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Elotuzumab plus lenalidomide and dexamethasone has shown improved progression-free and overall survival versus lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. We aimed to assess these regimens in patients with newly diagnosed multiple myeloma who are ineligible for haematopoietic stem-cell transplantation (HSCT).

Differential diagnosis between diffuse large B‐cell lymphoma (DLBCL) and follicular lymphoma (FL) becomes a challenge when adequate biopsy is unavailable. The present study aimed to investigate the applicability of DNA cell cycle analysis by flow cytometry (FC) for differentiating between CD10+DLBCL and FL. Data were collected from 57 specimens where CD5−/CD10+/light chain restricted B cells were detected. DNA staining was performed using the Coulter DNA Prep Kit. Cell cycle fractions were evaluated by automatic analysis using the ModFit LT software. Histopathological analysis confirmed the diagnosis of CD10+FL in 30 specimens (52.6%), CD10+DLBCL in 24 specimens (42.1%), and CD10+Burkitt lymphoma in 3 specimens (5.3%). A significantly higher rate of DNA aneuploidy was detected among CD10+DLBCL than FL specimens (50 vs. 13.3% respectively, p= .003). Likewise, DNA index was significantly higher in CD10+DLBCL relative to FL (1.26 ± 0.35 vs. 1.04 ± 0.16 respectively, p= .004). Notably, the proportion of cells in the S‐phase and proliferative fraction was significantly higher in CD10+DLBCL than in CD10+FL (S‐phase: 15.97 ± 13.94 vs. 4.43 ± 4.41 mean ± SD, respectively, p< .0001; proliferative fraction: 18.87 ± 15.17 vs. 5.78 ± 7.04 mean ± SD, respectively, p= .0001). Using a receiver operating characteristic analysis, optimal cutoffs for S‐phase ≥7% and proliferative fraction ≥9% were determined. These values could be used to differentiate between CD10+DLBCL and CD10+FL. Including DNA cell cycle analysis in the FC lymphoma assessment panel may be of diagnostic value in differentiating between CD10+ DLBCL and FL when adequate biopsy is unavailable.

Epstein-Barr virus (EBV) is associated with a variety of tumors and nonmalignant conditions. Latent EBV genomes in cells, including tumor cells, are often CpG methylated, whereas virion DNA is not CpG methylated. We demonstrate that methyl CpG binding magnetic beads can be used to fractionate among sources of EBV DNA (DNA extracted from laboratory-purified virions vs DNA extracted from latently infected cell lines). We then applied the technique to plasma specimens and showed that this technique can distinguish EBV DNA from patients with EBV-associated tumors (nasopharyngeal carcinoma, Hodgkin lymphoma) and viral DNA from patients without EBV-associated tumors, including immunocompromised patients and patients with EBV(−) Hodgkin lymphoma.

Epstein-Barr virus (EBV) is associated with a variety of tumors and nonmalignant conditions. Latent EBV genomes in cells, including tumor cells, are often CpG methylated, whereas virion DNA is not CpG methylated. We demonstrate that methyl CpG binding magnetic beads can be used to fractionate among sources of EBV DNA (DNA extracted from laboratory-purified virions vs DNA extracted from latently infected cell lines). We then applied the technique to plasma specimens and showed that this technique can distinguish EBV DNA from patients with EBV-associated tumors (nasopharyngeal carcinoma, Hodgkin lymphoma) and viral DNA from patients without EBV-associated tumors, including immunocompromised patients and patients with EBV(−) Hodgkin lymphoma.

