Introduction. Luspatercept has been recently approved for the treatment of red blood cell (RBC) transfusion-dependent (TD) Lower-Risk (LR) Myelodysplastic Syndrome (MDS) patients and can be administered either in the frontline or after erythropoietin failure. Our aim is to report its efficacy and safety in this study population in the everyday clinical practice using the well-defined IWG 2018 criteria for hematological response. Methods. We retrospectively studied LR, TD MDS patients from 15 Greek and 2 Turkish sites since October 2020. Transfusion burden was defined as high (HTB), intermediate (ITB) and low (LTB) if they had received ≥8, 3-7 or 1-2 RBC transfusions in the last 16 weeks before luspatercept onset respectively. Response was defined as transfusion independence (TI) for at least 8 weeks. Therefore, date of response was set at 8 weeks after the date of last recorded transfusion or after the date of luspatercept onset, if no more RBC transfusions were administered afterwards. If relapses were noted before the completion of 16 weeks since these timepoints, those responses were not considered meaningful and were excluded. All variables were reported as median (5-95% range). Fisher's exact test and Wilcoxon signed-rank test were performed for comparison of discrete and continuous variables respectively and the Kaplan-Meier method with log-rank test was used for time-to-event data. Results. A total of 98 patients, 59 male and 39 female, aged 75 ± 8 years were studied. 80 patients had bone marrow ring sideroblasts (RS) and 18 did not. In addition, 95 patients had prior erythropoietin failure and 3 were erythropoietin naive. There were 48 HTB, 37 ITB and 13 LTB patients. Out of 54 patients with available molecular results, 39 were SF3B1 positive and 15 were SF3B1 negative. 74 patients received maximum luspatercept dose (1.75 mg/kg), 12 received intermediate dose (1.33 mg/kg) and 12 received minimum dose (1 mg/kg). Median number of luspatercept doses was 14 (5-95% range: 4- 54). Median follow-up time was 13.1 (4.2-39,8) months and 20 deaths were observed within this time period. During follow-up, 57 patients stopped treatment, 8 due to adverse events (2 due to musculoskeletal pain, and the rest due to vertigo, hypertension, orthostatic hypotension, soft tissue infections, bleeding diathesis and one undetermined case), 8 because of death unrelated to treatment, 2 proceeded to transplantation and 36 stopped due to inadequate response. Notably, 3 patients stopped because of persistent hemoglobin levels>11g/dL. Out of 98 patients, 42 responded to treatment, 25% in the HTB, 57% in the ITB and 69% in the LTB group respectively (p=0.002). All LTB who became TI also exhibited >1,5g/dL increase in hemoglobin. There was 48.7% response in the SF3B1 positive vs 20% response in the SF3B1 negative group (p=0.051). HTB remained significant after controlling for SF3B1 status (Mantel-Haenszel p=0.002). On the other hand, there was no difference in response in the non-RS group (33,3%) compared with the RS group (45%, p=0.366). 29 and 33 patients who responded had ferritin and lymphocyte levels available upon response respectively. There was a significant decrease in ferritin upon response vs baseline (691 (52, 4375) vs 880 (93, 6291) ng/dL, p=0.008) and a significant increase in lymphocytes (1700 (748, 3902) vs 1635 (453, 2972) cells/uL p=0.05). For the 42 responders, time to response was 14.8 (8, 30) weeks and duration of response was 44.9 (4.3, 170.4) weeks at the time of data collection. 10 out of 42 patients lost response after having experienced 59 (10.3- 142) weeks of TI. Overall, patients who achieved response had better chances of survival (log-rank p=0.048). Conclusions. Luspatercept is tolerable and effective in the treatment of LR-TD MDS patients. Response depends mainly on transfusion burden at baseline and the presence of SF3B1 mutations. Most responses occur within the first six months of treatment and they are long lasting. Response to luspatercept treatment favorably affects overall survival in TD LR MDS patients.

Introduction: Ibrutinib, a Bruton's tyrosine kinase inhibitor, is a therapeutic agent commonly used for the treatment of chronic lymphocytic leukemia (CLL) patients, with a proved beneficial effect against chemotherapy. Myeloid-derived suppressor cells (MDSCs) are HLA-DRlow/-CD11b+CD33+ immunomodulatory cells with prominent T-cell suppressive activity. They are increased in neoplastic diseases and their numbers and functionality are correlated with worse disease outcome and poor treatment response. They are further divided in CD15+ polymorphonuclear cells (PMN-MDSCs) and CD14+ monocytic (M-MDSCs) subpopulations. In this study we aimed to investigate the number and the properties of PMN-MDSCs and M-MDSCs in CLL patients before and after Ibrutinib treatment. Materials and Methods: From four centers in Greece, 30 Rai stage III/IV CLL patients with indication for treatment, 38 Rai stage 0-II CLL patients with no indication for treatment and 36 age and sex-matched healthy controls were enrolled. Twenty patients from the first group successfully completed the study, i.e. were evaluated pre and after ibrutinib treatment initiation, between six to 24 months under therapy. PMN- and M-MDSCs were quantitated by flow cytometry in the PB mononuclear cell (PBMC) fraction and analysis was performed with the Kaluza software. Their suppressive capacity before and after ibrutinib treatment was assessed with a T-cell suppression assay (2 untreated patients, 3 patients under ibrutinib treatment, 4 healthy controls). More specifically, after three days of culture, the proliferation of T-cells was evaluated in the presence and absence of autologous MDSCs. Statistical analysis was performed with the GraphPad software. Results: The percentage of M-MDSCs in total CD14+ cells was 46,12% ± 18,95% (mean ± standard deviation) in CLL patients pre-treatment and 18,95% ± 12,87% after ibrutinib initiation, while the percentage of PMN-MDSCs in total CD15+ cells was 83,20% ± 12,26% in CLL patients pre-treatment and 77,59% ± 19,46% after ibrutinib initiation. When conducting paired analysis in individuals with measurements in both time points, the difference was statistically significant for both sub-populations (Wilcoxon matched-pairs signed rank test, p<0,0001 for M-MDSCs and p=0,0215 for PMN-MDSCs). The difference of both sub-populations was significant (p<0,0001, Kruskal Wallis non-parametric test) among the different groups of the study, i.e. healthy controls, stage 0-II CLL untreated patients, stage III/IV CLL patients pre ibrutinib treatment, CLL stage III/IV CLL patients after ibrutinib initiation. MDSCs were capable of suppressing T-cell proliferation. Importantly, the percentage of suppression tended to be higher in patients pre ibrutinib treatment (61,8% ± 12,1%), compared to patients that were receiving ibrutinib (31,2% ± 12,4%), and healthy controls (22,9% ± 11,7%). However, a larger sample would be needed to extract statistically significant results. Conclusions: The proportions of MDSC subsets are higher in CLL patients compared to healthy controls. MDSC counts are higher in patients of advanced stage compared to those of early stages. After treatment with Ibrutinib a significant reduction in the populations of MDSCs is observed. The results of our study, highlight the importance of MDSCs in the course of the disease in CLL and their potential role as biomarkers indicating disease severity and monitoring treatment response and relapse.

