National Comprehensive Cancer Network International Prognostic Index Research Articles

Expression and Clinical Significance of Exosome Component 4 in Newly Diagnosed Patients with Diffuse Large B-Cell Lymphoma

To explore the expression of Exosome Component 4（EXOSC4） in the tissues of newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL) and its clinical significance. The expression of EXOSC4 protein in the tissues of 181 newly diagnosed DLBCL patients was analyzed by immunohistochemical staining. Clinical data were collected. The correlation between EXOSC4 protein expression in the tissues of newly diagnosed DLBCL patients and clinical features were analyzed and its prognostic significance. The positive rate of EXOSC4 protein expression was 68.51% in the tissues of 181 newly diagnosed DLBCL patients. These patients were divided into two groups, with 44 cases in high expression group and 137 cases in low expression group. There were no significant differences in age, gender, B symptoms, serum lactate dehydrogenase (LDH) level, Eastern Cooperative Oncology Group (ECOG) score, Ann Arbor stage, extranodal disease, International Prognostic Index (IPI) score, National Comprehensive Cancer Network IPI (NCCN-IPI) score, and cell origin between the two groups (P>0.05). Cox multivariate regression analysis showed that high EXOSC4 protein expression in tissues was an independent poor prognostic factor for OS and PFS in newly diagnosed DLBCL patients (all P<0.05). K-M survival analysis showed that newly diagnosed DLBCL patients with high EXOSC4 protein expression had significantly shorter overall survival (OS) and progression free survival (PFS) than those patients with low EXOSC4 protein expression (all P<0.05). High EXOSC4 protein expression in tissues of newly diagnosed DLBCL patients is an independent poor prognostic factor for survival.

A Population-Based Study on Performance of Clinical Prognostic Models in Patients with Diffuse Large B-Cell Lymphoma Younger Than 70 Years

Background: In diffuse large B-cell lymphoma (DLBCL), the International Prognostic Index (IPI) and age-adjusted IPI (aaIPI) remain the primary prognostic tool for outcome predictions and risk stratification in clinical trials. Several prognostic indices with the same five risk factors included in the IPI have been developed for DLBCL patients, including Revised IPI (R-IPI) and National Comprehensive Cancer Network IPI (NCCN-IPI), showing a decreased prognostic value of the IPI. Additionally, an age-adjusted DLBCL-Prognostic Index (aaDLBCL-PI) developed in patients younger than years combining similar variables (excluding age and stage), but with the addition of albumin, showed better accuracy than the IPI. Younger patients without comorbidities and a history of cancer are typically candidates for clinical trials, but validation studies of prognostic indices in this population are mostly lacking. Aim: This study aimed to compare five clinical models (IPI, aaIPI, R-IPI, NCCN-IPI, and aaDLBCL-PI) in patients with DLBCL younger than 70 years identified from the Danish Lymphoma Registry (LYFO). Methods: Patients diagnosed between 2000 and 2021 and identified through the LYFO were included if they fulfilled the following criteria: 1) newly diagnosed DLBCL; 2) age &amp;lt;70 years; 3) treated with at least one cycle of immunochemotherapy (R-CHOP/R-CHOP-like); 4) availability of all parameters for calculation of all five prognostic models; and 5) no previous/concomitant malignancy (excluding non-melanoma skin cancer). Patients with isolated central nervous system lymphoma were excluded. Discriminatory ability was calculated using the concordance index (c-index), with 1 indicating perfect discrimination and 0.5 indicating random guess. Model fitness was compared with the Akaike Information Criterion (AIC), with the lower values indicating a better fit of a model and the difference ≥10 between models indicating a significant improvement in model fitness. Results: Of 3,184 DLBCL patients younger than 70 years, 2,456 had all parameters available for calculating five prognostic models and were included in the final analysis. The median age at diagnosis was 59 years (range 18-69) with a slight male predominance (n=1,440, 58.6%). Most patients (n=1,619, 65.9%) had advanced (III/IV) stage of disease and were in good performance status 0-1 (n=2,165, 88.2%). More than one extranodal localization was diagnosed in 738 patients (30%), and more than half of our population (n=1,462, 59%) had elevated LDH levels. All models stratified patients into four risk groups except R-IPI, which provided three risk groups. The proportion of patients allocated to the low-risk group according to the IPI, aaIPI, R-IPI, aaDLBCL-PI, and NCCN-IPI were 32.9%, 19.7%, 12.3%, 17.4%, and 15.3%, respectively. The lowest proportion of patients in the high-risk group was identified by NCCN-IPI (6.3%), followed by IPI (14.8%), aaIPI (20.2%), aaDLBCL-PI (22.0%), and R-IPI (40.7%), respectively. The median follow-up was 78.1 months (range 0.2-244 months). As presented in Table 1, NCCN-IPI produced the highest absolute 3- and 5-year difference between high and low-risk groups and was the only model with less than 50% of surviving patients in the high-risk groups in respective survival time points. Moreover, the highest c-index was calculated for NCCN-IPI (0.709), followed by IPI (0.703), aaDLBCL-PI (0.692), R-IPI (0.679), and aaIPI (0.667). NCCN-IPI showed a statistically significant difference in discriminatory ability compared to all models except IPI. The lowest AIC was found in NCCN-IPI (9,231), along with IPI (9,295), aaDLBCL-PI (9,369), R-IPI (9,310), and aaIPI (9,408). When patients aged ≤60 were selected (n=1,328), NCCN-IPI again produced the highest absolute 3- and 5-year difference between high and low-risk groups. Moreover, NCCN-IPI had the highest c-index and lowest AIC (0.758; 3,068) compared to IPI (0.742; 3,118), aaIPI (0.730; 3,124), R-IPI (0.729; 3,109), and aaDLBCL-PI (0.751; 3,110). Conclusion: In this retrospective population-based study investigating 2,456 patients with DLBCL 18-69 years of age, we found NCCN-IPI superior to IPI and, in particular, aaIPI and R-IPI. Therefore, we suggest reporting NCCN-IPI and IPI for risk stratification in future studies and clinical trials.