High-dose cytarabine is the backbone of acute myeloid leukemia (AML) treatment. Nevertheless, its use in older patients is considerably limited due to increased toxicity. BST-236 (INN aspacytarabine) is a novel cytarabine prodrug designed to deliver high-dose cytarabine to target cells with reduced systemic exposure to free cytarabine. This phase 1/2a dose-escalation study was designed to evaluate BST-236 safety, pharmacokinetics, and efficacy in older or unfit-for-intensive-therapy patients with acute leukemia. Twenty-six patients, unfit for standard therapy, who were either relapsed/refractory or newly diagnosed, received BST-236 in 6 dose-escalating cohorts (range 0.3 to 6 g/m2 per day). BST-236 was administered intravenously once daily over 60 minutes for 6 consecutive days. The median age was 76.5 (26 to 90), with 84.6% of patients ≥70 years. BST-236 was safe and well tolerated. The maximal tolerated dose was 6 g/m2 per day. Overall response rate was 29.6%. A subgroup analysis of newly diagnosed patients with AML, de novo or secondary to myelodysplastic syndrome, unfit for standard induction (median age 78), demonstrated overall response of 45.5%. The median overall survival was 6.5 months and was not reached in patients achieving complete remission. The findings of this phase 1/2 study suggest that BST-236 safely delivers high and efficacious cytarabine doses to older patients who are unfit for standard induction and lays the foundation for further studies of BST-236 in AML. This trial was registered at www.clinicaltrials.gov as #NCT02544438.

High-dose cytarabine is the backbone of acute myeloid leukemia (AML) treatment. Nevertheless, its use in older patients is considerably limited due to increased toxicity. BST-236 (INN aspacytarabine) is a novel cytarabine prodrug designed to deliver high-dose cytarabine to target cells with reduced systemic exposure to free cytarabine. This phase 1/2a dose-escalation study was designed to evaluate BST-236 safety, pharmacokinetics, and efficacy in older or unfit-for-intensive-therapy patients with acute leukemia. Twenty-six patients, unfit for standard therapy, who were either relapsed/refractory or newly diagnosed, received BST-236 in 6 dose-escalating cohorts (range 0.3 to 6 g/m2per day). BST-236 was administered intravenously once daily over 60 minutes for 6 consecutive days. The median age was 76.5 (26 to 90), with 84.6% of patients ≥70 years. BST-236 was safe and well tolerated. The maximal tolerated dose was 6 g/m2per day. Overall response rate was 29.6%. A subgroup analysis of newly diagnosed patients with AML, de novo or secondary to myelodysplastic syndrome, unfit for standard induction (median age 78), demonstrated overall response of 45.5%. The median overall survival was 6.5 months and was not reached in patients achieving complete remission. The findings of this phase 1/2 study suggest that BST-236 safely delivers high and efficacious cytarabine doses to older patients who are unfit for standard induction and lays the foundation for further studies of BST-236 in AML. This trial was registered at www.clinicaltrials.govas #NCT02544438.

Background:Treatment options for elderly unfit/frail (U/F) patients (pts) with diffuse large B-cell lymphoma (DLBCL) are often limited due to comorbidities or functional decline. Less toxic, efficacious alternatives to full-dose chemoimmunotherapy (CIT) are needed. Mosunetuzumab (Mosun) is a first-in-class CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate B cells. Mosun monotherapy has demonstrated efficacy, durable complete responses (CR), and manageable safety in U/F pts with untreated DLBCL (NCT03677154; Olszewski et al. ASH 2022). Subgroup analysis from an ongoing Phase Ib/II study (NCT03671018) of Mosun plus polatuzumab vedotin (Pola; M-Pola) in pts with relapsed/refractory DLBCL demonstrated efficacy and a manageable safety profile in pts ≥65 years (yrs) (Olszewski et al. ASH 2022). We report preliminary efficacy and safety data from the M-Pola cohort of study NCT03677154 in elderly U/F pts with newly diagnosed DLBCL.

Introduction- Glofitamab is a CD20-directed CD3 T-cell engager that has recently been approved by the FDA for relapsed and refractory diffuse large B cell lymphoma (R/R DLBCL). The approval was based on a pivotal phase II study including 154 patients with a median of 3 lines of treatment (a third post chimeric antigen receptor T (CAR-T) cell therapy) demonstrating an overall response rate (ORR) and complete response (CR) rate of 52% and 39%, respectively 1. However real-life data is still lacking. The present study was aimed to determine the efficacy and safety of glofitamab in real-life settings.

Preclinical studies have shown synergistic antitumour effects between ibrutinib and immune-checkpoint blockade. The aim of this study was to assess the safety and activity of ibrutinib in combination with nivolumab in patients with relapsed or refractory B-cell malignant diseases.

Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas.

Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT.

SUMMARY Maintaining complete remission in patients with acute myeloid leukemia (AML) is a great challenge. Targeting the remaining malignant clones, using different regimens of chemotherapeutic agents did not prove to be fruitful. Host residual leukemia stem cells may be eradicated by donor immune cells in case of allogeneic stem cell transplantation. However, only a minority of AML patients may benefit from this procedure. IL-2 is very well known in its ability to enhance activation and proliferation of natural killer and T cells, albeit in the clinical setting this effect is suppressed by myeloid cells derived oxygen species. Histamine dihydrochloride can inhibit myeloid cells activity, therefore reaugment antileukemic natural killer/T-cell cytotoxic activity. This review summarizes different strategies to maintain complete remission in AML patients focusing on the use of histamine dihydrochloride/IL-2 treatment.

Thrombomodulin (TM) is a predominantly endothelial transmembrane glycoprotein that modulates hemostatic function through a domain that controls thrombin-mediated proteolysis and an N-terminal lectin-like domain that controls inflammatory processes. To test the hypothesis that TM is a determinant of malignancy and dissect the importance of these functional domains in cancer biology, metastatic potential was evaluated in TMPromice expressing a mutant form of TM with reduced thrombin affinity and TMLeDmice lacking the N-terminal lectin-like domain. Studies of TMPromice revealed that TM is a powerful determinant of hematogenous metastasis. TMPromice exhibited a strongly prometastatic phenotype relative to control mice that was found to result from increased survival of tumor cells newly localized to the lung rather than any alteration in tumor growth. The impact of the TMPromutation on metastasis was dependent on both tumor cell-associated tissue factor and thrombin procoagulant function. In contrast, expression of a mutant form of TM lacking the lectin-like domain had no significant impact on metastasis. These studies directly demonstrate for the first time that TM-mediated regulation of tumor cell-driven procoagulant function strongly influences metastatic potential and suggest that endothelial cell-associated modulators of hemostasis may represent novel therapeutic targets in limiting tumor dissemination.

Thrombomodulin (TM) is a predominantly endothelial transmembrane glycoprotein that modulates hemostatic function through a domain that controls thrombin-mediated proteolysis and an N-terminal lectin-like domain that controls inflammatory processes. To test the hypothesis that TM is a determinant of malignancy and dissect the importance of these functional domains in cancer biology, metastatic potential was evaluated in TMPro mice expressing a mutant form of TM with reduced thrombin affinity and TMLeD mice lacking the N-terminal lectin-like domain. Studies of TMPro mice revealed that TM is a powerful determinant of hematogenous metastasis. TMPro mice exhibited a strongly prometastatic phenotype relative to control mice that was found to result from increased survival of tumor cells newly localized to the lung rather than any alteration in tumor growth. The impact of the TMPro mutation on metastasis was dependent on both tumor cell-associated tissue factor and thrombin procoagulant function. In contrast, expression of a mutant form of TM lacking the lectin-like domain had no significant impact on metastasis. These studies directly demonstrate for the first time that TM-mediated regulation of tumor cell-driven procoagulant function strongly influences metastatic potential and suggest that endothelial cell-associated modulators of hemostasis may represent novel therapeutic targets in limiting tumor dissemination.