Introduction Immune thrombocytopenia (ITP) is a rare disease characterized by low platelet counts and increased risk of bleeding, often resulting in reduced health-related quality of life (HRQoL). The term “illness perceptions” (IP) encompasses the patients' beliefs about the various components of their illness, including its identity, consequences, timeline, concern, coherence, emotional representations, causes, personal and treatment control. IP has been demonstrated to exert an influence on HRQoL in a range of disorders. This study aimed to explore, for the first time to our knowledge, the IP of ITP patients and their association with HRQoL. Methods A cross-sectional study was conducted from October 2022 to March 2024 among adult patients with persistent or chronic ITP attending the Hematology Outpatients Clinic at six tertiary hospitals throughout Greece. The Brief Illness Perception Questionnaire (B-IPQ) and the EuroQoL (EQ-5D-5L, EQ-VAS), were used to assess IP and HRQoL, respectively. The data pertaining to patients' characteristics, demographics, clinical information and platelet counts were subjected to descriptive statistical analysis. The relationship between HRQoL and IP was examined using Pearson's correlation coefficient. Correlations between 0.4 and 0.6 were deemed to be moderate, while those below 0.4 were considered weak. A correlation coefficient between 0.6 and 0.8 indicates a strong association. The level of statistical significance was determined by a p-value< 0.05. Results The study included sixty patients diagnosed with primary ITP. The median age of the patients was 59 years (range: 20-92) and the male to female ratio was 0.76. The majority of patients had chronic ITP (88.3%) and did not experience active bleeding (83.3%). Τhe median platelet count was 121×10^9/L (interquartile range: 80-204x10^9/L). The majority of patients (78.3%) received treatment with Eltrombopag or Romiplostim. The B-IPQ total score indicated that the overall perceived threat from the disease was slightly low. Regarding IP, the patients demonstrated a good understanding of their condition and did not report significant symptoms of ITP. The participants expressed a strong belief that the administered treatment could control their disease and demonstrated a moderate positive perception of their own capacity to manage their illness. On the other hand, they lacked a clear perception regarding the extent to which ITP affected their lives and were convinced that their illness would persist for an extended duration. Patients were concerned about their illness and demonstrated a moderate belief that ITP caused negative emotions, including fear, anger and anxiety. The majority of patients (62.71%) lacked knowledge regarding the cause of ITP. Some attributed the cause, at least partly, to stress/anxiety (47.46%), sadness (20.34%), fatigue (16.95%) or SARS-CoV-2 vaccine (11.86%). The EQ-5D-5L and the EQ-VAS scores indicated that the patients' HRQoL ranged from moderate to satisfactory. Weak negative statistical correlations were identified between the EQ-5D-5L Index total score and the time-line (r=-0.261, p=0.044), the illness consequences (r=-0.289, p=0.025), and the emotional representations (r=-0.312, p=0.015). Furthermore, a moderate negative statistical correlation was observed between the EQ-5D-5L Index total score and the IP total score (r=-0.415, p=0.001). Conversely, a weak positive statistical correlation was identified between the EQ-5D-5L Index total score and personal control over the disease (r=0.377, p=0.003). A weak negative statistical correlation was identified between the IP total score and the EQ-VAS scale (r=-0.271, p=0.036). Conclusion These preliminary findings suggest that IP may be linked to HRQoL in patients with ITP. Further investigation of these relationships is necessary to gain a deeper understanding of IP, its potential impact on patient outcomes, and the development of interventions aimed at improving patient HRQoL.

Introduction: The introduction of targeted agents has radically changed the management of patients with chronic lymphocytic leukemia (CLL). Randomized controlled trials have shown the superiority of targeted agents over chemoimmunotherapy (CIT) in patients with relapsed/refractory (R/R) CLL. Following these trials, the treatment paradigm of CLL in daily practice shifted from CIT to targeted agents in any line of treatment. However, it is largely unknown if this has improved the overall survival (OS) of patients with R/R CLL in the real world. Methods: This is a retrospective, observational study that aimed to explore differences in the OS of patients with CLL in a real-world setting. Patients who received second-line treatment for CLL between 2010 and 2019 in five European countries (Czech Republic, Greece, Italy, Spain, and the United Kingdom) were eligible for the study. The patients were allocated to two different groups (CIT-era and BTKi-era groups) according to the actual use of BTKis in R/R settings in each country. The year when the use of BTKis surpassed 30% in any line was defined as the cutoff year for each country. Cases treated before the cutoff year were allocated to the CIT-era group, and cases treated after the cutoff year were allocated to the BTKi-era group. We compared the OS from the initial date of second line treatment between the two groups. The analysis was also done after adjusting for age at second line treatment through propensity score matching. Results: A total of 1877 patients (1384 in the CIT-era group and 493 in the BTKi-era group) from 38 centers were eligible for the study. The cutoff year was 2019, 2018, 2017, 2016, and 2014 for the Czech Republic, Greece, Italy, Spain, and the United Kingdom, respectively. In both groups, most patients were males [919 (66.4%) in the CIT-era and 337 (68.4%) in the BTKi-era group, p=0.461]. Patients in the CIT-era group were younger at both diagnosis [64 years (interquartile range (IQR)=57-71) vs 66 (IQR=59-74), p=0.001 for CIT-era and BTKi-era groups, respectively] and the start of second-line treatment [69 years (IQR=63-76) vs 73 (IQR=65, 79) p=0.001 for the CIT-era and BTKi-era groups, respectively]. The CIRS score was higher in the BTKi-era group [3 (IQR=1.25-6) vs 4 (IQR=2-6), p=0.053 for the CIT-era and BTKi-era groups, respectively]. Unfavorable disease biomarkers were similarly distributed among the two groups [del(11q): 215 (27.7%) vs. 80 (24.2%), p=0.26 | del(17p): 117 (14.7%) vs. 54 (15.7%), p=0.7 | TP53 mutations: 94 (19%) vs. 41 (17.3%), p=0.66 | unmutated immunoglobulin heavy variable (IGHV) gene status: 792 (78.8%) vs 276 (76.2%), p=0.35 for the CIT-era and BTKi-era groups, respectively]. The follow-up time from diagnosis (153 months [95% confidence intervals (CI):149-160) vs 106.6 (95% CI:98-115) for CIT-era and BTKi-era groups, respectively] and second-line treatment [81 months (95% CI:77-86) vs 30 (95% CI:27- 33) for CIT-era and BTKi-era groups, respectively] were longer for the CIT-era group. Patients in the BTKi-era group had statistically significantly better OS compared to the CIT-era group (Hazard ratio (HR): 0.74 95% CI: 0.61-0.91, p=0.003). This difference was even more pronounced when comparing OS using propensity score matching (HR: 0.71, 95% CI: 0.58-0.88, p=0.001). The median OS for the CIT-era group was 65 months (95% CI=57-71), while the median OS for the BTKi-era group was not reached (95% CI=not estimable, not estimable). Finally, we performed a univariable and multivariable analysis (MVA) to assess the risk factors for death in the entire population. TP53 aberrations and unmutated IGHV gene status remained the only statistically significant risk factors for death in the MVA (HR: 1.7, 95% CI: 1.03-3.13, p=0.039, HR: 2.48, 95% CI: 1.08-5.66, p=0.032, respectively). The only protective factor against death was treatment with BTKis in the R/R setting (HR: 0.5, 95% CI: 0.28-0.88, p=0.017). Conclusion: Our findings demonstrated that the availability of BTKis has improved the OS of patients with R/R CLL in the real-world setting.