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.

Prognostic indices in diffuse large B-cell lymphoma: a population-based comparison and validation study of multiple models

Currently, the International Prognostic Index (IPI) is the most used and reported model for prognostication in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). IPI-like variations have been proposed, but only a few have been validated in different populations (e.g., revised IPI (R-IPI), National Comprehensive Cancer Network IPI (NCCN-IPI)). We aimed to validate and compare different IPI-like variations to identify the model with the highest predictive accuracy for survival in newly diagnosed DLBCL patients. We included 5126 DLBCL patients treated with immunochemotherapy with available data required by 13 different prognostic models. All models could predict survival, but NCCN-IPI consistently provided high levels of accuracy. Moreover, we found similar 5-year overall survivals in the high-risk group (33.4%) compared to the original validation study of NCCN-IPI. Additionally, only one model incorporating albumin performed similarly well but did not outperform NCCN-IPI regarding discrimination (c-index 0.693). Poor fit, discrimination, and calibration were observed in models with only three risk groups and without age as a risk factor. In this extensive retrospective registry-based study comparing 13 prognostic models, we suggest that NCCN-IPI should be reported as the reference model along with IPI in newly diagnosed DLBCL patients until more accurate validated prognostic models for DLBCL become available.

Construction and validation of prognostic scoring models to risk stratify patients with acquired immune deficiency syndrome-related diffuse large B cell lymphoma.

Acquired immune deficiency syndrome (AIDS)-related diffuse large B cell lymphoma (AR-DLBCL) is a rare disease with a high risk of mortality. There is no specific prognostic model for patients with AR-DLBCL. A total of 100 patients diagnosed with AR-DLBCL were enrolled in our study. Clinical features and prognostic factors for overall survival (OS) and progression-free survival (PFS) were evaluated by univariate and multivariate analyses. Central nervous system (CNS) involvement, opportunistic infection (OI) at lymphoma diagnosis, and elevated lactate dehydrogenase (LDH) were selected to construct the OS model; CNS involvement, OI at lymphoma diagnosis, elevated LDH, and over fourchemotherapy cycles were selected to construct the PFS model. The area under the curveand C-index of GZMU OS and PFS models were 0.786/0.712; 0.829/0.733, respectively. The models we constructed showed better risk stratification than International Prognostic Index(IPI), age-adjustedIPI, and National Comprehensive Cancer Network-IPI. Furthermore, in combined cohort, the Hosmer-Lemeshow test showed that the models were good fits (OS: p = 0.8244; PFS: p = 0.9968) and the decision curve analysisdemonstrated a significantly better net benefit. The prognostic efficacy of the proposed models was validated independently and outperformed the currently available prognostic tools. These novel prognostic models will help to tackle a clinically relevant unmet need.

A novel prognostic index for diffuse large B-cell lymphoma combined baseline metabolic tumour volume with clinical and pathological risk factors.

This study aimed to develop a novel prognostic index integrating baseline metabolic tumour volume (MTV) along with clinical and pathological parameters for diffuse large B-cell lymphoma (DLBCL). This prospective trial enrolled 289 patients with newly diagnosed DLBCL. The predictive value of novel prognostic index was compared with Ann Arbor staging and National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI). We used the concordance index (C-index) and a calibration curve to determine its predictive capacity. Multivariate analysis revealed high MTV (>191 cm 3 ), Ann Arbor stage (III-IV) and MYC/BCL2 double expression lymphoma (DEL) to be independently associated with inferior progression-free survival (PFS) and overall survival (OS). Ann Arbor stage and DEL could be stratified by MTV. Our index, combining MTV with Ann Arbor stage and DEL status, identified four prognostic groups: group 1 (no risk factors,), group 2 (one risk factor), group 3 (two risk factors), and group 4 (three risk factors). The 2-year PFS rates were 85.5, 73.9, 53.6, and 13.9%; 2-year OS rates were 94.6, 87.0, 67.5, and 24.2%, respectively. The C-index values of the novel index were 0.697 and 0.753 for PFS and OS prediction, which was superior to Ann Arbor stage and NCCN-IPI. The novel index including tumour burden and clinicopathological features may help predict outcome of DLBCL (clinicaltrials.gov identifier: NCT02928861).

Prognostic value of metabolic tumor volume and lesion dissemination from baseline PET/CT in patients with diffuse large B-cell lymphoma: Further risk stratification of the group with low-risk and high-risk NCCN-IPI

PurposeThe purpose of this study was to determine the prognostic value of metabolic tumor volume and lesion dissemination from baseline PET/CT in patients with diffuse large B-cell lymphoma (DLBCL) and the prognostic value of them in the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) subgroups. MethodsA total of 113 patients who underwent 18F-FDG PET/CT examination in our institution were retrospectively collected. The MTV was measured by iterative adaptive algorithm. The location of the lesion was obtained according to its three-dimensional coordinates, and Dmax was obtained. SDmax is derived from Dmax standardized by body surface area (BSA). The X-tile method was used to determine the optimal cut-off values for MTV, Dmax and SDmax. Cox regression analysis was used to perform univariate and multivariate analyses. Patient survival rates were derived from Kaplan-Meier curves and compared using the log-rank test. ResultsThe median follow-up time was 24 months. The median of MTV was 196.86 cm3 (range 2.54–2925.37 cm3), and the optimal cut-off value was 489 cm3. The median of SDmax was 0.25 m−1 (range 0.12–0.51 m−1), and the best cut-off value was 0.31 m−1. MTV and SDmax were independent prognostic factors of PFS (all P < 0.001). Combined with MTV and SDmax, the patients were divided into three groups, and the difference of PFS among the groups was statistically significant (P < 0.001), and was able to stratify the risk of NCCN-IPI patients in the low-risk (NCCN-IPI < 4) and high-risk (NCCN-IPI ≥ 4) groups (P = 0.001 and P = 0.031). ConclusionMTV and SDmax are independent prognostic factors for PFS in DCBCL patients, which describe tumor burden and tumor dissemination characteristics, respectively. The combination of the two could facilitate risk stratification between the low-risk and high-risk NCCN-IPI groups.