Introduction: In patients with hematological malignancies, COVID-19 is considered to be associated with a high risk of severe morbidity and mortality. While anti-COVID-19 vaccination of such patients has become the standard of care, many of them fail to generate protective serological response due to either the nature of their underlying disease or exposure to therapy. Surprisingly, none of the Hodgkin lymphoma (HL) patients treated or followed at our tertiary care center, has been hospitalized for severe COVID-19. Nevertheless, the vulnerability of this patient population to infections highlights the need for efficacious protection against this life-threatening disease. The current non-interventional single-center study has aimed to evaluate the serological response in HL patients vaccinated against the virus in comparison to those HL patients who had a history of COVID-19 infection. The impact of an additional background disease or use of lymphodepleting agents on the evaluated serological response of HL patients has also been assessed.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Introduction: Non-Hodgkin lymphoma (NHL), the most frequent hematological malignancy observed during pregnancy, is reported to be associated with advanced disease stage at diagnosis, essential involvement of reproductive organs, and a turbulent course. Immunosuppression is one of the key players in maternal-fetal tolerance that may have an impact on the tumor microenvironment (TME), thus contributing to cancer progression in this setting. Immunomodulatory cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), recruited by TME, are capable of inhibiting anti-tumor immune responses. The current study was designed to explore potential contribution of the pregnancy milieu to induction of immunosuppressive microenvironment supporting lymphoma growth and progression.

Background:

Yael: Janssen: Consultancy; Amgen: Consultancy, Research Funding; Neopharm: Consultancy; Takeda: Consultancy; Madison: Consultancy; VBL Therapeutics: Employment.

Zuckerman: BioSight Ltd.: Consultancy. Gengrinovitch: Biosight: Employment. Flaishon: BioSight: Employment. Ben Yakar: Biosight: Employment.

Introduction:First line therapy of AML has not changed significantly since the 1970s and still relies on cytarabine as its backbone. Older patients or patients with comorbidities have low tolerability to intensive cytarabine treatment due to increased morbidity and mortality related to its toxicity, such as cerebellar toxicity, bone marrow suppression, gastrointestinal toxicity and infections. Hence, currently available intensive cytarabine treatment is unjustified in this population due to its poor risk/benefit ratio, and therefore, older and unfit AML patients are usually treated with reduced intensity therapy with poor outcomes.

Bairey: Janssen: Consultancy.

Avivi: Tel Aviv Sourasky Medical center: Consultancy, Other: consultancy to :BMS Roche.

No relevant conflicts of interest to declare.

Zuckerman: BioSight Ltd: Consultancy, Research Funding. Gengrinovitch:BioSight Ltd: Employment, Equity Ownership, Patents & Royalties: Inventor all of the patents. Ben-Yakar:BioSight Ltd: Consultancy, Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor of all patents.

Introduction: Autologous stem cell transplantation (ASCT) is currently considered the standard first-line consolidation therapy for younger patients with mantle cell lymphoma (MCL). In general, there are limited data regarding a preferred high-dose therapy (HDT) regimen preceding ASCT to be used in patients with non-Hodgkin lymphoma (NHL). Although BEAM and BEAC regimens (including BCNU, etoposide, cytosar in both regimens and melphalan or cytoxan, respectively) have been commonly employed as conditioning HDT in patients with aggressive or recurrent NHL, there have been few reports comparing these two regimens. A retrospective analysis found the superiority of BEAM over BEAC in terms of overall survival (OS) and event-free survival (EFS). Regimen-related toxicities were similar, except that BEAM was associated with more frequent lower gastrointestinal mucositis. Other studies reported that these two regimens had equivalent efficacy and outcome, as measured by EFS and OS. Further studies are required to define the optimal regimen for each specific NHL subtype. The current study aimed to compare the efficacy and toxicity of BEAC versus BEAM as a consolidation HDT in young patients with MCL undergoing ASCT.

Introduction: Primary plasma cell leukemia (PPCL) is a rare and aggressive variant of multiple myeloma (MM), characterized by the presence of 20% and/or 2X109/L plasma cells (PCs) in the peripheral blood (PB) of the patient. Data regarding this entity are scarce and based on case reports and few retrospective case series. Most of the reports are dated prior to the incorporation of novel agents into MM treatment. The aim of this multicenter retrospective study was to evaluate the response and survival of PPCL patients in the era of the novel agents.