Topic: 32. Platelet disorders Background: ITP can be classified as primary or secondary based on the absence or presence of other causes or disorders associated with thrombocytopenia. Although these forms of ITP have been traditionally considered as distinct disease entities, comparative studies are rare and the differences and similarities between primary and secondary ITP have not been adequately elucidated thus far. Aims: To comparatively describe real world characteristics at diagnosis and evaluate disease outcome in patients with primary (Group-1) and secondary ITP (Group-2), using data from the national database (ITP registry) operated under the auspices of the Hellenic Society of Hematology. Methods: The Greek ITP registry recruits patients (n=1573) nationally through a network of 25 sites. In the present study, we retrospectively analyzed data from patients with primary and secondary ITP, aged over 18 years who were diagnosed from 1979 to 2022. Results: The number of evaluable patients was 580. Group-1 consisted of 464 (80%) and Group-2 of 116 (20%) patients. There were no differences in the median age, gender, the median platelet count or other hematological parameters between the 2 groups at diagnosis. Significantly fewer patients in Group-1 had comorbidities as compared to Group-2 (P=0.0206). Relevant medications were concurrently used at similar rates by the 2 patient groups. Bleeding manifestations were observed at a similar frequency between the 2 groups. Of those who were diagnosed as secondary ITP, 26.8% had infections, 24% had collagen disorders, 8.3% had Evans Syndrome, 5.5% had H.Pylori infection, 4.6% had Hashimoto thyroiditis and 3.6% antiphospholipid syndrome. In 3.7% of Group-2 patients ITP was drug-induced. Antiphospholipid antibody (Ab), platelet associated Ab, antinuclear Ab, HIV Ab and Rheumatoid Factor testing were performed more frequently in Group-2 patients. A significant higher proportion of Group-2 patients had a positive test for antinuclear antibodies, HCV Abs, antiphospholipid Abs and H.Pylori (P=0.0185, P=0.0004, P=0.0002 and P<0.0001, respectively). Fewer Group-1 patients received treatment at diagnosis (P=0.023). The choice of treatment at diagnosis did not differ between Group-1 and Group-2 patients with the exception of anti-CD20 which was administered more frequently in Group-1 patients (P=0.036). Overall response rates did not differ between the two groups. At 6 months post diagnosis significantly fewer Group-1 patients had bleeding manifestations and fewer Group-1 patients were treated with corticosteroids, IVIG, corticosteroids and IVIG and anti CD20 (P<0.0001, P=0.0144, P=0.0005 and P=0.039, respectively). At 6 months post diagnosis significantly fewer Group-1 patients had developed persistent ITP (p<0.005). Summary/Conclusion: The majority of adult Greek ITP patients suffered from primary ITP (Group-1). Secondary ITP (Group-2) was predominantly associated with collagen disorders and infections. Primary and secondary ITP patients did not differ in demographics, bleeding manifestations, and hematological parameters. However, patients with secondary ITP had a higher frequency of auto Abs. The form of ITP did not impact on the choice of initial treatment or the response rate but influenced the diagnostic work-up and the outcome of the disease, as suggested by the increased proportion of secondary ITP patients requiring treatment and developing persistent ITP at 6 months post diagnosis. Further investigation is warranted to probe more deeply into the differences and similarities of primary and secondary ITP in order to optimize management. Keywords: ITP, Immune thrombocytopenia (ITP)

Background: Patients with chronic lymphocytic leukemia (CLL) have a higher risk of developing other malignancies (OMs) compared to the general population. However, the impact of CLL-related risk factors and CLL-directed treatment is still unclear. Aims: We aimed to (i) determine the incidence of OMs in a population of patients with CLL, (ii) assess the overall survival (OS) of patients with CLL and OM, and (iii) find risk factors for the occurrence of OM in patients with CLL. Methods: This is a retrospective international multicenter study conducted by the European Research Initiative on CLL, in the context of HARMONY. Investigators at each participating site provided data on consecutive sets of patients diagnosed with CLL/small lymphocytic lymphoma (SLL) or high-count CLL-like monoclonal B-cell lymphocytosis (MBL) between 2000-2016. The study was approved by the local institutional ethics committees. Results: Data on 19,705 patients from 85 different centers in 33 countries was collected. The median age at CLL diagnosis was 65 years [interquartile range (IQR) 57-73], and the median follow-up from CLL diagnosis was 6.2 years (IQR 3.72-9.6). The majority of patients had CLL (18,386, 93.3%), while 528 (2.7%) and 791 (4%) were diagnosed with SLL and MBL, respectively. At last follow-up, 10,146 (53%) patients had received at least one line of treatment (median 1, IQR 1-2). Diagnosis of OM was reported in 4,134/19,705 (21%) patients with CLL [633 (3.2%) had Richter transformation (RT) or B cell prolymphocytic leukemia]. In 2,910/4,134 (70.4%) patients, the OM postdated the diagnosis of CLL; in 854/4,134 (20.6%), the OM either antedated or was diagnosed concurrently with CLL; finally, in 322/4,134 (7.8%), an OM was diagnosed both before and after CLL diagnosis. Overall, 3,513 OMs were diagnosed in 130,166.9 years of follow-up after CLL diagnosis (26.9 OMs/1,000 person-years). The most common hematological OMs were myelodysplastic syndrome (MDS) (87/19,705, 0.44%), followed by acute myeloid leukemia (AML) (42/19,705, 0.21%) and multiple myeloma (37/19,705, 0.19%). Treatment with fludarabine and cyclophosphamide with/without rituximab (FC+/-R) was the only statistically significant risk factor for MDS/AML in the multivariate analysis, while only 13q deletions were associated with hematological OMs (excluding MDS/AML and RT). Non-melanoma skin cancers (NMSC) (986/19,705, 5%) and prostate cancers (PCs) (530/19,705, 2.7%) were the most frequent solid tumors (ST), followed by colon (382/19,705, 1.9%) and breast cancers (343/19,705, 1.7%). Male patients and those with unmutated immunoglobulin heavy variable (IGHV) gene status had a higher risk of developing an ST (excluding NMSC). The most frequent STs (>100 cases) were analyzed separately and statistically significant (p<0.05) associations were found between (i) NMSC development and male gender, older age at diagnosis, and FC+/-R treatment; (ii) male gender and colorectal and bladder cancers; (iii) unmutated IGHV gene status and melanoma, lung and breast cancers. The effect of CLL-directed treatment varied between different STs. Treated patients were more likely to develop NMSC and PC (OR=1.8;95%CI=1.36-2.41; p<0.001/OR=2.11;95%CI=1.12-3.97; p=0.021), while breast cancers were more frequent in untreated patients (OR=0.17;95%CI=0.08-0.33; p<0.001). Patients with CLL and an OM had inferior OS than those without. MDS/AML conferred the worst OS (Figure). Summary/Conclusion: OMs in CLL impact on OS. FC+/-R is associated with increased risk of MDS/AML. Accurate assessment of the risk of OMs in patients treated with chemo-free regimens requires further investigation.Keywords: B cell chronic lymphocytic leukemia

