ALBERT

Description: Introduction: Currently, there is no consensus regarding diagnosis and treatment of occult lymphomatous menigeal involvement of cerebrospinal fluid (CSF) in patients with systemic non-Hodgkin lymphomas (NHL), especially in patients with minimal number of clonal cells detected by flow cytometry (FCM) or by cytology. Aim of the study: To describe a cohort of patients with occult lymphomatous involvement in cerebrospinal fluid including the diagnostic methods as well as management. Patients and methods: CSF at diagnosis of B-NHL was examined by FCM, cytology, biochemistry and microRNA analysis in a cohort of 62 patients (systemic DLBCL N=45, MCL N=15, Burkitt lymphoma N=2) between 2010 and 2013. Occult meningeal involvement was defined by: a/ FCM: absolute positive number of clonal cells

Description: Introduction Results of randomized studies showed benefit of maintenance therapy with monoclonal anti-CD20 antibody (rituximab) in terms of time to progression (PFS) and overall survival (OS) in follicular lymphoma (FL). General recommendation, based on large clinical trial, is to give 2 years of rituximab maintenance á 375mg/m2every 2 months (12 doses) in first line setting. On the other hand, there are various rituximab maintenance schedules; however, the clear comparison of clinical efficacy is missing. Our retrospective analysis compared two different schedule of rituximab maintenance in first-line treatment of FL used in university centers participating on CLG registry. Methods Data were recruited from 1702 FL patients registered in the prospectively maintained multicentric database (Czech Lymphoma Group; CLG). For the analysis, patients with stage II-IV of new diagnosed FL (grade 1-3a) responding (complete or partial remission) to 6-8 cycles first-line RCHOP (rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone) followed with rituximab maintenance (RM) were included. Completed planned maintenance was inclusion criterion. Patients with previous watch and wait or additional first line therapy (radiotherapy, other chemotherapy, transplant therapy) were excluded. Results Totally, 168 evaluable FL patients with median age 57ys (range 28-82) including 70 (41.7%) men treated with RCHOP + RM were found in CLG database. 52/168 patients received totaly 8 doses of rituximab maintenance every 3 months for 2 years (RM8 arm), whereas 47/168 patients were treated with totaly 12 doses (RM12 arm) of rituximab maintenance every 2 months for 2 years. All patients in both subgroups completed planned RM therapy. There was no difference in distribution of age, gender, FLIPI, grade, B-symptoms, bone marrow involvement, performance status, LDH and beta2microglobuline level between both arms. Induction treatment in terms of administered cycles CHOP (6xCHOP in 41/52 and 35/45 pts., for RM8 and RM12 arm) and rituximab doses (8xR in 48/52 and 41/45 pts., for RM8 and RM12 arm) was similar between arms (ns). There were 4/52 (7.7%) and 5/47 (10.6%) relapses in subgroups RM8 and RM12, with no statistical significance. Median PFS was 3.8 (2.1-5.8) years vs. 3.9 (2.4-7.8) years in RM8 and RM12 arms (not significant), and median OS 3.91 (2.2-6.94) years vs. 3.1 (2.48-8.6) years also with no statistical significance. Conclusion Our results show, that rituximab maintenance given every 2 or every 3 months for two years in first line treatment brings similar benefit to the FL patients in terms of remission duration and overall survival. Despite the fact, that presented data are retrospective observation, this is the first report comparing two different rituximab maintenance regimens in FL. Further prospective study and longer follow up are needed to confirm our preliminary data. This work was supported by grant NT/12193-5 and MHCZ-DRO (FNBr 65269705) Disclosures: Mayer: Roche: Consultancy, Research Funding; Glaxo: Consultancy, Research Funding. Trneny:Roche: Honoraria, Research Funding.

