ALBERT

Beschreibung: Background: Early events within 24 months (POD24) of initial immunochemotherapy (IC) were repeatedly confirmed to be associated with poor survival in follicular lymphoma (FL). Rituximab maintenance (RM) given to responding patients after IC is effective strategy to reduce relapse incidence and improve survival (Salles, Lancet 2011; Hill, BJH 2019). There is little known about the POD24 incidence pattern in chemosensitive patients, and the impact of subsequent RM application for POD24 reduction has not been studied yet. Aim: To (1) analyze the role of POD24 events in patients with responding FL and (2) describe whether post-induction RM changes the pattern of POD24 incidence and possibly post-POD24 outcome of the patients. Methods: The study comprised patients prospectively enrolled in the Czech Lymphoma Study Group network (ClinicalTrials.gov: NCT03199066) in 2000-2015, with grade 1-3A FL and treated with frontline R-CHOP/R-CHOP-like or R-bendamustine or R-CVP IC. Cases with previous WaW were not enrolled. No frontline stem cell (auto/allo) transplant was allowed. Only patients who achieved complete (CR/CRu) or partial remission (PR) at the end of induction (EOI) and were thus potential candidates for RM were included. Early event was defined as progression, relapse or death within 24 months after the date of EOI response assessment. Overall (OS) and progression-free survival (PFS) were calculated from the date of diagnosis and date of EOI response (OS-EOI). Patients who experienced an event before the median time to RM initiation were excluded from POD24 survival analyses to avoid overestimation of the RM group results. Results: A total of 1089 patients were identified, of whom 729 (67%) received RM (maintenance group) and 360 (33%) were followed without RM (observation group; OBS). When comparing both groups, we found no differences in age (median age 59 yrs for both; P=0.54), sex distribution (males 39% vs. 41% in OBS vs. RM, respectively; P=0.37) and ECOG 0-1 (90% vs. 93% in OBS vs. RM; P=0.10). There was a slightly lower proportion of advanced FL (Ann Arbor III-IV) in OBS (80%) as compared to RM (87%, P=0.01), which translated into a lower proportion of high FLIPI patients (46% vs. 52% in OBS vs. RM, respectively; P=0.003). The induction regimens were as follows: R-CHOP in 70% and 83%, R-COP in 18.6% and 10.7%, R-bendamustine 1% and 4%, R-fludarabine-based in 4% and 1% and others in 5% and 1% in RM and OBS, respectively. The EOI remission status was assessed 61 days (median) after the last IC dose with CR/CRu/PR rates of 65%/9%/26% and 65%/6%/29% in OBS and RM, respectively (P=0.14). The median time from EOI response to the first RM dose was 48 days (range 0-371 days), 89% of the pts have started RM within 120 days. The median number of RM doses given was 8 (range, 1-36), with 85% of patients receiving 8-12 doses of RM. After a median follow-up of 10.4 yrs (OBS) vs. 6.0 yrs (RM); P

Beschreibung: Abstract 4878 Background. Strong CD20 expression in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) suggests the feasibility of rituximab in the treatment of this disease. Methods. We analysed the outcome of 102 patients with NLPHL treated with or without rituximab in combination with conventional treatment: chemotherapy and/or radiotherapy. Histologies were reviewed for the purpose of this study. Rituximab was administered in 26 of 102 NLPHL patients (13 in the first line treatment and in 13 of 20 relapsed patients). Additionally, rituximab with chemotherapy was administered in 11 patients with histologic transformation to diffuse large-B cell lymphoma. Median follow-up was 7.1 years. Median patient age was 34.2 years. Results. The 10-year overall survival (OS) rate and progression - free survival (PFS) of the whole group was 88% and 65%, respectively. There was no difference in OS and PFS in patients with clinical stage IA without risk factors treated without or with rituximab (30 vs 3 patients) and conventional treatment, however the follow-up in the rituximab group was short. The addition of rituximab to conventional treatment did not affect the OS in the group of patients with more advanced disease: 58 patients without vs 10 with rituximab (94% [95% CI: 88 – 100%] vs 100% [-], P=0.566). PFS in both groups did not differ significantly in the first line treatment (69% [95% CI: 57 – 82%] vs 100% [-], P=0.165), however when all lines of treatment were analysed, PFS was significantly better in patients treated without rituximab (92% [95% CI: 84 – 100%] vs 38% [95% CI: 22 – 65%], P〈 0.001). Histologic transformation to diffuse large B - cell lymphoma was diagnosed in 11 rituximab naive patients, but this was not statistically significant when compared to 0 patients after rituximab treatment (14,5% vs 0%, P=0.061). Histologic transformation was the only poor prognostic factor that influenced OS (HR 7.936, P=0.004). Conclusions. Rituximab does not prevent relapses in NLPHL. This study confirms favorable OS of NLPHL patients regardless whether rituximab was used or not. The absence of histologic transformation in NLPHL patients treated with rituximab deserves further investigation. Disclosures: No relevant conflicts of interest to declare.