Topic: 13. Myeloma and other monoclonal gammopathies - Biology & Translational Research Background: Several T cell defects have been identified in multiple myeloma (MM), particularly pertaining to T cell exhaustion and senescence, likely as a result of chronic antigenic stimulation. Arguably, therefore, antigenic stimulation is highly relevant for shaping the T cell repertoire in MM, however the nature of the implicated antigens remains elusive. Similar to other mature B cell malignancies, immunoglobulin (IG) gene rearrangements in MM lead to the expression of unique, novel peptide sequences that can serve as neoantigens for T cells. Aims: We performed ad hoc prediction of putative T-cell class I/II neoepitopes contained within the MM clonotypic IG gene rearrangements. Methods: We studied 25 newly diagnosed patients with MM from whom we isolated the peripheral blood and/or bone marrow mononuclear cell fraction. Clonotypic IG heavy and light chain gene rearrangements were RT-PCR amplified on RNA extracted from the CD138+ myeloma cells using subgroup-specific leader primers for the IGHV/IGKV/IGLV gene and universal primers annealing to the constant domain. The corresponding sequences were determined by bidirectional Sanger sequencing. T cell receptor beta (TRB) chain gene rearrangements were RT-PCR amplified on RNA extracted from CD4+ and CD8+ T cells and then subjected to paired-end NGS. The deduced amino acid sequences of the IG heavy and light chains were subjected to bioinformatics analysis for the identification of putative T-cell class I/II neoepitopes using the NetMHCpan and NetMHCIIpan softwares. High- and medium-binding peptides (rank score <2%) were selected, considering the 4-digit HLA-A, -B, -C and DRB1 typing for each individual patient. Prediction of the binding specificity of T Cell Receptors (TR) to MHC-peptide complexes (pMHCs) was performed by the ERGO-II tool. The rank score was calculated, considering the peptides resulted by NetMHCpan/NetMHCIIpan, the HLA and the clonotypes for each patient (AUC>0.8). Exact matches to germline and/or proteome databases were excluded. Results: All patients displayed oligoclonal T cell expansions in both CD4+ and CD8+ T cells, albeit these were significantly (p<0.001) more pronounced in the latter. Both CD4+ and CD8+ T cell subpopulations displayed skewed TRBV and TRBJ gene repertoires (7 TRBV genes and 3 TRBJ genes accounting for about 40% and 59% of the repertoire, respectively). Overall, 821 predicted neoepitopes were identified. All patients had predicted CD4+ and CD8 + T-cell epitopes within the MM clonotypic IG, either in the heavy chain (25/25 pts, n=420 epitopes) or the light chain (25/25 pts, n=401 epitopes). Interestingly, 740/821 (90%) peptides with strong binding affinity resulted from IG gene sequence motifs outside the VH/VK/VL CDR3. Most of these peptides (618/821, 75%) resulted from somatic hypermutations (SHM) across the IG variable domain. Overall, 64,993 clonotypes of CD4+ T cells and 14,695 clonotypes of CD8+ T cells were in silico predicted to have strong binding affinity. Importantly, 1697 clonotypes with high binding score were found to be shared between CD4+ T cells of all patients and 222 clonotypes between CD8+ T cells of all patients and, thus, were deemed as public. Summary/Conclusion: The clonotypic IG of MM patients contains a significant number of putative T-cell class I/II neoepitopes, most of which derive from SHM. This implies that the SHM which shapes the MM BcR IG repertoire may produce immunogenic CD4+/CD8+ T cell epitopes. Their actual immunogenicity has to be tested in ex vivo studies, currently underway by our group. Keywords: Antigen-specific T cells, Immunoglobulin, Multiple myeloma, T cell

Background Patients with chronic lymphocytic leukemia (CLL) have a higher risk of developing other malignancies (OMs) compared to the general population. However, the impact of CLL-related risk factors and CLL-directed treatment is still unclear and represents the focus of this work. Methods We conducted a retrospective international multicenter study to assess the incidence of OMs and detect potential risk factors in 19,705 patients with CLL, small lymphocytic lymphoma, or high-count CLL-like monoclonal B-cell lymphocytosis, diagnosed between 2000 and 2016. Data collection took place between October 2020 and March 2022. Findings In 129,254 years of follow-up after CLL diagnosis, 3513 OMs were diagnosed (27.2 OMs/1000 person-years). The most common hematological OMs were Richter transformation, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Non-melanoma skin (NMSC) and prostate cancers were the most common solid tumors (STs). The only predictor for MDS and AML development was treatment with fludarabine and cyclophosphamide with/without rituximab (FC +/- R) (OR = 3.7; 95% CI = 2.79-4.91; p < 0.001). STs were more frequent in males and patients with unmutated immunoglobulin heavy variable genes (OR = 1.77; 95% CI = 1.49-2.11; p < 0.001/OR = 1.89; 95% CI = 1.6-2.24; p < 0.001). CLL-directed treatment was associated with non-melanoma skin and prostate cancers (OR = 1.8; 95% CI = 1.36-2.41; p < 0.001/OR = 2.11; 95% CI = 1.12-3.97; p = 0.021). In contrast, breast cancers were more frequent in untreated patients (OR = 0.17; 95% CI = 0.08-0.33; p < 0.001). Patients with CLL and an OM had inferior overall survival (OS) than those without. AML and MDS conferred the worst OS (p < 0.001). Interpretation OMs in CLL impact on OS. Treatment for CLL increased the risk for AML/MDS, prostate cancer, and NMSC. FCR was associated with increased risk for AML/MDS.