Description: Background: MCL is a distinct lymphoma entity with improved outcome achieved by the introduction of rituximab, high dose Ara-C and autologous stem cell transplantation (ASCT) into the first line therapy. The outcome of the relapsed patients (pts) remain however poor and there is little data on the outcome after subsequent relapses and there is no information on secondary MIPI prognostic value. Aim: To analyze the outcome of the MCL patients after first line treatment failure and to evaluate the prognostic role of the sec MIPI which is MIPI calculated at the time of relapse/progression. Methods: This analysis is a part of the Lymphoma project in which consecutive lymphoma patients are registered since the year 1999. Altogether 519 newly diagnosed MCL patients were registered in 5 university centers and 9 regional departments between 1999 and 2011. Patients who were treated with rituximab as part of the first line treatment (n=388) were included into the analysis. The diagnoses were confirmed according to WHO classification in the reference pathology centers. The median follow up is 4.5 years. Results: The whole cohort consists of 261 males and 127 females (2.1:1) with median age 65 y (28-87), the majority of pts had advanced disease (CS IV in 81.6% pts), PS ECOG ≥ 2 in 23.6% pts, elevated LDH in 52.5% of pts. The MIPI risk profile was as follows: low risk 21.7%, intermediate risk 27.2% and high risk in 51.1%. All pts received rituximab as part of the induction, 48.7% pts received CHOP, 5.7% alternation of CHOP and HD Ara-C, 26.2% intensive induction with HD Ara-C, 10.3% CVP, 6.4% FC. High dose therapy with ASCT was performed in 23.9% of pts. The ORR was 89.0% with 63.8 CR/CRu, 6.3% had stable disease and 4.9% were primary progressive. The PFS and OS were 2.9 y and 5.5 y with significant impact of MIPI risk (p

Description: Abstract 4619 Background. Expression of cyclin D1 demonstrated by immunohistochemistry is seen in 95% of mantle cell lymphomas and in other lymphoproliferative diseases including 10% of chronic lymphocytic leukemias (CLL). This study analyzed the impact of cyclin D1 positivity on time to treatment (TTT) and overall survival (OS) measured by RT PCR in newly diagnosed CLL patients and correlation with reported prognostic factors. Patients and methods. Level of cyclin D1 (quantitative real-time RT-PCR with a specific TaqMan flurescent hybridization probe) mRNA expression was analysed in 72 samples (57 peripheral blood and 15 bone marrow) from patients with newly diagnosed CLL. Cyclin D1 expression (cut-off according to ROC curve 〉3 over the threshold expression in healthy donors) was reported as positive. Fisher's exact test was used to analyze the relationship of cyclin D1 positivity and prognostic factors: del17p, del11q, unmutated IgVH, trisomy 12, ZAP 70 and CD38 positivity, elevated B2microglobulin, elevated LDH and lymphocyte doubling time (LDT)