Real-world efficacy of DA-EPOCH-R/HD-MTX regimen in CD5-positive diffuse large B cell lymphoma: a single-institute analysis.

CD5-positive diffuse large B cell lymphoma (CD5+ DLBCL) is a high-risk lymphoma type. Recently, the PEARL5 (a Phase II trial of DA-EPOCH and Rituximab with HD-MTX therapy for newly diagnosed DLBCL with CD5 expression) study demonstrated the efficacy of the DA-EPOCH-R (cyclophosphamide, etoposide, doxorubicin, vincristine, prednisone, and rituximab)/HD-MTX (high-dose methotrexate) regimen for CD5+ DLBCL. In this report, we revealed the impact of the DA-EPOCH-R/HD-MTX regimen on the clinical course of CD5+ DLBCL in the real-world. We retrospectively compared CD5+ and CD5- DLBCL patients diagnosed from January 2017 to December 2020 and analyzed their clinicopathological characteristics, treatment, and prognosis. There was no difference in age, sex, clinical stage, and cell of origin; however, the CD5-positive group had higher lactate dehydrogenase levels and a worse performance status than the CD5-negative group (p=0.00121 and p=0.0378, respectively). International prognostic index (IPI) was worse in the CD5-positive group than in the CD5-negative group (p=0.0498), but NCCN-IPI (National Comprehensive Cancer Network-IPI) was no different between the two groups. The CD5-positive group was more frequently treated with the DA-EPOCH-R/HD-MTX regimen than the CD5-negative group (p =0.001857). Complete remission rate and 1-year overall survival did not differ between the CD5-positive and -negative groups (90.0% vs 81.4%, p=0.853; 81.8% vs 76.9%, p=0.433). We conclude that the DA-EPOCH-R/HD-MTX regimen is effective for CD5+ DLBCL in this single institute analysis.

The prognostic value of IPI in patients with primary breast lymphoma, a multicenter retrospective study

BackgroundDue to the rarity of PBL and the lack of large-scale studies, the prognostic value of IPI in PBL was controversial. Especially in the rituximab era, the ability of IPI to stratify prognosis in patients receiving immunochemotherapy was severely reduced. Then revised IPI (R-IPI) and National Comprehensive Cancer Network IPI (NCCN-IPI) were introduced. The present study aimed to evaluate the prognostic value of IPI and the other IPIs in patients with PBL in a Chinese population.MethodsWe performed a multicenter retrospective study of 71 patients with PBL from 3 institutions in China. The Kaplan–Meier method and log-rank tests were used for the survival analysis. Cox regression analysis was performed to evaluate the prognostic factors. Subgroup analysis was performed to assess the prognostic significance of IPI scores, R-IPI scores, and NCCN-IPI scores.ResultsThe median follow-up was 4.7 years (0.7–21.8 years). The 5-year progression-free survival (PFS) and overall survival (OS) rates were 90.2% and 96.3%. In the multivariate analysis, only IPI scores and radiotherapy were significantly associated with OS and PFS (P < 0.05). Applying the R-IPI in our patient cohort indicates a significant difference in PFS between the two groups of R-IPI (P = 0.034) but not for OS (P = 0.072). And the NCCN-IPI was prognostic for OS (P = 0.025) but not for PFS (P = 0.066). Subgroup analyses of IPI showed that survival analysis of IPI scores for the PFS and OS of patients using rituximab were not significantly different (P > 0.05).ConclusionsOur study confirms the prognostic value of IPI in patients with PBL, but the predictive value of IPI proved to be relatively low with the addition of the rituximab. The R-IPI and NCCN-IPI can accurately assess the high and low-risk groups of PBL patients but were insufficient to evaluate the intermediate risk group.

A Comparison of Clinical Prognostic Indices in Elderly Patients with Diffuse Large B-Cell Lymphoma Treated with a Pegylated Liposomal Doxorubicin Combination Regimen in China.

BackgroundThere is no consensus regarding the risk stratification scores for elderly patients with diffuse large B-cell lymphoma (DLBCL). We aimed to compare the prognostic predictive ability of the current clinical scoring indices in DLBCL elderly patients treated with the R-CODP regimen (rituximab, cyclophosphamide, pegylated liposomal doxorubicin, vincristine, and prednisone).MethodsWe retrospectively collected the data of elderly DLBCL patients who received the R-CODP regimen as the first-line treatment. The efficacy of the regimen was evaluated. The Akaike information criteria (AIC), concordance index (C-index), and integrated discrimination improvement (IDI) were used to assess the fitness and prognostic performance of the current clinical prognostic indices.ResultsIn the total of 158 patients enrolled, the median follow-up time was 6.7 years (95% CI: 6.3–7.9), and the 5-year OS was 52.8% (95% CI: 45.5%–61.2%). The International Prognostic Index (IPI), National Comprehensive Cancer Network-IPI (NCCN-IPI), and Elderly International Prognostic Index (E-IPI) were all significantly associated with OS (P < 0.001 for all). However, no significance was observed in 5-year OS in the low- vs low-intermediate-risk groups for IPI (P = 0.377), NCCN-IPI (P = 0.238), and E-IPI (P = 0.080). Compared with the IPI and NCCN-IPI, the E-IPI had the lowest AIC value of 747.5 and the highest C-index of 0.692. For predicting 5-year mortality, the E-IPI showed better performance (AUC: 0.715 for E-IPI vs 0.676 for IPI, P = 0.036), with the IDI of 6.29% (95% CI: 3.71%-8.88%, P < 0.001) and 4.80% (95% CI: 1.32%-8.28%, P = 0.007) compared to the IPI and NCCN-IPI, respectively.ConclusionThe E-IPI might be a better prognostic prediction model in Chinese DLBCL generics treated with R-CODP for predicting 5-year mortality. However, the IPI, NCCN-IPI, and E-IPI did not seem to be able to distinguish patients with a favorable prognosis well.