In this retrospective international multicenter study, we describe the clinical characteristics and outcomes of patients with chronic lymphocytic leukemia (CLL) and related disorders (small lymphocytic lymphoma and high-count monoclonal B lymphocytosis) infected by SARS-CoV-2, including the development of post-COVID condition. Data from 1540 patients with CLL infected by SARS-CoV-2 from January 2020 to May 2022 were included in the analysis and assigned to four phases based on cases disposition and SARS-CoV-2 variants emergence. Post-COVID condition was defined according to the WHO criteria. Patients infected during the most recent phases of the pandemic, though carrying a higher comorbidity burden, were less often hospitalized, rarely needed intensive care unit admission, or died compared to patients infected during the initial phases. The 4-month overall survival (OS) improved through the phases, from 68% to 83%, p = .0015. Age, comorbidity, CLL-directed treatment, but not vaccination status, emerged as risk factors for mortality. Among survivors, 6.65% patients had a reinfection, usually milder than the initial one, and 16.5% developed post-COVID condition. The latter was characterized by fatigue, dyspnea, lasting cough, and impaired concentration. Infection severity was the only risk factor for developing post-COVID. The median time to resolution of the post-COVID condition was 4.7 months. OS in patients with CLL improved during the different phases of the pandemic, likely due to the improvement of prophylactic and therapeutic measures against SARS-CoV-2 as well as the emergence of milder variants. However, mortality remained relevant and a significant number of patients developed post-COVID conditions, warranting further investigations.

Mounting evidence suggests that the T cell repertoire in multiple myeloma (MM) is actively shaped by antigen selection. However, the molecular underpinnings of this observation are not fully understood, while relevant studies have been mostly based on immunophenotypic characterization of T cell subsets, with considerably less information regarding T cell receptor (TR) gene repertoire profiles. Moreover, most available information derives from the analysis of a single tissue compartment [i.e. peripheral blood (PB) or bone marrow (BM)], thus hindering addressing the potential impact of local T cell responses. Here we sought to overcome these limitations through paired analysis of PB and BM aspirates of 20 newly diagnosed patients with MM before the administration of any treatment, from whom we isolated the PB and BM mononuclear cell (PBMC/BMMC) fraction, as well as CD4 + and CD8 + T cells. TR beta (TRB) chain gene rearrangements were RT-PCR amplified on RNA extracted from CD4 + and CD8 + T cells and then subjected to paired-end next generation sequencing (NGS). Raw reads (n=14,369,410 | median 179,618/sample) were processed through a purpose-built bioinformatics pipeline. Productive TRBV-TRBD-TRBJ gene rearrangements were taken into consideration (n=9,212,507 | median 115,156/sample) for the computation of clonotypes (i.e. TRB rearrangements with identical TRBV gene usage and amino acid complementarity-determining region 3 sequence). Overall, 1,005,150 TRΒ distinct clonotypes were assessed (median=12,565/sample). Both CD4 + and CD8 + T cell populations displayed skewed TRBV repertoires (7 TRBV genes and 3 TRBJ genes accounting for about ~40% and ~60% of the repertoire) in both BM and PB. All patients displayed oligoclonal T cell expansions in both CD4 + and CD8 + T cells, albeit these were significantly (p<0.001) more pronounced in CD8 + T cells for both BM and PB samples. That said, oligoclonality was more pronounced in BM vs. PB for both CD4 and CD8 T cells, reaching statistical significance in the former: in particular, the median cumulative frequency of the most expanded clonotypes/sample was ~40% higher in CD4 + BM T cells vs. CD4 + PB T cells (p<0.001). Additionally, a significant shift was noticed in the major clonotype repertoire of CD4 + and CD8 + T cells in both PB and BM. In more detail, the 10 most expanded clonotypes/sample in PB had significantly lower frequency in BM, and, vice versa, the 10 most expanded clonotypes in BM were represented at diminished frequency or were absent in the PB in 12/20 patients. Flow cytometry analysis revealed distinct T cell subset composition in CD4 + or CD8 + T cells, also in different tissue compartments (BM vs. PB). Significant (p<0.001) differences concerned the over-representation of: (i) effector T cells (CD45RA +/CCR7 -, Temra) in CD8 + vs. CD4 + T cells in both BM and PB (median frequencies in BM and PB: 22.5% and 7% for CD8 + T cells; 6% and 1.6% for CD4 + T cells); (ii) CD8 + Temra cells in BM vs. PB (median frequencies of 22.5% vs. 7% in BM and PB, respectively; p<0.001); (iii) CD4 + vs. CD8 + central memory T cells (CD45RO +/CCR7 +, Tcm) in both PB and BM (median frequencies in PB and BM: 42.7% and 49.1% for CD4 + Tcm and 14% and 18.8% for CD8 + Tcm); (iv) CD8 + effector memory T cells (CD45RO +/CCR7 -, Tem) in BM vs. PB (median frequencies of 21.8% vs. 2.7% in BM and PB, respectively); (v) CD8 + naïve T cells (CD45RA +/CCR7 +, Tn) in PB vs. BM (median frequencies of 67.7% vs. 24.2% in PB and BM, respectively). In conclusion, oligoclonal expansions of CD4 + and, particularly, CD8 + T cells in MM that are more pronounced in the BM (at least for CD4 + cells) argue for selection by BM-biased antigens, a claim also supported by the significant differences in the relative frequency of dominant clonotypes in BM vs. PB. The distinctive T cell subset distribution in the BM, characterized by a significant increase of effector at the expense of memory T cells, likely reflects an antigen-driven albeit ineffective immune response.