Introduction: Chronic lymphocytic leukemia (CLL) cells exhibit inhibitory features of regulatory B-cells (Bregs), which are suspected to modulate cancer immune evasion on the one hand, and to promote immunosuppression leading to opportunistic infections on the other. One of the major mechanisms through which Bregs restrain the immune system is production of the anti-inflammatory cytokine interleukin 10 (IL10). Our previous study has demonstrated that CLL cells generate IL10, inhibit autologous CD4+T-cell proliferation and induce regulatory T-cells (Tregs) from autologous CD4+T-cells. All these abilities were found to be triggered by activation of toll like receptor 9 (TLR9) with the agonist CpG-ODN (ODN). Of note, Treg induction was also observed following CD40 activation with CD40 ligand (CD40L), while intracellular IL10 levels and proliferation inhibition were unaffected by this stimulant. Given the magnitude of the regulatory effects induced by ODN, the current study aimed to explore the contribution of TLR9 activation to the control of IL10 generation by CLL cells and to assess the role of this inhibitory cytokine in mediating the above Breg abilities of these cells.

Introduction: Patients with diffuse large B cell lymphoma (DLBCL) and high International Prognostic Index(IPI) or extra-nodal disease are at an increased risk of systemic and central nervous system (CNS) relapse. Presently, the management of DLBCL patients at the Rambam Health Care Campus (Haifa, Israel) and Hadassah Medical Center (Jerusalem, Israel) includes 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) along with 4 doses of intrathecal (IT) methotrexate (MTX), which may be followed by 2 additional cycles of an intermediate dose (3 g/m2) of intravenousMTX (ID-MTX). The current study compared progression-free survival (PFS), overall survival (OS) and CNS relapse rate in a cohort of DLBCL patients with risk factors for CNS relapse who did or did not undergo prophylactic therapy with ID-MTX.

No relevant conflicts of interest to declare.

Avivi: Tel Aviv Sourasky Medical center: Consultancy, Other: consultancy to :BMS Roche.

Introduction: Therapy of acute myeloid leukemia (AML) has not changed significantly during several decades. High-dose cytarabine, although used as the first-line treatment for AML since 1970s and as a second-line treatment for acute lymphoblastic leukemia (ALL), is associated with severe side effects, such as cerebellar toxicity and bone marrow suppression. Hence, while the incidence of AML increases with age, doses of cytarabine are significantly attenuated or the drug is entirely excluded from the regimen used in older adults due to its potential toxicities, particularly in individuals with hepatic or renal dysfunction.

In a patient with systemic multiorgan disease with overlapping features, the differential diagnosis included infectious diseases, malignancies, and systemic autoimmune or inflammatory diseases. We present an unusual case of a young male with B cell lymphoma who presented with symptoms mimicking systemic vasculitis and review the existing literature.

Introduction: The treatment of advanced Hodgkin lymphoma (HL) has undergone many changes in recent years. The original International Prognostic Score (IPS) introduced by Hasenclever et al (1998) was based on a cohort of 1618 patients (pts) mainly treated with MOPP-ABV or ABVD between the years 1983 and 1992. One third (33%) of those pts also underwent involved field radiation therapy (IFRT). Staging was based on CT. The 5-y freedom from progression (FFP) results ranged between 84% and 42%, depending on the presence of 0-≥5 risk factors. The IPS has been validated in a number of studies and settings. Currently, staging is based on baseline PET/CT, which upgrades the disease stage in 15% and downgrades it in 5% of pts compared to CT scan. Positive interim PET/CT (PET-2) is predictive of an inferior prognosis in pts with early and advanced HL. Based on these findings, several studies have used a positive PET-2 as an indication for therapy escalation. However, the majority of relapses still occur in pts with negative PET-2, highlighting the need for additional prognostic markers. We evaluated baseline factors and lab results in a prospectively collected database of pts enrolled in a multicenter clinical trial (NCT00392314) where treatment was modified based on PET-2 results. The current study aimed to develop a model for refined prediction of HL progression risk in advance-disease pts with negative PET-2, using baseline risk factors.