Enhancement of the International prognostic index with β2-microglobulin, platelet count and red blood cell distribution width: a new prognostic model for diffuse large B-cell lymphoma in the rituximab era

BackgroundThis study aimed to propose a new user-friendly, cost effective and robust risk model to facilitate risk stratification for diffuse large B-cell lymphoma (DLBCL) treated with frontline R-CHOP regimens.MethodsData on 998 patients with de novo DLBCL diagnosed between Jan 1st, 2005 and Dec 31st, 2018 at our center, who received frontline R-CHOP or R-CHOP-like regimens, were retrospectively collected. Patients were randomly divided into the training cohort (n = 701) and the validation cohort (n = 297). A new prognostic model for overall survival (OS) was built based on the training cohort. The performance of the new model was compared with International prognostic index (IPI), revised IPI (R-IPI) and National Comprehensive Cancer Network (NCCN)-IPI (NCCN-IPI). The new model was validated in the validation cohort.ResultsThe multivariate analysis of the training cohort showed that the IPI, β2-microglobulin, platelet count and red blood cell distribution width were independent factors for OS, which were incorporated into the new prognostic model. Patients were stratified into low risk, low-intermediate risk, high-intermediate risk, high risk and very high risk groups, with distinct survival outcomes. The new model achieved good C-indexes for 5-year OS prediction of 0.750 (95%CI 0.719–0.781) and 0.733 (95%CI 0.682–0.784) in the training and validation cohorts, respectively, and displayed well-fitted calibration curves. The C-index and the time-dependent ROC analysis demonstrated better performance of the new model than the IPI, R-IPI and NCCN-IPI in both training and validation cohorts. The integrated Brier score for predicting 5-year OS of the new model was lower than that of the IPI, R-IPI and NCCN-IPI in both cohorts, and decision curve analysis also showed a higher net benefit, indicating the superiority of the new model over the conventional models.ConclusionThe new prognostic model might be a useful predictive tool for DLBCL treated with R-CHOP regimens. Further external validation is warranted.

Patient Survival With and Without Radiation Therapy for Early-Stage Diffuse Large B-Cell Lymphoma in the Era of PET and Rituximab

PurposeThe benefit of radiation therapy (RT) becomes uncertain in the treatment of early stage diffuse large B-cell lymphoma (DLBCL) in the era of rituximab, positron emission topography (PET), and computed tomography (CT). We sought to retrospectively review modern patients with early stage I-II DLBCL treated with rituximab and staged by PET-CT to better define which patients benefit from consolidative RT. Methods and MaterialsPatients with early stage I-II DLBCL from 1998 to 2017 were reviewed coinciding with our institutional utilization of rituximab with the standard regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone and PET-CT. Relevant clinical information was used to calculate National Comprehensive Cancer Network international prognostic index (IPI) scores. Kaplan-Meier survival analysis and a Cox proportional hazards model were used for overall survival (OS). ResultsSeventy-seven patients received chemoimmunotherapy alone, and 41 received chemoimmunotherapy plus RT. Median follow-up time was 9.5 years. On univariate analysis, extranodal disease (P = .04) and National Comprehensive Cancer Network IPI (P < .001) were significantly correlated with OS. Five-year OS was 87% versus 67%, and 10-year OS was 67% versus 58%, numerically higher favoring RT (P = .16). On multivariate Cox regression analysis of OS controlling for IPI and extranodal disease, the addition of RT was associated with improved OS (hazard ratio of 0.4, P = .01). ConclusionsThe current analysis supports the use of consolidative RT in early stage DLBCL given an OS benefit on multivariate analysis. Further prospective randomized data are needed to confirm these findings.

Prognostic Scoring Systems in Diffuse Large B Cell Lymphoma Patients - Is Kyoto Prognostic Index an Added Value?