The involvement of the central nervous system (CNS) in Waldenström’s Macroglobulinemia (WM) is a rare extramedullary manifestation of the disease known as Bing-Neel syndrome (BNS). To expand our understanding of this disease manifestation, we conducted a retrospective analysis of the incidence of BNS in 86 consecutive patients with WM [70% male, median age 65 years (range 33-86)] seen in our center during a 30-year period. Six patients (7%) from this group were diagnosed with BNS. The median period of time between WM diagnosis and BNS diagnosis was 6.8 years (range 2.3-15). They demonstrated a range of neurological deficits, including transient expressive aphasia, impaired vision, resting hand tremor, foot drop, and headache. Between the onset of symptoms and the diagnosis of BNS, the median time interval was 12.5 months (range 1-30). The diagnosis was made not on the basis of neurological symptoms or radiological evidence, but on the basis of the presence of WM cells in cerebrospinal fluid (CSF). Intrathecal chemotherapy with methotrexate, cytarabine, and dexamethasone (IT MTX, ARA-C, DEX) was used as front-line treatment, followed by intensive immunochemotherapy with rituximab, high-dose MTX, and ARA-C (R-Hi MTX/ARA-C) in three patients who were fit enough to receive this type of cytotoxic regimen, and rituximab plus bendamustine (R-Benda) in two patients who simultaneously required treatment for WM. Ibrutinib was administered to five patients (three as consolidation and two for initial treatment). All patients responded to front-line treatment, with four (67%) achieving partial response (PR) and two (33%) achieving complete response (CR). This study provides insight into the clinical presentation, diagnostic and treatment options, as well as the outcome of patients who have BNS.

Despite remarkable therapeutic advances in recent years, multiple myeloma (MM) remains incurable, hence representing an unmet clinical need. Therapeutic approaches based on induced T cell anti-tumor immunity towards cancer eradication show promising results in many hematologic malignancies, including multiple myeloma (MM), highlighting the need for comprehensive understanding of the implicated mechanisms. Similar to other mature B cell malignancies, immunoglobulin (IG) gene rearrangements in MM lead to the expression of unique, novel peptide sequences that can be used as neoantigens, conceivably representing a potential attractive target for cancer-specific immune responses. Here we sought to explore this possibility by performing ad hoc prediction of putative T-cell class I/II neoepitopes contained within the MM clonotypic IG gene rearrangements. To that end, we investigated 16 newly diagnosed patients with MM from whom we isolated the peripheral blood and/or bone marrow mononuclear cell (PBMC/BMMC) fraction as well as CD138+ myeloma cells, CD4+ and CD8+ T cells. Clonotypic IG heavy and light chain gene rearrangements were RT-PCR amplified on RNA extracted from the PBMC/BMMC fraction using subgroup-specific leader primers for the IGHV/IGK/LV gene and universal primers annealing to the constant domain (IGHG, IGHM, IGKC, IGLC), in order to produce the full-length V-(D)-J gene rearrangement sequence, plus the start of the constant domain. The corresponding sequences were determined by bidirectional Sanger sequencing. Moreover, T cell receptor beta (TRB) chain gene rearrangements were RT-PCR amplified on RNA extracted from CD4+ and CD8+ T cells and then subjected to paired-end next generation sequencing (NGS). The deduced amino acid sequences of the IG heavy and light chain variable/constant domains were subsequently parsed in peptides and subjected to bioinformatics analysis for the identification of putative T-cell class I/II neoepitopes using the NetMHCpan and NetMHIICpan softwares. The rank score was calculated, considering the 4-digit HLA-A, -B, -C and DRB1 typing for each individual patient. High- and medium-binding peptides (rank score <2%) were selected. Prediction of the binding specificity of T Cell Receptors (TR) to MHC-peptide complexes (pMHCs) was performed by the ERGO-II tool. The rank score was calculated, considering the peptides resulted by NetMHCpan/ NetMHIICpan, the HLA, and the clonotypes for each patient (AUC>0.8). Exact matches to germline and/or proteome databases were excluded. Overall, 757,263 TRΒ distinct clonotypes were assessed (median= 18,244 /sample). All patients displayed oligoclonal T cell expansions in both CD4+ and CD8+ T cells, albeit these were significantly (p<0.001) more pronounced in the latter. Both T cell subpopulations displayed skewed TRBV and TRBJ gene repertoires (7 TRBV genes and 3 TRBJ genes accounting for about 40% and 59% of the repertoire, respectively). Overall, 1,219 predicted neoepitopes were identified. All patients had predicted CD4+ and CD8 + T-cell epitopes within the MM clonotypic IG, either in the heavy chain (16/16 pts, n=459 epitopes) or the light chain (16/16 pts, n=760 epitopes). There was no statistically significant difference in the rank score of peptides involving the complementarity determining region 3 (CDR3) vs. all other IG regions. Interestingly, 998/1,219 (82%) peptides with strong binding affinity resulted from IG gene sequence motifs outside the CDR3. Most of these peptides (853/1,219, 75%) resulted from somatic hypermutations (SHM) across the IG variable domain. Overall, 51,574 clonotypes of CD4+ T cells and 35,751 clonotypes of CD8+ T cells were in silico predicted by ERGO to have strong binding affinity. Relevant to mention, 528 clonotypes with high binding score were found to be shared between CD4+ T cells of all patients and 209 clonotypes between CD8+ T cells of all patients and, thus, were deemed as public. In conclusion, in silico prediction identified a significant number of putative T-cell class I/II neoepitopes contained within the clonotypic IG of MM patients. Many of the identified peptides derive from SHM, implying that the SHM which shapes the MM BcR IG repertoire may produce immunogenic CD4+/CD8+ T cell epitopes. Their actual immunogenicity has to be tested in ex vivo studies, currently underway by our group.

Cardiac amyloidosis (CA) represents a myocardial disorder developed by fibril deposition of a heterogeneous group of misfolding proteins. Despite being rare, a high clinical index of suspicion and novel advanced diagnostic methods seem to facilitate its early recognition. Currently nine types of cardiac amyloidosis have been described with AL and ATTR being the most common. Light chain amyloidosis (AL) is a life-threatening disease, resulting from clonal plasma cells that produce amyloidogenic light chain fragments causing organ damage including the heart. Morbidity and mortality of these patients is strongly associated with the severity of cardiac involvement. Thus, early and precise diagnosis is crucial for prompt treatment initiation. In this study, we retrospectively analyzed data of 36 consecutive patients who were diagnosed with AL amyloidosis and treated in our center over the past 15 years. Heart involvement was present in 33 (92%) of them while 76% had severe cardiac disease as of stage IIIa and IIIb, according to the Mayo2004/European staging system. Almost one third of these patients experienced an early death occurring the first five months of diagnosis. To capture everyday clinical practice, we provide details on clinical presentation, diagnostic challenges, and outcome of these patients.