Description: Introduction: Temsr (Torisel®) administered at 175 mg IV once weekly for first 3 weeks, followed by 75mg IV once weekly (Temsr 175/75 mg) is approved in the European Union for the treatment of adult patients with relapsed and/or refractory MCL based on an overall positive benefit-risk relationship demonstrated for this treatment regimen in the pivotal phase III study (Hess et al. J Clin Oncol. 2009;27:3822-9). This ongoing phase 4, multicenter, randomized, open-label study was conducted to explore whether similar efficacy can be achieved for the treatment of patients with relapsed/refractory MCL with a Temsr regimen that is expected to yield fewer side effects than the Temsr 175/75 mg dose regimen, by skipping the first 3 doses of Temsr 175 (Clinicatrials.gov: NCT01180049). Methods: In this study, previously treated (2-7 lines of prior therapy) patients with relapsed/refractory mantle cell lymphoma were stratified by the histologic subtype (blastoid vs. non blastoid vs unknown histology) and randomized (1:1) to receive Temsr 175/75 mg, or 75mg IV once weekly (Temsr 75 mg). Treatment continued until disease progression, provided that patients were tolerating treatment and achieving clinical benefit. The primary endpoint was progression-free survival (PFS) based on independent assessment. Secondary endpoints included objective response rate (ORR), overall survival (OS) and safety with a particular focus on bleeding- and infection-related adverse events (AEs). Results: Of the 90 patients (77.8% males; 93.3% white, mean age 66.6 years) randomized, 47 were treated with Temsr 175/75 mg, 42 were treated with Temsr 75 mg, and 1 patient was randomized but not treated. At the cutoff date for analysis (November 12, 2015), 39 (83.0%) patients in Temsr 175/75 mg arm and 41 (95.3%) patients in Temsr 75 mg arm discontinued treatment with the primary reason being objective disease progression (53.8% in Temsr 175/75 mg and 56.1% in Temsr 75 mg). Median duration of treatment was comparable in the Temsr 175/75 mg arm and Temsr 75 mg arm (3.2 vs. 3.1 months). Median PFS (80% CI) was 4.3 (3.3-6.4) months in Temsr 175/75 mg arm versus 4.5 (2.7-4.9) months in Temsr 75 mg arm (hazard ratio [HR] 0.731; 80% CI 0.520-1.027). ORR (80% CI) was 27.7% (19.1%-37.7%) in Temsr 175/75 mg arm versus 20.9% (13.0%-31.0%) in Temsr 75 mg arm. Median OS (80% CI) was 18.7 (7.5-48.2) months in Temsr 175/75 mg arm versus 11.0 (6.3-16.2) months in Temsr 75 mg arm (HR 0.681, 80% CI 0.472-0.982). Median duration of response was comparable in both treatment arms (9.0 vs. 8.7 months in Temsr 175/75 mg and Temsr 75 mg arms, respectively). Overall, the safety profile was comparable in both treatment arms, although the number of patients with serious AEs, dose reduction and deaths was lower in the 175/75mg arm compared with 75 mg arm (57.4%, 48.9% and 48.9% vs. 73.8%, 64.3% and 65.1%, respectively), and the number of treatment discontinuations due to AEs was higher in the Temsr 175/75mg arm compared with 75mg arm (19.1% vs. 14.3%). Common (〉10%) grade ≥3, all-causality, treatment-emergent AEs in the Temsr 175/75 mg arm and Temsr 75 mg arm, respectively, were thrombocytopenia (46.8% vs. 38.1%), neutropenia (25.5% vs. 21.4%), and pneumonia (10.6% vs. 19.0%). Treatment-emergent bleeding-related grade ≥2 AEs in the Temsr 175/75 mg arm and Temsr 75 mg arm, respectively, included epistaxis (10.6% vs. 2.4%) and ecchymosis (2.1% vs. 0). Only 1 grade 3 AE of epistaxis which was not related to Temsr was reported in the Temsr 175/75 arm, and no grade 3 events were reported in Temsr 75 arm. Pneumonia was the most commonly occurring treatment-emergent infection-related grade ≥2 AEs 12.8% in Temsr 175/75 mg arm and 19.0% in Temsr 75 mg arm. Of the 51 deaths reported during the study, none were treatment-related and most were due to disease progression. Conclusions: Overall, PFS, ORR and OS favored the Temsr 175/75 arm, although no formal statistical conclusions were made as the study was not powered for differences. The safety profile in both study arms was comparable, but there was a lower incidence of serious AEs, dose reductions and deaths in the 175/75 mg arm. Temsr 175/75 mg remains the preferred dose regimen for patients with relapsed/refractory MCL. Disclosures Jurczak: Sandoz - Novartis, Morphosys, Roche: Speakers Bureau; Acerta, Novartis, Pfizer, Celgene, Gillead, Janssen, Celtrion, Bayer, Morphosys, Takeda, Servier, Teva, and Roche: Research Funding; Morphosys: Consultancy. Clancy:Pfizer Inc: Consultancy. Lechuga:Pfizer Inc: Employment, Equity Ownership. Casey:Pfizer Inc: Employment, Equity Ownership. Boni:Pfizer Inc: Employment, Equity Ownership. Hess:Roche, CTI, Pfizer, Celgene: Research Funding; Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria.