Background: Diffuse large B cell Lymphoma (DLBCL), the most common non-Hodgkin lymphoma, is a clinical and biological heterogeneous entity. R-CHOP is the standard treatment, however 30%-40% of DLBCL patients will have primary refractory or relapsed disease. Several prognostic scoring systems, that include simple clinical parameters, have been developed to assist risk stratification and treatment decisions, namely the International Prognostic Index (IPI), the National Comprehensive Cancer Network IPI (NCCN-IPI) and the GELTAMO-IPI. However, the accurate identification of very high-risk patients is not accomplished by these scores. Recently, the Kyoto Prognostic Index (KPI) was able to identify an extremely poor prognostic group in a Japanese cohort and was proposed as a new robust prognostic model for DLBCL. Our aim was to assess the discriminative performance of IPI, NCCN-IPI and GETALMO-IPI in overall survival (OS) and progression-free survival (PFS) and compare them with the new score KPI, in a cohort of DLBCL patients treated with immunochemotherapy.Methods: Retrospective analysis of HIV-negative DLBCL patients, newly diagnosed between 2010 and 2019 in a single tertiary center, treated with R-CHOP/R-CHOP-like protocol. The Kaplan-Meier method was used to estimate the probabilities of OS and PFS. Stratified models for each of the risk scores (IPI, NCCN-IPI, GELTAMO-IPI and KPI) were compared using Akaike's information criterion (AIC) and the Harrell's concordance index (C-index). The inter-score classification concordance was evaluated by Cohen's kappa test. P-value<0.05 was considered statistically significant.Results: We included 232 patients, 52.6% (n=122) male, with a median age of 64 years (22-87). According to IPI, patients classified as Low (L), Low-Intermediate (LI), High-Intermediate (HI) and High (H) were 73 (31.47%), 59 (25.43%), 63 (27.16%) and 37 (15.95%), respectively. According to NCCCN-IPI, patients classified as L, LI, HI and H were 23 (9.91%), 94 (40.52%), 89 (38.46%) and 26 (11.21%), respectively. GETALMO-IPI was calculated in 170 of 232 patients, classified as L, LI, HI and H in 14 (8.24%), 119 (70.0%), 22 (12.94%) and 15 (8.82%), respectively. According to KPI, patients classified as L, LI, HI and H were 67 (28.88%), 122 (52.59%), 31 (13.36%) and 12 (5.17%), respectively.Between KPI and IPI, a fair concordance was observed (kappa 0.363; with only 10 [27%] IPI-H patients classified as KPI-H, and 10 [83.3%] patients KPI-H as IPI-H). Slight concordance was observed between KPI and NCCN-IPI (kappa 0.115; 9 [34.6%] patients NCNN-IPI-H classified as KPI-H, and 9 [75%] patients KPI-H as NCCN-IPI-H), as well as between KPI and GELTALMO-IPI-H (kappa 0.175; 6 [40%] patients GELTALMO-IPI-H classified as KPI-H, and 6 [60%] patients KPI-H as GELTALMO-IPI-H).With a median follow-up of 55.2 months, 5-year median OS and PFS for the global cohort were not reached (NR) and 128.2 months, respectively. All the scores identify different prognosis groups for OS and PFS, although with modest ability to distinguish between intermediate and high-risk groups (Table 1; Figure 1). GELTAMO-IPI provided the best fit for the data in both OS and PFS (AIC 479.4 and 631.0, respectively) followed by NCCN-IPI (AIC 727.3 and 933.8) and IPI (AIC 738.3 and 937.9), while KPI had the worst performance (AIC 745.6 and 943.7). NCCN-IPI discriminated better between patients with poor and favorable OS (C-index 0.667), compared with the remaining scores (C-index for IPI, GELTAMO-IPI and KPI 0.653, 0.647 and 0.612, respectively). Concerning PFS, IPI had the best discrimination capacity (C-index 0.6313), followed by NCCN-IPI (C-index 0.6232), GELTAMO-IPI (C-index 0.6086) and KPI (C-index 0.5940).Conclusions: In our cohort, GELTAMO-IPI had the best fit to the observed data regarding OS and PFS. NCCN-IPI and IPI discriminated better between patients with poor and favorable OS and PFS, respectively, although the differences in the C-index were small, and all scores exhibited an acceptable difference between short and long survival times. KPI did not seem to improve the capacity for predicting OS and PFS in our population, which could be explained by differences in pathophysiology and genetics of DLBC of Asian and Western patients. Novel risk scores that integrate molecular tumor features might help improve risk stratification, especially in high-risk group. [Display omitted] DisclosuresGomes: Takeda: Consultancy; Gilead: Consultancy; Janssen: Consultancy.

Systemic Inflammation Response Index (SIRI) Predicts Clinical Outcome and Improves NCCN-IPI Scoring in Primary Gastrointestinal Diffuse Large B-Cell Lymphoma

Background: Systemic inflammation response index (SIRI) is a novel inflammatory hallmark that is proposed as an adverse prognosticator in a variety of malignancies. Nevertheless, the correlation between SIRI and primary gastrointestinal diffuse large B cell lymphoma (PGI-DLBCL) remains unknown. Our study aimed to evaluate the prognostic value of SIRI in PGI-DLBCL patients treated with CHOP-based therapies and establishing a highly discriminating risk prediction model compared with the National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) score.Methods: This retrospective analysis incorporated 102 PGI-DCBCL patients (57 patients with gastric DLBCL and 45 patients with intestinal DLBCL) newly diagnosed between January 2011 and June 2020. The SIRI was calculated by utilizing the peripheral blood neutrophil (N), monocyte (M), and lymphocyte (L) counts collected in the last ≤3 days before the initiation of the immunochemotherapy: SIRI= N × M/L. Pretreatment SIRI cutoff that may distinguish the study population into two gatherings with distinctive overall survival (OS) results which was calculated by the receiver operating characteristic (ROC) curve analysis. The prognostic factors associated with OS, the primary endpoint, were screened by multivariate Cox regression analyses and log-rank test as well as progression-free survival (PFS), the secondary endpoint. Performances of the novel model were compared using the area under the curve (AUC) and C-index in the cohort.Results: Among the 102 patients analyzed, there were 64 (62.7%) males and 38 (37.3%) females. The median follow-up time was 39.5 months (95% CI: 30.7-48.2), ranging from 2 to 102 months. A total of 33 patients (32.4%) presented B symptoms at the initial assessment, 74 (72.5%) of patients revealed stage III or IV disease, and 24 (23.5%) of patients had more than one extranodal involvement. Twenty-seven patients (26.5%) showed ECOG PS>2. The optimal SIRI cutoff was identified as 1.34 value by OS outcome, which divided patients into two groups. There were not significant differences in clinical characteristics between two groups (Table 1).Based on the cut-off value of SIRI, the outcomes of patients were distinct within two groups, which was shown in Figure 1. At a median follow-up of 39.5 (95% CI: 30.7-48.2) months, 86 (84.3%) patients were still alive (98.4% for SIRI <1.34 vs 62.5% for SIRI ≥1.34; p < 0.001). Cox regression analysis found three negative prognostic factors on OS: SIRI≥ 1.34 (P=0.001), B symptom (P=0.001), LDH>ULN (P=0.005). Accordingly, SIRI≥ 1.34 (P=0.002), age>60 (P=0.011) and LDH>ULN (P=0.002) emerged to be the indicators in relation to considerably inferior PFS times. Consequences of the multivariate analyses revealed that the prognostic significance of the SIRI on OS and PFS outcomes was independent of other confounders.SIRI could be used to combine with NCCN-IPI and develop a risk score to improve the NCCN-IPI score and identify PGI-DLBCL patients with poor prognosis. Patients with SIRI≥1.34 were allocated 2 points as a risk factor which was calculated in terms of the β coefficients compared with the effect of LDH level (>ULN) in the multivariate analysis of OS. This established an integrated scoring model with a maximum of 10 points when we combined NCCN-IPI with SIRI. Patients were divided into four risk groups and identified as low-risk group (0−3 points), low-intermediate-risk group (4−5 points), high-intermediate-risk group (6−7 points), and high-risk group (≥8 points). As a result, the prognostic and discriminatory capability of the NCCN-IPI plus SIRI was superior to NCCN-IPI alone (AUC: 0.858 vs. 0.814 and C-index: 0.826 vs. 0.801) based on OS in this patient population (Figure 2). Regarding the PFS, SIRI-PI also surpassed the NCCN-IPI with superior AUC (0.766 vs 0.709) and C-index (0.736 vs. 0.709) in discrimination.Conclusion: The results of this retrospective analysis suggested that the pretreatment SIRI was a potent and independent prognostic indicator that may be a potential candidate for identifying patients with poor prognosis in the future clinical practice of PGI-DLBCL.Keywords: Aggressive lymphoma, Clinically relevant, Systemic inflammation response index [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Primary Progression on Frontline Therapy for Diffuse Large B-Cell Lymphoma Is Associated with a Poor Outcome Despite Subsequent CD19 Targeted CAR T-Cell Therapy