OBJECTIVE:Cardiomyopathy is a common manifestation of transthyretin amyloidosis (ATTR), leading to heart failure, associated with high morbidity and mortality. The aim of this study was to investigate the effect of Tafamidis treatment by means of cardiac radiotracer uptake on myocardial scintigraphy.SUBJECTS AND METHODS:Five male patients, mean age 76.2 years, with wild-type ATTR were included in the protocol. Total body scanning using technetium-99m-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) (in four patients) and technetium-99m-hydroxymethylene diphosphonate (99mTc-HMDP) (in one) was performed pre- and one year post-Tafamidis therapy. A novel quantitation method for assessing radiotracer cardiac uptake was employed. The geometric mean was computed for both cardiac and thigh region of interest (ROI) and the heart-to-thigh (HtT) ratio was assessed by dividing the corresponding geometric mean counts.RESULTS:Heart-to-thigh ratio was improved (decreased) in four of the patients receiving Tafamidis, in keeping with lower uptake to the cardiac region. These patients also demonstrated a relatively favorable clinical response to Tafamidis. The patient evaluated by 99mTc-HMDP exhibited minimal HtT ratio reduction and stable clinical and echocardiographic characteristics.CONCLUSION:Sequential HtT ratio measurements could potentially identify patients with a favorable response to Tafamidis treatment at earlier stages, compared to other imaging modalities or serological biomarkers.

The use of novel small molecule inhibitors alone or in combination with anti-CD20 monoclonal antibodies for chronic lymphocytic leukemia (CLL) has raised a number of questions on efficacy, tolerability, long-term treatment adherence in patients with heterogeneous clinical features. To fill this gap, we designed a study focusing on treatment sequencing in patients with CLL in order to (i) compare the outcome of patients treated with chemoimmunotherapy (CIT) combinations in first-line versus those receiving Bruton's tyrosine kinase inhibitors (BTKi); (ii) characterize the efficacy and tolerability of venetoclax-based regimens; (ii) understand the impact of treatment sequencing when it comes to chemo-free options including venetoclax after BTKi and vice versa. Data from consecutive sets of patients diagnosed with CLL between 2000-2020 attended at 77 institutions affiliated with ERIC were collected and analyzed. Collected variables included: demographics, clinical stage at diagnosis, IGHV gene somatic hypermutation status; cytogenetic status for chromosomes 11q, 13q 17p and 12 determined by fluorescence in situ hybridization; TP53 gene mutation status; treatment; treatment response; discontinuation; reason for discontinuation; death. We included 9173 patients with a diagnosis of CLL who received at least one line of treatment. The median age at diagnosis was 67 years with a male:female ratio of 1.9. The median follow-up was 78 months (IQR, 48-120 months). Regarding novel targeted agents, 1860/9173 (20.2%) patients had received at least one line of treatment with BTKi (ibrutinib, n=1788; acalabrutinib, n=72) over the disease course; 631/9173 (6.9%) with venetoclax; and, 447/9173 (4.9%) with the PI3K inhibitor idelalisib. Seventy-nine patients were treated with both BTKi and venetoclax (59 BTKi followed by BCL2i, 20 vice versa). At last follow-up, 5870/9173 patients (64.0%) were alive, 3229/9173 (35.2%) died and 74/9173 (0.8%) were lost to follow-up. Patients treated with BTKi in first-line were enriched for TP53 aberrations [del(17p) 27.6%, TP53 mutation 26.3%] and unmutated IGHV genes (69%) and obtained an ORR of 87.7%. Of these, 136 (26.3%) discontinued treatment after a median of 1.2 years (0.07-5.98); main reasons of discontinuation were toxicity (40.5%) and failure (26.2%). Among 631 patients treated with venetoclax at any line, 100 (15.8%) received BCL2 +/- anti-CD20 as first-line; 170 (26.9%) as second line (125 previously treated with CIT, 27 with BTKi); and, 361 as third or subsequent line. ORR ranged between 71.5% (≥3 lines) with 30.5% CR/CRi to 90.3% (first-line) with 68.1% CR/CRi. Treatment discontinuation was due to toxicity in 28.6% of patients treated in the first-line, and 17.6% and 21.8% of patients treated in second and third-or-higher-line, respectively. Disease progression led to treatment discontinuation in 14.3%, 20.6% and 33.6% in first, second and third-or-higher line, respectively. CIT was used as front-line treatment in 5465 patients (59.6%). Of these, 2070 (37.9%) and 1018 (18.6%) patients received a second and third line of treatment, respectively. The great majority (865/1086 cases, 79.7%) of patients who received a second line before 2014 were retreated with CIT, most commonly Bendamustine-Rituximab (284/1086, 26.1%) and Fludarabine-Cyclophosphamide-Rituximab (252/1086, 23.2%); alemtuzumab monotherapy was used in 55/1086 (5%) of patients. After 2014, 415/984 patients (42.1%) were retreated with BTKi; 93 (9.5%) with venetoclax; 70 (7.2%) with idelalisib; 50 (5%) with Alemtuzumab monotherapy, and 315 (32%) with CIT. Similarly, in the third-or-higher line of treatment, most patients (86.3%) were retreated with CIT before 2014, while BTKi, BCL2i, and PI3Ki were mainly used after 2014 (in 43.1%, 15.7% and 14.7% of cases, respectively). Finally, our cohort included 1075 patients with TP53 aberrations. The ORR of patients receiving BTKis (n=171) as first-line of treatment was 86.5% (22.2 CR+64.3 PR), while the ORR with venetoclax +/- anti-CD20 (n=15) was 91% (45.5% CR+45.5 PR). Patients treated with CIT (n=694) had an ORR of 68.7% (28.3% CR+40.4% PR). In conclusion, in a large international study we provide real world data regarding the selection and sequencing of treatment in CLL, charting a major shift in treatment patterns before and after the introduction of novel trargeted agents and confirming their efficacy even in high-risk CLL.

Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to Coronavirus disease 2019 (COVID-19) due to age, disease, and treatment-related immunosuppression. We aimed to assess risk factors of outcome and elucidate the impact of CLL-directed treatments on the course of COVID-19. We conducted a retrospective, international study, collectively including 941 patients with CLL and confirmed COVID-19. Data from the beginning of the pandemic until March 16, 2021, were collected from 91 centers. The risk factors of case fatality rate (CFR), disease severity, and overall survival (OS) were investigated. OS analysis was restricted to patients with severe COVID-19 (definition: hospitalization with need of oxygen or admission into an intensive care unit). CFR in patients with severe COVID-19 was 38.4%. OS was inferior for patients in all treatment categories compared to untreated ( p < 0.001). Untreated patients had a lower risk of death (HR = 0.54, 95% CI:0.41–0.72). The risk of death was higher for older patients and those suffering from cardiac failure (HR = 1.03, 95% CI:1.02–1.04; HR = 1.79, 95% CI:1.04–3.07, respectively). Age, CLL-directed treatment, and cardiac failure were significant risk factors of OS. Untreated patients had a better chance of survival than those on treatment or recently treated.

