Abstract: Primary splenic diffuse large B‐cell lymphoma generally presents with abdominal pain, high lactose dehydrogenase levels, and a splenic mass. Splenectomy at diagnosis improves progression‐free and overall survival for patients with early‐stage disease.

Abstract: Patients with chronic lymphocytic leukemia (CLL) have a suboptimal humoral response to vaccination. Recently, BNT162b2, an mRNA COVID-19 vaccine with a high efficacy of 95% in immunocompetent individuals, was introduced. We investigated the safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with CLL from nine medical centers in Israel, Overall 400 patients were included, of whom 373 were found to be eligible for the analysis of antibody response. The vaccine appeared to be safe and only grade 1-2 adverse events were seen in 50% of the patients. Following the second dose, an antibody response was detected in 43% of the cohort. Among these CLL patients, 61% of the treatment-na ve patients responded to the vaccine, while responses developed in only 18% of those with ongoing disease, 37% of those previously treated with a BTK inhibitor and 5% of those recently given an anti-CD20 antibody. Among patients treated with BCL2 as monotherapy or in combination with anti-CD20, 62% and 14%, respectively, developed an immune response. There was a high concordance between neutralizing antibodies and positive serological response to spike protein. Based on our findings we developed a simple seven-factor score including timing of any treatment with anti-CD20, age, treatment status, and IgG, IgA, IgM and hemoglobin levels. The sum of all the above parameters can serve as a possible estimate to predict whether a given CLL patient will develop sufficient antibodies. In conclusion, the BNT162b2 mRNA COVID-19 vaccine was found to be safe in patients with CLL, but its efficacy is limited, particularly in treated patients.

Abstract: The incidence of systemic diffuse large B cell lymphoma (DLBCL) concurrently involving the central nervous system (CNS) at diagnosis, is very low and data regarding the clinical course of these patients are scarce. We investigated characteristics, efficacy of treatment regimens including consolidative autologous stem cell transplantation and outcome of patients presenting with concomitant systemic and CNS DLBCL. The records of 44 patients, diagnosed between 2004 and 2017, who fulfilled the inclusion criteria, were retrospectively reviewed. CNS involvement was diagnosed as solely parenchymal in 41%, solely leptomeningeal in 43%, and paranchymal with leptomeningeal in 11% of the patients. Induction regimens were anthracycline‐based combined with high‐dose methotrexate (HD‐MTX) in 80% (n = 35) of patients, anthracycline‐based combined with intrathecal MTX in 3, cytarabine‐based (without antracyclines) in 2, HD‐MTX in 1 and palliative in three. Five of 41 patients treated with chemotherapy died of treatment‐related toxicity, all due to infections. Nineteen patients had consolidative autologous transplantation. Overall response rate following induction was 80% (complete responses 66% and partial responses 15%). All relapses (n = 11) occurred within less than 2 years. Within a median follow‐up of 26.8 months, 3‐years projected overall survival (OS) and progression free survival rates for the entire cohort were 56% ± 8.3 and 42% ± 8.9, respectively. In multivariate analysis, RCHOP‐HD MTX‐based induction [HR = 0.228, (0.054‐0.964)], administration of 3.5 g/m 2 MTX [HR = 0.735 (0.620‐0.871)], and attaining CR following induction [HR = 0.185, (0.051‐0.667)] predicted longer OS. RCHOP‐HD MTX can provide prolonged remissions in DLBCL patients presenting with concomitant systemic and CNS involvement whereas role of autograft remains uncertain.