Primary Progression on Frontline Therapy for Diffuse Large B-Cell Lymphoma Is Associated with a Poor Outcome Despite Subsequent CD19 Targeted CAR T-Cell Therapy

Suppression of Extracellular Vesicle CD47 Induces Systemic Anti-DLBCL Immunity

Purpose:Tumor cells evade the immune surveillance by up-regulating surface expression of CD47, which interacts with SIRPa on macrophages to elicit the immune checkpoint response. Anti-CD47 antibody (IBI188) has shown promise in treating tumors, including Diffuse large B cell lymphoma (DLBCL). The objective response rate among DLBCL was 73% (ClinicalTrials.gov number, NCT02953509.). The basis of differential therapeutic success between patients remains unknown. Extracellular vesicles (EVs) carry bioactive molecules that influence the immune system. CD47 has be found on surface of EVs. The purpose of this study is to explore whether EV CD47 contributes to immunosuppression and is associated with anti-CD47 response in DLBCL.Methods: 1.Kaplan-Meier curves and Cox regression models were used to analyze PFS and OS. The area under the ROC curve (AUC) was used to assess the predicted validity of the National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) model and the NCCN-IPI+ CD47 model.2.Immunofluorescence experiment was used to detect the infiltration of M1 and M2 subtype macrophages in DLBCL tumor tissue. M1 and M2 macrophages were generated from peripheral blood mononuclear cells obtained from healthy donors. Immunoelectron microscopy, flow cytometry and western blot were performed to detect CD47 on the surface of the EVs derived from DLBCL cells. The activity of macrophage phagocytosis of DLBCL cells was detected by confocal-based phagocytosis assay and flow cytometry-based phagocytosis assay.3.In DLBCL xenografts, the IBI188 antibody was a macrophage immune checkpoint inhibitor blocking CD47 that induces tumor-cell phagocytosis.4.Peripheral blood mononuclear cells from DLBCL patients and healthy donors was collected for EVs purification and subsequent detection of human CD47 proteins by ELISA.Results 1.The elevated expression of CD47 in DLBCL is significantly correlated with poor PFS and OS in a univariate analysis, and is statistically significant after adjusting for the NCCN-IPI in the univariate and multivariate analysis (Figure 1A, B). AUC analysis with cross-validation showed that the combination of the CD47 signature and NCCN-IPI had a better prediction of PFS and OS than without the CD47 signature (Figure 1C). Thus, CD47 in DLBCL can be used as a biomarker of prognosis and developed the prognostic stratification of DLBCL patients.2.EV CD47 derived from DLBCL cells has the same membrane topology as the cell surface CD47, with its extracellular domain exposed on the surface of the EVs (Figure 1D-G). Moreover, EV CD47 could function similarly to cell-surface CD47 in the suppression of macrophage phagocytosis of DLBCL cells (Figure 1H, I). DLBCL cells that had higher levels of cellular CD47 protein packaged greater amounts of CD47 into EVs, and these EVs displayed an increased binding to SIRPa of macrophages, thus inhibiting macrophage-mediated phagocytosis of DLBCL cells (Figure 1J-O).3.Antibodies against human CD47 specifically identified human CD47 on the circulating exosomes from mice bearing DLBCL xenografts but not the control mice. The level of circulating EV CD47 positively correlated with tumor size. Injection of EVs derived from DLBCL cells promoted the growth of tumors, whereas pre-treatment of the EVs with anti-CD47 antibodies (IBI188), but not IgG isotype or CD63-blocking antibodies, inhibited the effect (Figure 1P, Q).4.The presence of CD47 in the EVs isolated from the plasma of DLBCL patients, and the level of CD47 on the circulating EVs was significantly higher in DLBCL patients than that in healthy donors (Figure 1R, S). The receiver ROC curve shows that the level of circulating EV CD47 could distinguish DLBCL patients from healthy donors.ConclusionOur studies suggest that the EV CD47-SIRPa interaction may represent a critical mechanism by which DLBCL cells escape immune-mediated clearance. Our study also raises the possibility that disrupting the interaction between the EV CD47 and macrophage SIRPa is a mechanism in the CD47-SIRPa blockade-based therapies. Moreover, high levels of circulating EV CD47 would follow and correlate positively with the phagocytic activity of macrophages, and reflect the presence of a successful anti-tumor immunity elicited by the anti-CD47 therapy. Together, these findings show that EV CD47 represents an unexplored therapeutic target, which could overcome resistance to current CD47 antibody approaches. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Novel Prognostic Index for Patients with EBV-DLBCL NOS: A Study from the Grupo De Estudio Latinoamericano De Linfoproliferativos (GELL)