Transplant‐ineligible relapsed/refractory (rr) diffuse large B‐cell lymphoma (DLBCL) patients represent an unmet medical need. Polatuzumab vedotin (Pola), an anti‐CD79b antibody‐drug‐conjugate (ADG), with bendamustine‐ rituximab(BR) has recently gained approval for these patients, both in the USA and Europe, based on the GO29365 phase IIb trial. Real‐life data with Pola are extremely limited. We report the outcomes of 61 Greek patients, who received Pola‐(B)R mainly within a compassionate use program. Treatment was given for up to six 21‐day cycles. Bendamustine was omitted in three cases due to previous short‐lived responses. Fourty‐nine rrDLBCL(efficacy cohort‐EC) and 58 rr aggressive B‐NHL (safety cohort‐SC) patients received at least 1 Pola‐BR cycle. Twenty‐one (43%) patients of the EC responded with 12/49 (25%) CR and 9/49 (18%) PR as best response. Median progression–free survival, overall survival and duration of response were 4.0, 8.5, and 8.5 months respectively, while 55% of patients experienced a grade ≥3 adverse event, mainly hematologic. Treatment discontinuations and death during treatment were mainly due to disease progression. Twenty‐two (41%) patients received further treatment; 11/22 are still alive, including one after CAR‐T cells, and two after stem cell transplantation. Our data confirm that Pola‐BR is a promising treatment for rrDLBCL patients, inducing an adequate response rate with acceptable toxicity. Pola‐BR could be used as bridging therapy before further consolidative treatments.

Background - Objectives: Primary Bone non-Hodgkin's Lymphoma (PB-NHL) is a rare disease and constitutes about 3% of the total NHL patient population. We estimated the prevalence of this type of lymphoma in the local lymphoma registry of Western Greece and retrospectively analyzed 102 cases, in an effort to describe the clinical, histological and prognostic features of this tumor. Patients and Methods: Among 1225 patients (pts) with all types of NHL, diagnosed between 1.1.1991 and 31.12.2018 in the area of Western Greece, 32 (2.6%) had PB-NHL. We analyzed the data of these 32 pts, together with those of additional 70 pts, treated in 7 large Hematology Departments in Greece. Pts were 60 males and 42 females (♂/♀ ratio 1.43) with a median age of 62 years (range 20-93 years) and 55% of them were <65 years at initial diagnosis. Systemic treatment was offered in 97 pts; one elderly patient received only radiotherapy. Anthracycline-based chemotherapy was given in 94 pts (96.9%) and 39 of them (40.2%) received also local/adjuvant radiotherapy. A total of 79 pts received rituximab with chemotherapy (78%). Results: In 81 pts (79.4%) the disease presented with local symptoms only, in 4 (3.9%) with systemic/constitutional symptoms, and in the remaining 17 (16.7%), with both, local and constitutional symptoms. The mainly affected bones were pelvis (iliac-pubertal-sacral, 23 pts), femur (15), lumbar vertebrae (14), thoracic vertebrae (12), mandible, humerus and tibia (7 each), ribs/sternum (5), skull, clavicle and scapula (3 each), maxilla (2) and patella (1). The most common histological type was Diffuse Large B-cell Lymphoma Not Otherwise Specified (DLBCL-NOS: 92 pts), followed by Ki-1+ anaplastic (3), small lymphocytic (3), mantle cell (3) and follicular lymphoma (1). A B-cell phenotype was revealed in 99 cases and non-B/non-T cell CD30+ in 3. One bone site was affected in 68 pts (66.7%), alone in 25, with contiguous extranodal or lateral nodal involvement in 23, and with one additional non-contiguous extranodal or distal nodal involvement in 20. Two bone sites with or without additional nodal or extranodal involvement was found in 12 pts and multiple bone sites with or without additional nodal or extranodal involvement in the remaining 22 pts. Ann-Arbor stage was early (I-II) in 51 pts and advanced (III-IV) in 51, B-symptoms were present in 21 pts (20.6%) and the marrow was involved in 20/87 pts (23%). Anemia was present in 33 pts, leukocytosis in 14, neutrophilia in 22, thrombocytosis in 15 and symptomatic hypercalcemia in 1 patient. Elevated serum LDH was found in 60/101 pts (59.4%), CRP in 35/55 pts (63.6%), alkaline phosphatase in 20/69 pts (29%) and beta2-microglobulin in 24/60 pts (40%). Six out of 51 pts (11.8%) were HBsAg(+), 1/51 anti-HCV(+) and 1/55 anti-HIV(+). Active treatment was administered in 97 pts, which was chemoimmunotherapy (Ch-Im) alone in 58, combined modality [Ch-Im + Radiotherapy (Rx)] in 38 and Rx alone in 1. Anthracycline-based regimens were administered in 93 pts. Five pts were not evaluable for response (lost from follow-up N=4, still on treatment N=1). Seventy-three pts achieved a CR (79.3% or 75.3% on an intention to treat basis) and treatment failed in 20 (20.6%). The median DFS was 29.5 months. Survival analysis was restricted to DLBCL pts who received Ch-Im: After a median follow-up of 33 months (range, 1-207) 58/76 pts were still alive for a 5-year OS of 71%. The 5-year progression free survival (PFS) was 59%. No survival benefit in terms of PFS and OS was found among pts, who received adjuvant Rx compared to pts who received Ch-Im alone, p=0.40). Age >60 yrs, PS ≥2, elevated LDH and tumor burden were all predictive of PFS and OS in univariate analysis. Ann Arbor stage III/IV had only borderline significance restricted on PFS. Only LDH (p=0.04) and tumor burden (intermediate and high versus low; p=0.07) were independent predictors of PFS in backward stepwise multivariate analysis. LDH and poor PS were the only potential independent predictors of OS in multivariate analysis but both had borderline significance. Discussion and Conclusive remarks: PB-NHL is a rare aggressive lymphoma subtype, with a main histology of DLBCL-NOS, which responds favorably to anthracycline-based Ch-Im and response rates are similar to other nodal and extranodal aggressive lymphomas. Radiotherapy appears not to add on survival and should only be used for local palliation. Disclosures Symeonidis: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Pappa:Gilead: Honoraria, Research Funding; Amgen: Research Funding; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Angelopoulou:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene / GenesiaPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hatzimichael:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zikos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Terpos:Genesis: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Janssen: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria. Pangalis:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vassilakopoulos:WinMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.