Beschreibung: Background: Classical Hodgkin lymphoma (cHL) is the most common lymphoid malignancy under the age of 30. Despite the relatively high curability, about 20-30% of patients relapse after front-line therapy. Since the International Prognostic Factors Project score became obsolete in the era of dose-intensive regimens (BEACOPP), a clinically applicable tool for outcome prediction is lacking. Recent years have brought much novel information about close Hodgkin/Reed-Sternberg (HRS) microenvironment cross-talk promoting tumor growth. Many studies have tested the predictive value of microenvironment cells using immunohistochemistry but none have been concerned with HRS cell density. Aim: To assess the prognostic role of HRS cell density in lymph node biopsies using a novel automated system for scanning large tumor sample areas in cHL patients. Methods: Thirty-eight high-quality tissue samples obtained at time of cHL diagnosis were analyzed. The median age at diagnosis was 35 (17.5-93) years; the male-to-female ratio was 0.66:1. The lymphoma subtypes were nodular sclerosis (NS) in 25 (66%) and mixed cellularity (MC) in 13 (34%) patients. At the time of analysis, detailed baseline clinical information was available in 35 (92%) patients. Ann Arbor stages I through IV were observed in 2, 18, 9 and 6 patients, respectively. Systemic symptoms were present in 26 (75%) cases and large lymphoma mass (≥5 cm) was detected in 19 (56%) patients. German Hodgkin Study Group stages were: limited in 4 (12%), intermediate in 8 (23%) and advanced in 23 (66%) patients. Chemotherapy was given to 35 patients (92%): BEACOPP in 20 (57.1%), ABVD in 6 (17.1%), Stanford V in 4 (11.4%) and other (COPP, COPP/ABV) in 5 (14.3%) cases. Involved-field radiotherapy was applied in 11 (29%) cases. Tissue array analyses were performed using the TissueFAXS (TissueGnostics, Austria) system combining detailed morphologic information offered by microscopy with the scientific accuracy of multi-channel flow cytometry. Data were analyzed with TissueQuest software. Paraffin-embedded biopsies were prepared from pre-selected diagnostic samples stained with hematoxylin-eosin for morphology analyses and using CD30 (HRS) for cell density analyses. Each sample was previewed by the scanning software and only significant tumor tissue was manually gated by an experienced pathologist for further analyses. Fibrotic (≥10%), necrotic or residual lymphatic structures were excluded. Results: After treatment, 31 (82%) patients achieved complete remission, three partial remission, one stable disease and three patients progressed. After a median follow-up of 64.3 months, 9 (24%) patients relapsed or progressed and 7 (18%) of them died. Five-year overall survival (5-y OS) reached 81.0% (95%CI 0.68-0.94); 5-year progression survival (PFS) was 68.3% (95%CI 0.53-0.83). Tissue data: The mean scanned area covered 27.2±13.5 mm2 with the mean (median) total number of cells 461,504±286,491 (466,138). The mean (median) total cell density and CD30+ HRS cell density were 17,886±7,884 (16,557) and 279±232 (181) cells per mm2, respectively. Total cell density was 1.28-fold higher (p=0.14) and HRS cell density 1.44-fold (p=0.19) higher in MC compared to NS. HRS cell density did not correlate with sex (p=0.46), systemic symptoms (p=0.38), tumor bulk (p=0.34) or Ann Arbor stage (p=0.59). There was a trend for older age among low HRS cell density (below the median) patients (p=0.19). Low HRS cell density was associated with inferior 5-y PFS (44.4% vs 90.0%, p=0.0024) and OS (57.5% vs 100%, p=0.002). Multivariate Cox regression identified low HRS cell density as an unfavorable prognostic factor for PFS (p=0.037, HR=5.50) independent of age and lymphoma subtype. Conclusions: This is the first evidence about the possible predictive role of HRS cell density in cHL patients. Low density at diagnosis was associated with 5.5-fold higher risk of lymphoma progression or death. Automated image analysis is a new tool overcoming technical limitations caused by small (microarray) samples in lymphomas with high intra-tumor heterogeneity. Further analyses will define the role of HRS cell analysis in cHL in the context of risk-adapted and CD30-targeted therapies. Acknowledgment - Supported by: Palacky University Olomouc (IGA-LF-2015-001), Takeda Restricted Educational Grant and J. W. Fulbright Commission. Figure 1. Figure 1. Disclosures Prochazka: Takeda: Research Funding.