Introduction: Epstein Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) is a newly recognized entity by the World Health Organization. EBV+ DLBCL, NOS is commonly encountered in Latin American countries and carries a dismal prognosis. Current prognostic models such as the Oyama and the International Prognostic Index (IPI) score have limited prognostic value in this patient population. Therefore, we aim to evaluate the ability of these models to risk stratify patients and propose a novel prognostic model in the largest cohort of Latin American patients with EBV+ DLBCL, NOS.Methods: This retrospective cohort study included patients ≥18 years from six Latin American countries diagnosed and treated at tertiary centers from 2010 to 2020. Hematopathologists at each institution reviewed pathological samples to confirm the diagnosis of EBV+ DLBCL, NOS. We collected clinicopathological data by reviewing the medical records of the patients. The primary endpoint was overall survival (OS), defined as the time from the date of diagnosis until death from any cause or last visit. The secondary endpoint, progression-free survival (PFS), was defined as the time from diagnosis until death, progression, or last visit. Our novel model (Grupo de Estudio Latinomericano de Linfoproliferativos [GELL] Score) includes the Eastern Cooperative Oncology Group (ECOG) performance status ≥2, extranodal involvement >1, serum albumin <3.5 g/dL, serum lactate dehydrogenase (LDH) above the upper limit of normal, and platelet-to-lymphocyte ratio >455. We assigned a value of 1 to each of the abovementioned elements in the score and classified the patients as low (0 points), intermediate (1-2 points), and high (3-5) risk. OS and PFS probabilities were computed with the Kaplan-Meier method and compared with the log-rank test. We used Cox regression to evaluate the proportional hazard ratios (HR) of each score for our study outcomes. The C-index was employed to measure discrimination of each model. We used cross-validation to evaluate the model performance.Results: A total of 154 patients with EBV+ DLBCL, NOS were included in this analysis. The median age at diagnosis was 58 years (range 19-86 years) with a slight male predominance (53%). EBER was positive in all cases (range 1-100%). Clinically, 39% presented ECOG ≥2, 57% had B symptoms, 50% had an extranodal disease as a primary tumor, and 71% had Ann Arbor stage III/IV. Fifty-one percent of the patients had an elevated LDH level, and 43% had albumin <3.5 g/dL. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen was administered in 79% of individuals as first-line treatment. The overall response rate was 80% (62% complete response and 18% partial response). With a median follow-up of 61 months, the 5-year OS and PFS rates were 61% and 47%, respectively. The 5-year OS rates of patients with low, intermediate, and high-risk disease according to the GELL score was 90%, 59%, and 33%, respectively (Fig 1A). The 5-year PFS rates were 82%, 39%, and 23%, respectively (Fig 2A). Table 1 shows the Cox regression and the discrimination analysis for each of the scores. The GELL score has the highest discriminatory index for OS and PFS compared to the IPI, Revised-IPI, National Comprehensive Cancer Network-IPI, and the Oyama score (Figure 1 and 2).Conclusions: This study proposes a novel score for risk stratification of patients with EBV+ DLBCL, NOS. The GELL score appears to better discriminate OS and PFS than previous scores. Our results should be validated in an independent prospective cohort. [Display omitted] DisclosuresRamirez-Ibarguen: Asofarma: Consultancy; MSD: Consultancy; Abbvie: Speakers Bureau; Astra Zeneca: Speakers Bureau; Janssen: Speakers Bureau; Roche: Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Perini: Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Astra Zeneca: Honoraria, Speakers Bureau; MSD: Honoraria, Speakers Bureau. Oliver: Roche: Other: conference support and fees ; Abbvie: Other: conference support and fees . Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding.

Prognostic nutritional index, a novel biomarker which predicts worse prognosis in diffuse large B cell lymphoma

The prognostic nutritional index (PNI), an indicator of nutritional status and systemic inflammation, is associated with survival in several types of lymphoma. The purpose of this study was to investigate the prognostic value of PNI in diffuse large B cell lymphoma (DLBCL). With three hundred and ten patients were enrolled, the median level of PNI was 45.90 (range 25.30–139.70). According to the receiver operating characteristic (ROC) curve, 44.85 was determined to be the best cutoff value to divide patients into two different groups. With a median follow-up of 33.3 months (range 3.5–118.5), compared with the high PNI group, the 3-year and adjusted 3-year progression-free survival (PFS) and overall survival (OS) were worse in the low PNI group (all P < 0.050). Multivariate Cox analysis suggested that low PNI was an independent risk factor for PFS (hazard ratio (HR) 2.196, 95 % CI 1.197–4.030, P = 0.011) and showed a tendency to predict inferior OS (HR 1.918, 95 % CI 0.932–3.948, P = 0.077). Furthermore, PNI combined with other significant prognostic factors to build a novel prognostic index, namely NPI, was more accurate than the National Comprehensive Cancer Network international prognostic index (NCCN-IPI) to predict worse PFS and had a similar effect on predicting OS. All these findings suggested that PNI, as a novel available biomarker, was of prognostic significance in DLBCL patients.

