrent EN involvement more than one site and elevated LDH was a significant predictor of CNS relapse (Hazard Ratio [HR] 2.39, P =0.004). Kidney/adrenal gland and gonadal involvement were not associated with higher risk of CNS relapse whereas breast involvement showed a trend toward higher incidence of CNS relapse (HR 2.46, P =0.07). Either immunochemotherapy or intrathecal chemoprophylaxis was not associated with lower risk of CNS relapse; in fact patients who received intrathecal chemotherapy had more CNS relapse though this could be due to selection bias. Median survival of patients with CNS relapse was 13.2 months which was significantly worse than patients without CNS relapse (81.8 months, P<0.001).Conclusion: The 2-year cumulative incidence of CNS relapse in DLBCL in this analysis was 2.7% which was comparable to other series. Using the DSHNHL prognostic model was able to define DLBCL patients into low, intermediate and high risk for CNS relapse. The high-risk group in our series had lower incidence of CNS relapse compared to German and recently reported British Columbia cohorts. Our study confirms poor survival outcome of DLBCL patients with CNS relapse and no protective effect of immunochemotherapy or intrathecal chemoprophylaxis on the incidence of CNS relapse. Novel risk-adapted CNS prophylaxis strategies are warranted to be further investigated in prospective studies. [Display omitted] [Display omitted] [Display omitted] DisclosuresKhuhapinant:Roche: Honoraria.

Expression of c-myc in anaplastic large cell lymphoma and its significance

Objective To investigate the protein expression and genetic alterations of c-myc in primary systemic anaplastic large cell lymphoma(ALCL)and discuss its relationship with clinicopathologic features and immunophenotypes. Methods 87 cases of ALCL were selected. Immunohistochemical method was used to detect the protein expression of c-myc, ALK, CD3, CD10, CD20, CD30 and EMA. c-myc and ALK genetic alterations were detected by using fluorescence in situ hybridization(FlSH). The interrelationships between protein expression, genetic alterations and clinicopathological parameters were analysed statistically. Results Immunohistochemical results: of 87 cases, ALK protein was expressed in 54 cases(62.1 %). c-myc protein was expressed in 27 cases(31.0 %). ALK and c-myc were co-expressed in 20 cases(23.0 %). c-myc protein expression, ALK and c-myc co-expression increased with the upgrade of ALCL clinical stages, and the expression was higher in International Prognostic Index(IPI)high-risk groups than in low-risk groups(P 0.05), while they were statistically significant in c-myc groups(P < 0.05)and in different IPI groups(P < 0.05). Conclusion c-myc protein expression and aneuploidy were related with ALCL clinical stages and IPI, which could be used as an indicator of estimating ALCL malignant degree and predicting prognosis. Key words: Anaplastic large cell lymphoma; c-myc; Immunohistochemistry; Fluorescence in situ hybridization

Prognostic Implication Of Circulating Vascular Endothelial Growth Factor In Patients With Diffuse Large B-Cell Lymphoma

BackgroundVascular endothelial growth factor (VEGF) plays an important role in angiogenesis and progression of cancer, and blood level of VEGF has been known to predict of outcome in several types of cancer. However, the impact of blood VEGF levels on prognosis of diffuse large B-cell lymphoma (DLBCL) has not been fully elucidated. Here we investigated the prognostic implication of circulating VEGF levels in patients with DLBCL. Patients and MethodsThe study involved 127 DLBCL patients treated by rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at National Cancer Center, Korea. Both serum and plasma of the patients were obtained at diagnosis. VEGF were measured using ELISA kit (R&D systems) according to manufacturer's guidance. We investigated the correlation between clinical parameters and blood VEGF levels. Survival rates and hazard ratios (HRs) in terms of risk for overall survival were determined using Kaplan-Meier method and Cox proportional hazard regression analysis. ResultsThe median patient age was 56 years, and 75 (59%) patients were men. Clinical characteristics and international prognostic index (IPI), including age, performance, lactate dehydrogenase (LDH), Ann Arbor stage and extranodal involvement were evaluated. The mean (±SD) value of serum and plasma VEGFs were 713 (±599.8) and 107 (±164.4) pg/mL, and they were correlated as r=0.61 (p<0.001). Both serum and plasma VEGF showed the significant (p<0.01) correlation with serum LDH level, Ann Arbor stage and multiple extranodal involvement, but not with age, gender nor performance. IPI showed strong prediction for prognosis in our data set (HR 3.80, 95%CI 1.64-8.81, p=0.02), and the VEGF levels of high/high-intermediate IPI group were significantly higher than those of low/low-intermediate group [serum VEGF 1088(±838.0) and 557(±377.2), p<0.001 and plasma VEGF 79(±131.6) and 176(±212.2), p=0.002]. With the median follow-up of 44 months, high serum VEGF levels (higher than the median) were significantly associated with short survival (HR 2.74, 95%CI 1.13-6.60, p=0.025), though the plasma VEGF levels did not show the association similar to the serum samples (HR 1.40, 95%CI 0.63-3.12, p=0.414). The patients with higher serum VEGF than the median value showed significantly lower survival rate compared to the low group (3-year survival rates, 68.6% vs. 85.6%, p=0.019). ConclusionThese findings suggest that high serum VEGF levels can predict poor clinical outcome in patients with DLBCL. This study also represents the different type of specimen for VEGF measurement affected the results. We might have to select adequate specimen type for VEGF measurement, although further validation in large cohort and mechanism studies for this data are warranted. Disclosures:No relevant conflicts of interest to declare.

A New Prognostic Model for Extranodal Natural Killer/T Cell Lymphoma, Nasal Type

BackgroundExtranodal natural killer (NK)/T–cell lymphoma, nasal type (ENKTL) is an aggressive disease with a poor prognosis. A better risk stratification is beneficial for clinical management in affected patients. Our recent study has shown that fasting blood glucose (FBG) was a novel, prognostic factor, (Cai et al, British Journal of Cancer, 108: 380–386,2013). This finding has not been integrated in the previous prognostic models for ENKTL Therefore, we aimed to design a new prognostic model, including FBG, for ENKTL which supports to identify high–risk patients eligible for advanced or more aggressive therapy. Patients and methods158 newly diagnosed patients with ENKTL were analyzed between January 2003 and January 2011 at Sun Yat–sen University Cancer Center, China. Overall survival (OS) and progression free survival (PFS) were estimated using the Kaplan–Meier method. The significance of differences between survival was tested using the Log–rank test. Significant variables in the univariate analysis were selected as variables for the multivariate analysis of survival. The latter was performed by the Cox regression mode. We constructed receiver operating characteristic (ROC) curves and compared the areas under the ROC curves of total protein (TP), FBG, Korean Prognostic Index (KPI) and their combinations in comparison to the survival outcome. ResultsOf 158 patients, 156 patients had complete clinical information for the parameters of the International Prognostic Index (IPI) model and KPI model. The estimated 5–year overall survival rate in 158 patients was 59.2%. Independent prognostic factors included TP < 60 g/L, FBG > 100 mg/dL, KPI score ≥ 2. A new prognostic model was constructed by combining these prognostic factors: Group 1 (64 cases, 41.0%), no adverse factors; Group 2 (58 cases, 37.2%), one adverse factor; and Group 3 (34 cases, 21.8%), two or three adverse factors. The 5–year overall survival of these groups were 88.9%, 35.6% and 12.7%, respectively (p < 0.001). The survival curves according to the new prognostic model are shown in Fig. 1. The new model categorized three groups with significantly different survival outcomes. The new prognostic model was also efficient in discriminating the patients with low to low–intermediate risk IPI group and high–intermediate to high risk IPI group into three subgroups with different survival outcomes (p < 0.001). The KPI model balanced the distribution of patients into different risk groups better than IPI prognostic model (score 0: 12 cases, 7.7%; score 1: 38 cases, 24.4%; score 2: 42 cases, 26.9%; score 3–4: 64 cases, 41.0%), and it was able to differentiate patients with different survival outcomes (p < 0.001). In addition, the new prognostic model had a better prognostic value than did KPI model alone (p < 0.001), suggesting that TP and FBG reinforced the prognostic ability of KPI model (Table 1). [Display omitted] ConclusionsThe new prognostic model we proposed for ENKTL, including the new prognostic indicator total protein and FBG, demonstrated balanced distribution of patients into different risk groups with better prognostic discrimination as compared to KPI model alone. Disclosures:No relevant conflicts of interest to declare.

Genomic Instability and Activation Of The DNA Damage Response Pathway Is An Independent Predictor Of Poor Prognosis, Is Associated With MYC Expression and Is a Promising Target For Therapy In Diffuse Large B Cell Lymphoma

IntroductionGenomic instability and constitutive activation of the DNA damage response (DDR) pathway has been recently described in models of aggressive myc-driven lymphoid malignancies. The MYC oncogene has been reported to induce genomic instability by a mechanism involving replication stress. On the other hand, MYC is overexpressed in a fraction of diffuse large B-cell lymphomas (DLBCLs), and its overexpression has been reported to be associated with poor prognosis. The checkpoint kinases 1 (CHK1) and 2 (CHK2), are serine-threonine kinase involved in the DDR pathway. DDR activation triggers the phosphorylation of the histone H2AX at ser 139, a known marker of DNA damage and genomic instability. The correlation between genomic instability, MYC expression, and prognosis has not been investigated yet in DLBCL. MethodsImmunohistochemistry (IHC) for phospho (γ) H2AX, pCHK1, pCHK2 was performed in tissue microarrays (TMAs) from 97 consecutive patients treated at our Institution between 2004 and 2011 with R-CHOP/CHOP-like regimens, with available paraffin embedded tissue from initial diagnosis. Moreover, to evaluate the therapeutic potential of DDR pathway inhibition in DLBCL, the DLBCL cell lines HBL-1, U2932, TMD8, SUDHL-6, BJAB, SUDHL-4 and primary DLBCL cells were incubated with the CHK inhibitor PF-0477736 (Pfizer). ResultsIn the TMA study 57% of patients (n=55) displayed high levels of basal γH2AX (>30% of positive cells), 55% (n=53) displayed pCHK1/pCHK2 activation and of note all DLBCL cell lines showed detectable baseline activation of CHK1/CHK2 and/or H2AX phosphorylation, by western immunoblotting. γH2AX positive cases distributed equally in germinal center (GC) and in non GC DLBCLs, and were significantly associated with MYC expression (p<0.01). Five-year survival rate was 70% vs 41% for γH2AX-low and γH2AX-high patients respectively (p=0.01). Factors significantly related to the outcome in multivariate analysis were International Prognostic Index (IPI) score and γH2AX expression. Remarkably the prognostic significance of γH2AX was particularly evident in the low risk IPI group (0-2 risk factors), identifying a subgroup characterized by worse outcome (54% 5-year OS). In the in vitro study a significant growth inhibition (WST-1 assay), was evident after 48 hrs in all cell lines (IC50 10-230 nM). PF-0477736 25-500 nM induced cell death by apoptosis (annexin V- propidium iodide staining) in a time and dose dependent manner. Notably PF-0477736 demonstrated activity also in primary DLBCL cells (IC 50 of 50-500 nM, 24 hrs). We observed inhibition of phosphorylation of the downstream target CDC25c (ser 216), coupled with a marked increase in γH2AX ser 139 and CHK1 phosphorylation (ser317 and 345) following treatment. ConclusionsA significant fraction of DLBCLs shows high levels of inherent genomic instability; the DDR activation marker γH2AX is a poor prognostic predictor in DLBCL and interestingly is significantly associated with MYC expression. DDR inhibition resulted to be highly effective in DLBCL cell lines and primary DLBCL cells; on treatment modifications of CHK1 and H2AX phosphorylation could be useful biomarkers of CHK inhibitors activity. These data provide strong rationale for targeting the DDR pathway and for clinical investigation of CHK inhibitors in DLBCL. Disclosures:No relevant conflicts of interest to declare.

MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma

AbstractMYC rearrangements occur in 5% to 10% of diffuse large B-cell lymphomas (DLBCL) and confer an increased risk to cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (CHOP) and rituximab (R)–CHOP treated patients. We investigated the prognostic relevance of MYC-, BCL2- and BCL6-rearrangements and protein expression in a prospective randomized trial. Paraffin-embedded tumor samples from 442 de novo DLBCL treated within the RICOVER study of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) were investigated using immunohistochemistry and fluorescence in situ hybridization (FISH) to detect protein expression and breaks of MYC, BCL2, and BCL6. Rearrangements of MYC, BCL2, and BCL6 were detected in 8.8%, 13.5%, and 28.7%, respectively. Protein overexpression of MYC (>40%) was encountered in 31.8% of tumors; 79.6% and 82.8% of tumors expressed BCL2 and BCL6, respectively. MYC translocations, MYChigh, BCL2high, and BCL6low protein expressions were associated with inferior survival. In multivariate Cox regression modeling, protein expression patterns of MYC, BCL2 and BCL6, and MYC rearrangements were predictive of outcome and provided prognostic information independent of the International Prognostic Index (IPI) for overall survival and event-free survival. A combined immunohistochemical or FISH/immunohistochemical score predicts outcome in DLBCL patients independent of the IPI and identifies a subset of 15% of patients with dismal prognosis in the high-risk IPI group following treatment with R-CHOP. Registered at http://www.cancer.gov/clinicaltrials: RICOVER trial of the DSHNHL is NCT 00052936.

Adverse Prognostic Impact of Vascular Endothelial Growth Factor Gene Polymorphism in Patients with Non-Hodgkin Lymphoma.

AbstractAbstract 2674Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis and progression of many types of cancer, and VEGF expression has been known to be associated with polymorphism of gene. However, the impact of polymorphisms of the VEGF gene on non-Hodgkin lymphoma (NHL) prognosis has not been fully elucidated. Here we investigated the association between VEGF polymorphisms and prognosis of NHL. The study involved 96 NHL patients treated at National Cancer Center, Korea. The median patient age was 57 years, and 60 patients (62.5%) were men. A total of 5 polymorphisms with heterozygous allele were analyzed. Clinical characteristics (e.g., cell lineage) and international prognostic index (IPI), including age, performance, LDH, stage and extra-nodal involvement, were evaluated and related to VEGF polymorphism. Hazard ratios (HRs) were determined in terms of risk for overall survival using Cox proportional hazard regression analysis. Diffuse large B cell lymphoma (n=73) was most common histologic type, and others were as follows: T-cell lymphoma (n=14), mantle cell lymphoma (n=6), and Burkitt lymphoma (n=3). IPI and stage were predictors for prognosis (p <0.01), and both index did not have correlation with VEGF polymorphisms. The genotype frequency of rs1570360 was GG (70%), GA (26%), and AA (4%), and it has significantly association with poor prognosis with HRs of 2.52 [95% confidence interval (CI), 1.36 to 4.67] in NHL patients and 2.41 [95% confidence interval (CI), 1.15 to 5.05] in DLBCL treated by rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), respectively. In IPI subgroup analysis, rs1570360 had association in higher IPI group (IPI ≥ 3) (p=0.02). These findings suggest that VEGF polymorphisms may be significant prognostic indicators for patients with NHL and DLBCL. Disclosures:No relevant conflicts of interest to declare.

Prognostic significance of T cell subsets in peripheral blood of B cell non-Hodgkin’s lymphoma patients

The role of tumor-infiltrating T cell subsets in the prognosis of non-Hodgkin's lymphoma (NHL) has previously been reported. In the present study, we investigated the prognostic significance of different T cell subsets in the peripheral blood of NHL patients. Immunophenotyping was performed on the peripheral blood samples of 45 patients with newly diagnosed B cell NHL using flow cytometry. The relationship between T cell subsets of CD4+, CD8+, CD3+CD25+, CD4+CD25+, CD4+CD25high [as T regulatory cells (T reg)], and the CD4/CD8 ratio with international prognostic index (IPI) and response to therapy was determined. The percentages of CD3+, CD4+, and CD8+ T cells in the peripheral blood of the patients were 49.1±20.3%, 23.6±11%, and 31.4±14.4%, respectively (CD4/CD8 ratio: 0.92±0.6). There were 4.2±3.2% T reg cells. A study of the percentage of T cells in relation to IPI score showed a higher proportion of CD3+CD25+, CD4+, and CD4+CD25+ cells in low-risk patients compared with intermediate/high risk groups (p<0.05). The above cells, as well as CD4+CD25high T reg cells, indicated a positive correlation with complete remission (CR) and survival. CD4 positivity correlated significantly with survival and CR durations, which were longer in patients with ≥20% CD4+ cells than those with <20% CD4+ cells, thus indicating the prognostic value of CD4+ T cells in NHL patients. There was no significant data on CD8+ cells as well as the CD4/CD8 ratio between distinct IPI groups and response to therapy. These data indicated the importance of CD4+ cells and the activation status of T cells in immunity against lymphoma and the prognostic implication of enumeration of these cells in NHL patients.