Abstract: Richter's syndrome (RS) is the rare development of an aggressive lymphoid malignancy in a patient with pre-existing, or concomitant chronic lymphocytic leukemia (CLL). This complication occurs in about 5 % of patients with CLL, and the most frequent form is the development of diffuse large B-cell lymphoma (DLBCL) and less frequently Hodgkin lymphoma (HL) or prolymphocytic leukemia (PLL). Most of the available data on RS is derived from case reports or small series of patients, and only a few larger cohorts have been published. Aim The purpose of this retrospective study was to summarize our experience with RS in CLL, examine possible risk factors and analyze relevant demographic, laboratory and clinical parameters, including outcome. Methods We collected a total of 119 patients diagnosed with RS from 12 medical centers in Israel during the period 1971-2010.We then summarized clinical, demographic and some biological features related to CLL at diagnosis and examined possible risk factors for their transformation to RS. Results Of the 119 patients with RS, 61 % were males, 82% developed DLBCL, 14% HL and 4% PLL. In terms of ethnicity: 95% were Jews (64% Ashkenazi) and only 5 % were Arabs, which is similar to the reported data for CLL in Israel. The median time from CLL diagnosis to development of RS was 60 months (range, 0-182 months), and the median overall survival from diagnosis of RS was 9.5 months;34 % of the cases developed extranodal RS, and the most frequent sites of involvement were the gastro-intestinal tract and bone marrow. These results further confirm that there are no established “sanctuary sites” of extranodal RS, which can develop in all tissues and organs. None of the conventional clinical and laboratory parameters examined and evaluated as possible risk factors in CLL were able to predict transformation to RS, including: occurrence of autoimmune phenomenon during the course of CLL, spleen size, serum beta 2 microglobulin levels, degree of CD38 positivity, and the number of previous treatments given for CLL, or the prior use of rituximab in these regimens. The only parameters, present at the time of RS diagnosis which were found to correlate with adverse prognosis, included: performance status 〉 2 (HR- 3.45), high IPI (HR- 3.28) and high Richter score (HR-7.45). In regard to therapy for RS, patients treated with chemotherapy followed by autologous stem cell transplantation (ASCT) had a better outcome with improved overall survival (p=0.034) (Figure). Conclusions RS remains a heterogeneous entity. In this large series of patients none of the conventional clinical, epidemiological or laboratory parameters, often evaluated as possible prognostic factors in CLL, were associated with the risk of transformation to RS. In this retrospective study molecular genetic data were not available to examine their possible significance, as reported recently in other series. In terms of therapy, prior treatment of CLL with rituximab – containing regimens did not appear to impact the eventual outcome of patients who developed RS. On the other hand, ASCT did significantly improve overall survival in patients who had transformation to RS. On behalf the Israeli CLL study Group. Disclosures: No relevant conflicts of interest to declare.

Abstract: Introduction: Although the spleen is involved in about a third of patients with non-Hodgkin's lymphoma (NHL), primary splenic diffuse large B-cell lymphoma (PS-DLBCL) is rare having a reported incidence of less than 1% of all NHL. Most of the described series include small numbers of patients before the rituximab era and the role of splenectomy treatment in addition to immuno-chemotherapy is unknown. Methods: Data were retrospectively collected for 87 patients (pts) with PS-DLBCL treated in 7 medical centers in Israel during the years 1982-2013. Patients presenting with systemic disease with splenic involvement or those having a diagnostic biopsy from other nodal or extranodal disease were excluded. Results: The mean age was 59.6 years (range, 24-89 years); 57.5% were male. Abdominal pain was reported in 61 pts (81%), B symptoms in 49 pts (59%), ECOG performance status 0 - 1 in 85%. Stage I disease was recorded in 28%, II in 33%, III in 18%, and IV in 21%. Thrombocytopenia ( 〈 100,000/µl) was recorded in only 6 pts. Lactic dehydrogenase levels (LDH) were elevated in 69 pts (84%). Favorable International Prognostic Index (IPI) 0-2 was recorded in 62 pts (72%). The mean splenic length was 17.34±6 cm (range 7- 37 cm) and the mean splenic weight was 1216 gm±1243 gm (range 180-6000 gm). A splenic mass was found in 97% of pts, and its mean size was 9.26 cm (range 3-18 cm). The diagnostic procedure was core needle biopsy in 46 pts and splenectomy in 39 pts: 27 underwent open splenectomy and 12 laparoscopic splenectomy. Splenectomized pts had lower IPI (p 〈 0.05) and lower stage (p 〈 0.05) compared to non-splenectomized pts. Treatment: The CHOP regimen was given to 80 pts (92%), DA-EPOCH was given to 2 pts (2%) and 5 pts (6%) received other regimens. Rituximab was given to 68 pts (78%). Complete response was achieved in 67 pts (80%) and partial response in 8 (9%). Relapse occurred in 17 pts (22%). Survival: The median follow-up time was 7 years (range 0-19.4 years). During this period 24 pts died (27.5%). The 5-year overall survival (OS) was 76.6±4.9% and 5-year event-free survival (EFS) 67.2±5.5%. Splenectomy at diagnosis improved survival: the 5-year EFS was 85.4±6% and 54.7±8% for splenectomized and non-splenectomized pts respectively (p=0.02) and the 5-year OS was 91.2±5% and 67.9±7% respectively (p=0.08). For the 53 pts with stage I-II disease, both 5-year EFS and OS were better in the splenectomized pts (p 〈 0.02, Fig 1). The 5-year EFS and OS in pts with stage I and II disease that were splenectomized at diagnosis was 89.6±6% and 96.4±3.5% as compared with 50.5±11% and 63.2±11% in pts who were not splenectomized (p=0.012 and 0.009). The EFS and OS were not influenced by the stage of the disease. Overall survival was associated with B symptoms (p=0.02), weight loss (p=0.04) and ECOG performance status (p=0.03). In a multivariate model, low ECOG PS and splenectomy independently predicted a better EFS (p=0.03 and 0.02 respectively), however for OS, low ECOG PS independently predicted better OS (p=0.03), while splenectomy had only marginal effect on the OS (p=0.056). Conclusions: In our group of pts, PS-DLBCL generally presented with abdominal pain, high LDH and a splenic mass. We demonstrate for the first time that splenectomy at diagnosis improves survival in early stages of PS-DLBCL. Our study is a retrospective one. Therefore, until prospective studies prove that early splenectomy in PS-DLBCL is beneficial in terms of overall survival, the risk and benefit of performing splenectomy should be weighed for each patient. Fig 1: (A) Event-free survival and (B) Overall survival in patients with primary splenic DLBCL and stages I - II disease who did or did not undergo splenectomy at diagnosis. Fig 1:. (A) Event-free survival and (B) Overall survival in patients with primary splenic DLBCL and stages I - II disease who did or did not undergo splenectomy at diagnosis. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Abstract: Introduction: In previously untreated patients with chronic lymphocytic leukemia (CLL), treatment with ibrutinib plus rituximab improved progression-free survival (PFS) and overall survival (OS) compared to the standard fludarabine, cyclophosphamide and rituximab (FCR) chemoimmunotherapeutic regimen, based on the results of the phase III ECOG-E1912 trial. The improvement in PFS with ibrutinib plus rituximab was observed in patients with unmutated immunoglobulin heavy chain variable region gene (IGHV) but not in those with an IGHV mutated profile. However, the efficacy of ibrutinib compared to FCR has not yet been investigated in the real-world setting. Methods: A multi-center retrospective "real-world" study to compare the efficacy of front-line ibrutinib monotherapy versus standard FCR in patients with CLL. Demographic and clinical data of the FCR cohort were retrieved from the Israeli CLL Study Group database and of the ibrutinib from the Italian multicenter "Campus CLL" network and the CLL database of the department of hematology at the Sourasky Medical Center. Patients with a documented del(17p) or those who are participating in clinical trials were excluded. In order to fit both treatment samples, the maximum follow-up was censored at 48 months. IBM SPSS Statistics was used to analyze PFS and OS by Kaplan Meier Estimator, Log-Rank test and Cox Regression. In order to control for differences in patients' characteristics, the inverse probability of treatment weighting (IPTW) method with stabilized weights and truncation of 5% extreme score was applied by R. Results: A total of 235 patients who had been front-line treated with either FCR (n=136, 57.9%) or ibrutinib (n=99, 42.1%) were included (Table 1). Most patients were males (n=160, 68.1%), had an unmutated IGHV status (n=115, 70.6%) and were Binet stage B/C (n=191, 83.8%). By FISH, the most frequent abnormality was del(11q) (n=45, 23.1%) followed by trisomy12 (n=34, 17.4%) and del(13q) (n=43, 22.1%). Median time to first treatment was 29.4 months (IQR, 11.9-56.2), and it was not significantly different between ibrutinib (median=24.9 months, IQR 10.3-46.6) and FCR (median=34.0 months, IQR 13.8-60.1; p=0.101). Patients treated with FCR were younger than those treated with ibrutinib (median=58.4 years vs. 71.9 years; p & lt;0.001). The median follow-up for the entire cohort was 48.0 months (37.2 months and 48 months for ibrutinib and FCR, respectively). PFS was longer with ibrutinib than with FCR, with a 3-year rate of PFS of 89.7% vs. 65.8%, respectively (HR=3.5, 95% CI [1.8-6.9], p & lt;0.001) (Figure 1). By subgroup analysis, the PFS benefit with ibrutinib over FCR was maintained in the subgroups of patients age & gt;65 years (n=100, 3-year PFS 89.4% vs. 53.1%; HR=3.9, 95% CI [1.6-9.9], p=0.002), Binet stage B/C (3-year PFS: 90.5% vs. 67.8%; HR=3.5, 95% CI [1.7-7.5] , p & lt;0.001) and unmutated IGHV (3-year PFS: 83.0% vs. 78.0%; HR=5.8, 95% CI [2.4-14.5], p & lt;0.001). Among mutated IGHV patients the PFS was not significantly different between ibrutinib and FCR (3-year PFS: 83.0% vs. 78.0%; HR=1.2, 95% CI [0.3, 4.5]; P=0.795). In multivariate analysis (Table 2), only FCR was an independent predictor of decreased PFS (HR=5.1, 95% CI [1.8, 14.3] , p=0.002). OS was also better with ibrutinib than with FCR, with a 3-year OS of 96.8% vs. 87.5%, respectively (HR=3.52, 95% CI [1.04-11.92], p=0.031) (Figure 2). Using IPTW, both PFS and OS were still superior with ibrutinib compared to FCR (HR=0.2, 95% CI 0.1-0.5, p & lt;0.001 and HR=0.2, 95% CI [0.1-0.7], p=0.008, respectively). Conclusions: In a real-world setting, front-line treatment with ibrutinib improves PFS and OS in patients with CLL. Similar to the results of the phase III ECOG-E1912 trial, the improvement in PFS was preferentially observed in patients with unmutated IGHV. Figure 1 Figure 1. Disclosures Herishanu: AbbVie: Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria; Medison: Honoraria. Goldschmidt: AbbVie: Consultancy, Research Funding. Fineman: AbbVie: Research Funding. Mauro: Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Speakers Bureau; Astra Zeneca: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Tskeda: Consultancy, Honoraria. Reda: Abbvie: Consultancy; Astra Zeneca: Consultancy; Beigene: Consultancy; Janssen: Consultancy. Ruchlemer: AbbVie: Consultancy, Honoraria, Research Funding. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Laurenti: AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Honoraria; Roche: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; BeiGene: Honoraria. Shvidel: AbbVie: Honoraria, Research Funding. Coscia: Janssen: Honoraria, Other, Research Funding; Gilead: Honoraria; AbbVie: Honoraria, Other; AstraZeneca: Honoraria. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Varettoni: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; beigene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; roche: Membership on an entity's Board of Directors or advisory committees. Aviv: AbbVie: Honoraria, Research Funding. Murru: Abbvie: Consultancy, Honoraria, Other: travel and accommodation; Janssen: Consultancy, Honoraria. Rossi: Abbvie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Verastem: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Cellestia: Honoraria, Research Funding. Gaidano: Incyte: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cuneo: AbbVie: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Gattei: abbVie: Research Funding; Janssen: Research Funding; Menarini: Research Funding.

Abstract: Primary central nervous system lymphoma (PCNSL) is a rare disease with an incidence of 0.4/per 100,000 person‐years. As there is a limited number of prospective randomized trials in PCNSL, large retrospective studies on this rare disease may yield information that might prove useful for the future design of randomized clinical trials. We retrospectively analyzed the data of 222 newly diagnosed PCNSL patients treated in five referral centers in Israel between 2001 and 2020. During this period, combination therapy became the treatment of choice, rituximab has been added to the induction therapy, and consolidation with irradiation was largely laid off and was mostly replaced by high‐dose chemotherapy with or without autologous stem cell transplantation (HDC‐ASCT). Patients older than 60 comprised 67.5% of the study population. First‐line treatment included high‐dose methotrexate (HD‐MTX) in 94% of patients with a median MTX dose of 3.5 g/m 2 (range 1.14–6 g/m 2 ) and a median cycle number of 5 (range 1–16). Rituximab was given to 136 patients (61%) and consolidation treatment to 124 patients (58%). Patients treated after 2012 received significantly more treatment with HD‐MTX and rituximab, more consolidation treatments, and autologous stem cell transplantation. The overall response rate was 85% and the complete response (CR)/unconfirmed CR rate was 62.1%. After a median follow‐up of 24 months, the median progression‐free survival (PFS) and overall survival (OS) were 21.9 and 43.5 months respectively with a significant improvement since 2012 (PFS: 12.5 vs. 34.2 p  = 0.006 and OS: 19.9 vs. 77.3 p  = 0.0003). A multivariate analysis found that the most important factors related to OS were obtaining a CR followed by rituximab treatment and Eastern Cooperative Oncology Group performance status. The observed improvement in outcomes may be due to multiple components such as an intention to treat all patients regardless of age with HD‐MTX‐based combination chemotherapy, treatment in dedicated centers, and more aggressive consolidation with the introduction of HDC‐ASCT.

Abstract: Decreased absolute lymphocyte counts (ALCs) following frontline therapy for chronic lymphocytic leukemia may be associated with disease control, even in patients without evidence of minimal residual disease. We studied the prognostic significance of ALCs during the first year following treatment with fludarabine, cyclophosphamide, and rituximab (FCR). We evaluated 99 patients who achieved a partial response without lymphocytosis ( 〈 4.0 × 10 3 cells/μL) or better after FCR. Absolute lymphocyte counts were recorded at 3‐, 6‐, 9‐, and 12‐month posttreatment and correlated with overall survival (OS) and event‐free survival (EFS). For each time point, analyses were limited to patients without lymphocytosis, so as to avoid possible biases from undocumented disease progressions. Lymphopenia (ALC  〈  1.0 × 10 3 cells/μL) at 3 m after FCR (69% of patients n = 68), was associated with a longer OS (5y OS 91% vs 64%, P  = .001), as were ALC ≤ 2 × 10 3 cells/μL at 6 m (5y OS 85% vs 48%, P  = .004) and ALC ≤ 1.8 × 10 3 cells/μL at 9 m (5y OS 93% vs 54%, P  = .009). A normal‐range ALC (≤4 × 10 3 cells/μL) at 12 m was also associated with a 91% 5y OS. Higher ALCs (but without lymphocytosis) were associated with shorter EFS (median EFS 27 months for ALC  〉  1.8 vs not reached for ALC ≤ 0.7 at 9 months, P   〈  .0001). In conclusion, lower ALC levels in the first few months following frontline FCR therapy were associated with longer OS and EFS. Possible explanations may be that lower ALCs reflect deeper clonal suppression or protracted T reg depletion. Absolute lymphocyte count levels may be a cheap and widely available prognostic marker, though the added value for clinical practice is the minimal residual disease era needs to be explored.