Description: Background: Follicular lymphoma (FL) is an indolent lymphoma with chronically relapsing disease course. Treatment of relapses with 2nd line regimens such as salvage and autologous stem cell transplant (ASCT) is considered successful, i.e. the relapse itself does not shorten life expectancy. However, LymphoCare registry study (Casulo et al., JCO 2015) identified an early progression of the disease (POD24, i.e. progression within 24 months after R-CHOP commencement) to be a strong unfavorable event. Early progressors experienced only 50% 5-year OS compared to 90% in the control group) irrespective of the salvage treatment delivered. It is unclear whether post R-CHOP maintenance immunotherapy (MAINT) decreases POD24 incidence. Potential predictors identifying patients at risk of POD24 have not been analyzed yet. Aims: (1) To analyze the impact of MAINT on POD24 occurrence, (2) to find clinically applicable predictors of POD24 at the time of FL diagnosis. Methods: The Czech Lymphoma Study Group (CLSG) database was searched using the LymfoCare (LC) study methodology for previously untreated FL grade I-IIIa patients (pts), CS II-IV (Ann Arbor), no watch-and-wait before R-CHOP. Early progressors were defined as pts with progression or relapse within 24 months after FL diagnosis. OS was calculated both from diagnosis and from the Risk-defining event (rdOS) - it means from the date of early progression (POD group) or 24 months after diagnosis (non POD group). We have identified 821 FL pts, who met the inclusion criteria above and were diagnosed before DEC-2014. Median age of the CLSG group (58 years; range 26-82 years) was identical to the LC group (58 years; 22-88). Fifty-eight percent were females (46% in LC) and 50.5 % had high risk FLIPI (44% in LC). 80.8% of our pts had FL grade I-II and 19.2% had FL grade IIIa (62% and 38% in LC, respectively) Results: Treatment response was available in all but 15 pts (99.9%): CR/CRu, PR and SD/PD was achieved in 70.0%, 25.5% and 4.5%, respectively. After median follow up of 5.02 years 244 (29.7%) pts relapsed or progressed and 101 (12.3%) of the pts died. Five year OS and progression-free survival (PFS) was 90.1% (95% CI 0.88-0.92) and 63.7% (95% CI 0.60-0.68), respectively. In total, 99 POD24 (12.3%) were identified in the whole cohort of 821 patients. Five-year OS without POD24 (93.8%) was superior to 5-year OS in the POD24 group (64.3%, p

Description: Background. Hodgkin lymphoma (HL) that develops in the course of chronic lymphocytic leukemia (CLL) is a rare event. Optimal management of these patients (pts) is not defined. We analyzed outcome of 10 pts treated for Hodgkin´s variant (HV) of Richter syndrome. Patients and methods. Overall 10 pts (8 males) with CLL and subsequent HV were treated between 1996 and 2015. Median age at diagnosis of HV was 68 (range 54 - 83) years. Prognostic markers of CLL at diagnosis: unmutated IGHV (5 pts), del(17p) or TP53 mutations (0 pt), del(11q) (2 pts), deletion of 13q14 region (4 pts), trisomy 12 (2 pts), ZAP 70 pos. (6 pts), CD38 pos.(4pts). The diagnosis of HV included various subtypes of HL: nodular sclerosis (3pts), mixed cellularity (3pts), lymphocyte rich (1pt), not othervise specified (3pts). EBV status of pts at diagnosis of HV of Richter syndrome: 6 pos., 1 negat. nad 3 not done. Initial and second-line treatments of CLL consisted of fludarabine- based regimens combined with rituximab or alemtuzumab and 3 pts received chlorambucil. Treatment of HV of Richter syndrome included: ABVD (7 pts) in combination with rituximab (2 pts), COPP (3 pts) and involved field radiotherapy of 30 Gy after chemotherapy (2 pts). Further treatment was required in 6 pts due to insufficient response with persistent CLL: rituximab alone (2 pts), R-bendamustine (1pt), R-DHAP (1 pt), cyclophosphamide and dexamethasone (1 pt) and gemcitabine (1 pt). None of these patients underwent autologous or allogeneic stem cell transplantation. Results. The median time from CLL diagnosis to development of HV was 8.4 (range 2.6 - 16.5) years. Median overall survival from diagosis of CLL was 17.3 years and median survival after diagnosis of HV was 3.5 years. Out of 10 pts 5 are alive :3 in complete remission (CR), 1in partial remission of CLL (HL in CR), 2 in progression of CLL (HL in CR). Five pts died (3 lymphoma progressions, 1 second cancer, 1 unknown causality). Conclusion. Our results indicate a long period for developing of HV of Richter syndrome and its subsequent poor outcome. Current HL based chemotherapy is not sufficient in HV of Richter syndrome and new treatment approaches should be considered. Disclosures No relevant conflicts of interest to declare.

Description: Introduction Localized stages of follicular lymphoma (I-II) have been traditionally treated with involved field radiotherapy (IF-RT), which seems to be able to cure a significant proportion of patients. On the other hand, nearly half of patients relapse within 10 years. The late distant relapses remain the problem. Rituximab (anti CD20 antibody) is low-toxic, efficient systemic therapy for follicular lymphoma (FL). In vitro models bring the evidence of significant synergism between rituximab and radiotherapy. Up to now, there are no clinical data about clinical benefit of rituximab addition to the IF-RT. This study compares IF-RT alone vs. IF-RT with rituximab in early-stages of FL. Methods Between 2005-2012, through the prospectively maintained multicentric database (Czech Lymphoma Group; CLG), we identified patients with stage I-II FL treated with IF-RT (dose ≥ 24Gy) or IF-RT (dose ≥ 24Gy) with rituximab or rituximab alone. Patients receiving IF-RT with chemotherapy were not included. Complete staging including CT (neck, thorax, abdomen and pelvis) and bone marrow biopsy was performed at diagnosis. We compared EFS and OS between these three treatment arms. Rituximab (4 doses á 375mg/m2) was administered prior start of radiotherapy in combined arm. The total doses of rituximab varied between 4-8 doses á 375mg/m2 in rituximab monotherapy subgroup as well as in combined arm. Response to treatment was evaluated with CT 6-12 weeks after last dose of therapy. Results For the study period, approximately 1700 pts. of FL were identified in CLG database; 101pts with stage I-II FL (grade 1-3A) were included in the analysis. 65 patient were treated with radiotherapy alone (RT), 14 pts. with rituximab alone (R) and 14 pts. received rituximab and radiotherapy (R+RT), 8 pts. were excluded because of incomplete data. Median follow up was 4.57 (2.25- 12.6) years since diagnosis. There were no differences of age, performance status, FLIPI, proportion of bulky or extranodal tumor. In subgroup treated with R+RT was higher proportion of FL grade 3A in comparison with R or RT alone arms (35% vs. 1.5% vs. 7.5%; p.007). Complete response rate was 92% in RT arm, 100% in arm with R+RT and 86% in group treated with R alone, difference did not reach statistical significance. Median of event free survival was 3.35years in RT group, not reached in R+RT arm and 5.1 years in patients treated with R alone. EFS differences are statistically significant (p.035), but with no impact on overall survival. Conclusions In spite of fact, that RT is considered to be a good initial treatment for localized FL, rituximab alone or better in combination with RT seems to give better results in terms of long-term global control of disease. Our preliminary results should be confirmed with other studies and longer follow up is needed to verify or not the impact of rituximab on survival in early stages of FL. The work is support by research grant NT/12193-5 and MHCZ-DRO FNBr65269705. Disclosures: Mayer: Roche: Consultancy, Research Funding; Glaxo: Consultancy, Research Funding. Trneny:Roche: Honoraria, Research Funding.

Description: Background: The outcome of DLBCL patients is improving, it however seems to be very poor for those who are refractory to the therapy. We have decided to analyze this group of patients. Methodology: As part of an observational clinical study NiHiL (GovTrial No NCT03199066) we identified the patients treated in the first line by R-CHOP like immunochemotherapy who met at least one criterium: 1. refractory (stable disease - SD or progression) on 1st line therapy (1st l- R), 2. refractory (SD or progression) on salvage (platinum based regimen) (Salv-R), 3. refractory to or relapse/progression within 12 months after ASCT (ASCT-R/R). There were 210 patients diagnosed in the period 2001-2017 who fulfilled the criteria. Progression-free survival (PSF) and overall survival (OS) were estimated from the time of determination of a refractory disease. Results: The cohort consisted of 163 patients primarily resistant to the first-line therapy, 31 patients were resistant to the salvage therapy and 16 patients progressed within 12 months after ASCT . At the time of the diagnosis, the median age was 65 years (22-91) (the same as at the refractory disease), 54% were males, 74% had advanced clinical stage (III+IV), 68% had IPI 〉3, 77% had above-normal LDH, and 45% had a tumor mass 〉10cm. The OS from the time of determination of refractory disease was 0.53 years, median PFS was 0.29 years. Patients under 65 years had median survival 0.8 years compared to 0.4 years in the group of patients above 65 years of age. The median PFS for 1st l-R, Salv-R and ASCT-R/R resp. was 0.3, 0.26 and 0.35 years resp. and 5y survival 22%, 0% and 6% resp. The median OS for 1st l-R, Salv-R and ASCT-R/R resp. was 0.55, 0.39 and 0.65 y resp. and 5y survival was 28%, 0% and 13% resp. Our results demonstrate that resistant DLBCL has an extremely poor prognosis, clearly new effective therapeutic strategies such as CAR-based therapies or others are required. This work was supported by a research program Progres Q28-9. Disclosures Belada: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: 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