Beschreibung: Abstract 4138 Background: 18F-FDG-positron emission tomography (PET) is a powerful tool for imaging of various lymphomas. Follicular lymphoma (FL) is the most common indolent lymphoma with usually slow progressive course, where growing is dependent on accumulation of cells with defect in apoptosis. In spite of its indolent nature, FL belongs to tumours with high 18F-FDG avidity. Semi-quantitative evaluation of PET activity can be defined as a standard uptake value (SUV max). Up to now, it is unclear, why FL is so highly 18F-FDG avid and whether SUV max can be of some prognostic value. Aims: We tried to correlate PET activity defined as SUV max with grade, tumor growth activity (Ki67), and prognosis using progression free survival (PFS). FL has, however, generally low proliferative activity. Therefore, other cells are expected to be responsible for 18F-FDG avidity in this disease. We selected suitable cells of “microenvironment”, and tried to correlate their numbers wit SUV max. Methods: Patients with newly diagnosed FL having PET with defined SUV max were included in this retrospective study. Diagnosis of FL including grading (grade 1–3) was confirmed by experienced hematopathologist on original lymph node samples and proliferation activity was evaluated by immunostaining with Ki67. In 25 cases, material was available and tissue microarrays (TMA) were done; populations of CD34 (endothelial marker), CD3 (global T-lymphocytes), CD8 (cytotoxic lymphocytes), FOXP3 (T-regulatory lymphocytes), CD23 (follicular dendritic cells) and CD68 (lymphoma associated macrophages) were evaluated. Ki67 as well as numbers of non-malignant elements were given in % of positive cells. Lymph node samples chosen for TMA were taken in our institution only, to avoid interlaboratory variability. Results: Data from 73 FL patients of stage II-IV were analyzed. Median age was 57 (31-76) years, and grading distribution was as follows: grade 1, 2 and 3 were observed in 40, 21 and 12 patients. Median follow up of the whole group was 45 months (1-73). PET activity defined as SUV max had median 7,8 (0-22,2), proliferation activity measured by Ki67 (n=53) ranged between 1,5-80% with median 25%. SUV max did not seem to correlate with grade or Ki67; moreover, SUV max did not predict course of follicular lymphoma in terms of PFS. No differences in gender, age or FLIPI were observed between subgroups with high and low SUV max. Additionally, 25 samples were available for TMA and subpopulations of microenvironment were evaluated. Although the number of samples was limited, we observed a tendency of positive correlation between amount of CD34+ cells (angiogenesis marker) and CD68+ (lymphoma associated macrophages) with SUV max (using cut off 8,0). Unfortunately, statistical significance could not be reached in these subpopulations (p 0.11 and 0.13). Surprisingly, we could identify strong negative correlation between number of interfolicullary localized CD8+ cells (cytotoxic lymphocytes) and SUV max using cut off 8 and 9 (p 0.02 and 0.003). Conclusions: Our data support the assumption, that proliferation activity, although various in FL, seems have nothing to do with 18F-FDG avidity. On the contrary, we observed strong correlation of CD8+ cells and SUV max and certain tendency that cells involved in angiogenesis (CD34+) and inflammatory response (CD68+) may influence SUV max as well. Based on our pilot results, we suggest that the microenvironment gives global 18F-FDG activity in FL. The microenvironment, however, is a mixture of various cells, and that could be the reason why SUV max does not seem to be a prognostic tool in this disease. Our preliminary results require confirmation by further research. Disclosures: No relevant conflicts of interest to declare.