Validation of the NCCN-IPI and the Geltamo-IPI in a Large Cohort of Patients Diagnosed of Diffuse Large B-Cell Lymphoma (DLBCL) Treated with R-CHOP/R-CHOP-like in a Single Institution

▪Introduction: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease and the identification of risk groups is important to plan different therapeutic strategies. The International Prognostic Index (IPI) has been an easy and universal prognostic index during the past 20 years. New prognostic indexes are needed to improve the identification of higher risk groups. The objective of this study is to validate and compare the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) and the Grupo Español de Linfomas/Trasplante de Médula ósea (GELTAMO-IPI) in a large cohort of DLBCL patients treated homogeneously with immunochemotherapy in a single institution.Methods: 371 adults with de novo DLBCL consecutive diagnosed from 2004 to 2016 at Insitut Català d'Oncologia in Barcelona and treated with curative intention based on immunochemotherapy [310(81%) R-CHOP, 61 (19%) R-CHOP-like] were included in the analyses. Prognostic indexes were compared in patients with complete data: NCCN-IPI vs. IPI (371 patients) and GELTAMO IPI vs. IPI (268 patients). All survival curves were obtained by the Kaplan-Meier method, and compared using the log-rank test.Results: The number of patients in the low risk (LR), low-intermediate risk (LIR), High-intermediate risk (HIR) and high risk (HR) groups are shown in table 1. OS curves for each prognostic index are shown in Figure 1. In all the risk indexes, the four risk groups had 5-yearOS and PFS rates with significant differences in the global comparisons. The NCCN-IPI discriminated better low-risk subgroups than IPI (5-year OS: 90.6% vs 75.5%, respectively). The GELTAMO-IPI compared to IPI improved the discrimination of the LR group (5-year OS: 81.8% vs 75.5%, respectively) and the HR group (5-year OS: 26.4% vs 39.4%, respectively).Conclusion: GELTAMO-IPI has been validated in an independent cohort of patients equally treated in a single centre. GELTAMO-IPI is a good prognosis index capable of differentiating a high-risk group with a 5-year OS of 26% unlike NCCN-IPI and IPI. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Impact of Pre-Therapeutic Haemoglobin Levels on the Outcome of Patients with Diffuse Large B-Cell Lymphoma Treated with Anthracycline Containing Chemotherapy before and after the Introduction of Rituximab: A Nation-Wide Cohort Study

▪Introduction: In diffuse large B-cell lymphoma (DLBCL), hemoglobin (Hb) at diagnosis is often low. In other cancers, pre-therapeutic anemia has been identified as an independent predictor of poor outcome and incorporated in well-established prognostic indices. The aim of our study was to investigate whether this also could apply to DLBCL.Methods:Clinical and laboratory data from DLBCL patients diagnosed between 2000 and 2012 were retrieved from nation-wide registries. Inclusion criteria were: a confirmed diagnosis of de novo DLBCL, treatment with anthracycline-containing chemotherapy with or without rituximab and no primary CNS-lymphoma. Four subgroups of pre-treatment Hb values (g/L) were defined for men/women: (i) >149/>133, (ii) 134-149/118-133, (iii) 98-133/98-117 and (iv) <98. While subgroup i and ii represented normal Hb levels either over or under the mean value for healthy individuals, subgroups iii and iv defined increasing grades of anemia. Correlation analyses between Hb subgroups and the clinical parameters contained in the National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI), sex, comorbidity and rituximab treatment were performed. Five-year overall (OS) and progression free survival (PFS) were estimated according to the method of Kaplan and Meier. A uni- and multivariable Cox regression model was used to calculate 5-year hazard rate ratios (HRR) for death or disease progression depending on Hb subgroup (where subgroup i was used as reference), NCCN-IPI, sex, comorbidity, and rituximab treatment with mutual adjustment. Finally, restricted cubic splines, stratified on sex, were used to illustrate the relative risk for death as a function of Hb at diagnosis.Results:In total, 3,531 patients fulfilled the inclusion criteria. Hb levels below normal (subgroup iii and iv), were found in 1,612 patients (46%). Notably, pre-therapeutic anemia was more frequent in men (53%) than in women (38%). Anemia was correlated with elevated lactate dehydrogenase, disseminated disease and involvement of extranodal sites such as bone marrow, gastrointestinal tract, lung or liver. Patients with a normal Hb, but below the median value for healthy individuals had inferior outcome with a HRR for death of 1.55 (95% confidence interval [95%CI] 1.29-1.88). In subgroups iii and iv the HRR was 2.79 (95%CI 2.34-3.31) and 4.56 (95% CI 3.70-5.61). After adjusting for NCCN-IPI, sex, comorbidity and rituximab treatment, the HRR remained significantly increased for Hb subgroups ii, iii and iv, compared with subgroup i (reference). Patients treated with rituximab had a significantly better OS in all Hb subgroups and an adjusted HRR of 0.62 (0.55-0.70). When progression free survival was used as end point similar results were obtained. The restricted cubic splines illustrated the inverse correlation between Hb at diagnosis and the risk of death over a subsequent five-year period (Figure 1).Conclusion:In this nationwide cohort study, anemia at diagnosis was a strong and independent predictor of both overall and progression free survival. This finding persisted after adjusting for NCCN-IPI score, sex, treatment with rituximab and comorbidity. The importance of Hb for prognosis was further evidenced by the fact that even a lowering of Hb within the range of normal (subgroup ii), resulted in an increased risk of death. [Display omitted] DisclosuresClausen:Takeda: Research Funding. Nørgaard:Program for Clinical Research Infrastructure (PROCRIN): Research Funding. d'Amore:Les Laboratoires Servier: Honoraria, Other: Advisory Board; Nordic Nanovector: Other: Advisory Board; Sanofi: Research Funding; Takeda Pharma: Honoraria, Other: Advisory Board, Research Funding.