An Index of SNPs in Immune Genes May Enhance the Prognostic Value of IPI in Patients with Aggressive Non-Hodgkin's Lymphoma

Abstract 2653 INTRODUCTION:Non-Hodgkin's lymphoma (NHL) is a heterogeneous disease. The current International Prognostic Index (IPI) is useful, but not perfectly predictive and there is a need for a more precise prognostic index. The host immune response to cancer has been shown to predict outcome in multi-variate analyses in many types of cancer. We hypothesized that its genetics may contribute to prognostication. We focused on an evaluation of inherited functional polymorphisms in key immune genes that have previously been shown by others to influence outcome in various cancers. The objective was to determine whether an index of SNPs that alter function of critical immune system genes would enhance the predictive value of the IPI in patients with aggressive NHL.PATIENTS AND METHODS: Our study cohort consisted of 192 patients with NHL enrolled at diagnosis between 1990 and 1996. Patients provided informed consent and demographic, clinical and outcome data as well as tumor and blood samples were collected and stored on all patients. Patients were treated as per the standard of care at the time. 124 were of the aggressive type while 68 were low grade. We focused on the aggressive cohort in this analysis. DNA was extracted from blood, bone marrow and biopsy tissue. We evaluated the following genes; IL1A rs1800587, CXCR2 rs1126580, IL4R rs2107356, TNF rs1800629, IL4R175V rs454078, IL8 rs4073, FCGR3A rs396991, P2RX7 rs3751143, IL12B rs3212227. Genotyping was performed using allele-specific PCR primers tagged with GC tails to enhance melting point discrimination. PCR reactions were set up with the aid of a robot and run on a real-time PCR instrument. Kaplan-Meyer curves were generated for the overall survival of each genotype. Univariate analysis was performed to compare genotypes with IPI score, IPI factors and disease bulk. RESULTS:We evaluated relationships to existing standard prognostic factors. We found a significant relationship between IL12B CC carriers and IPI score 0–1 (p=0.0012). Patients with IL12B CC had less extranodal disease, lower stage and bulk. We modeled the data to identify combinations of SNPs with the most predictive power. The most predictive genotype combination included the genes for IL8, IL12B, IL4R, CXCR2 and TNF. A SNP score, determined by the number of favourable genotypes, showed significance in survival, p=0.004 [fig.1]. The group of 68 patients with an IPI score of 2–3 was analyzed to determine whether the SNP score could distinguish outcome within this IPI group [fig 2]. Patients with 3 of these favourable alleles had significantly improved survival [HR= 2.791]. Scoring with an index made up of three genes-IL8, CXCR2 and TNF alone -was also significant, p=0.02 [not shown]. CONCLUSIONS:We evaluated 10 SNPs with functional consequences on the immune response in a population of previously untreated aggressive lymphoma patients undergoing standard management. We found that a combination of SNPs statistically predicted outcome of these 124 patients with aggressive lymphoma. Although Habermann et al [Blood 2008 112(7); 2694–2702] had created a SNP score based on IL1A, IL8RB (CXCR2), IL4R and TNF, we have found that outcome is best predicted in our cohort with IL8, IL12, CXCR2, IL4R and TNF. A useful model could also be obtained using 3 SNPS (IL8, CXCR2 and TNF). Our results are important in that we have shown that this combination of SNPs can further enhance prognostification beyond IPI. Specifically statistically significant overall survival differences in IPI 2,3 patients was found based upon the SNP score using IL8, IL12, CXCR2, IL4R and TNF and the three-SNP combination. Incorporating SNP scores into IPI may be a useful strategy to further identify patients with increased likelihood of improved or adverse outcomes. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.