Beschreibung: Background: Twenty percent of patients (pts) with high-tumor burden follicular lymphoma (FL) develop progression/relapse of disease within 24 months of frontline immune-chemotherapy (POD24). Those ultra-high-risk cases are at 50% risk of dying within 5-years since the POD event. Unmet need is to identify such pts at the time of initial treatment. The traditional approach used for building predictive scores (such as FLIPI, PRIMA-PI) is multivariable logistic regression (LR). LR is the tool of choice in case of many predictors (continuous or categorical) and a single binary (yes/no) outcome. Bayesian network (BN) offer an alternative strategy which may overcome several drawbacks of LR (risk of overfitting, missing data handling, problems of odds ratio interpretation), brings more insight into the complex relations among the variables, and offer an individualized prediction. Aim: The goal was to build a model to predict the risk of POD24 from the parameters known at diagnosis and compare LR to BN approach. Methods: The study (ClinicalTrials.gov No NCT03199066) comprised 1394 FL (grade I-IIIA) patients from the Czech Lymphoma Study Group registry treated with frontline rituximab-containing regimen and diagnosed between 10. 4. 2000 and 28. 12. 2016. The following parameters were analyzed: gender, age at diagnosis, clinical stage, lymphoma grade, no. of LNs regions, bone marrow involvement, no. of extranodal localizations, longest tumor diameter, systemic symptoms, performance status, LDH, beta-2-microglobulin, hemoglobin, and leucocyte, lymphocyte, and thrombocyte counts, induction regime, radiotherapy, ASCT, maintenance application, response to treatment, and OS, PFS and POD24 as outcome parameters. POD24 was defined as relapse, progression, change of therapy for 24 months since the induction started. Only parameters known at diagnosis were used for the prediction of POD24. Results: The median age was 59 yrs (range 26-89 yrs) with female predominance (59.2%), advanced disease stage (III/IV) was seen in 85.9% of the cases and FLIPI risk groups distribution was as follows: low (18.8%), intermediate (30.9%) and high (50.3%). The most frequent regime used was R-CHOP (76.8%), followed by R-CVP (12.4%), R-bendamustine (4.7%), intensive protocols (3.3), and fludarabine-based (2.8%). Consolidative IF-radiotherapy was applied in 5.1% and up-front ASCT in 2.9% of the pts. Maintenance immunotherapy was given in 67.1% of the pts. Response to therapy was known in all but 28 pts (98%) with CR/CRu 67.9%, PR 26.6%, SD 1.8%, and PD in 3.2% of the cases. After a median follow-up of 7.64 yrs, 484 (34.7%) of the pts progressed or relapsed and 316 (22.6%) have died. POD24 was recorded in 266 (19.0%) of the pts. The 5-year OS reached 86.4% and 5-year PFS 64.2%. LR model (PFS) building strategy included testing for significance as this model performed better than the model with all parameters. Overfitting was prevented by splitting the data into training (75%) and testing (25%) set. The performance of the model was assessed using the AUC criterion computed on the ROC curve. The LR model reached AUC of 0.69, and at 80% specificity, it reached about 51% sensitivity. Next, the BN (Augmented Naïve Bayes Classifier) was trained. Links of all predictors to POD24 were forced and all links to age and gender were forbidden, otherwise the network structure was inferred from the data. The performance of the BN was similar to the LR - AUC of 0.67 and about 50% sensitivity at the specificity of 80%. Both these models were compared to the standard PRIMA-PI risk classifier and were found to better stratify the population into risk groups (Table 1). An example of a patient is presented who was low-risk according to PRIMA-PI but actually experienced the POD24 event. The BN estimated the probability of the event to 91% (Figure 1). Conclusion: Lymphoma-related death following POD24 remains the most frequent cause of mortality in FL patients. BN modelling is a non-inferior prognostic tool compared to LR in term of POD24 prediction. Unlike LR, it also allows visualisation of complex relations among the predictors and individualized prediction of the patient's POD24 risk, even if some of the predictors are unknown. Both "ad hoc" trained LR and BN were found to better stratify the population into risk groups with respect to POD24 event than the traditional PRIMA-PI score. Acknowledgement: MZ Czech Republic DRO grant (FNOL, 00098892). Disclosures Procházka: F. Hoffmann-La Roche AG: Consultancy, Honoraria; Takeda Pharmaceuticals, Inc: Consultancy, Research Funding. Belada:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Celgene: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding. Trněný:Janssen: Consultancy, Honoraria, Other: Travel Expenses; Gilead: Consultancy, Honoraria, Other: Travel Expenses; Takeda: Consultancy, Honoraria, Other: Travel Expenses; Bristol-Myers Squibb Company: Consultancy, Honoraria, Other: Travel Expenses; Amgen: Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel Expenses; Roche: Consultancy, Honoraria, Other: Travel Expenses; MorphoSys: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy.