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This article discusses the acceleration of non-Hodgkin lymphoma (NHL) progression during pregnancy in a murine model. The study found that pregnant mice had significantly greater tumor volume and weight compared to non-pregnant mice. While pregnancy-related hormones were found to play a role in creating a favorable immunological environment for successful gestation, they did not directly contribute to lymphoma cell proliferation. However, the study did find increased infiltration of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment of pregnant mice, suggesting that these immunosuppressive cells may mediate enhanced cancer progression during pregnancy. [Extracted from the article]

This study sought to correlate the SARS-CoV-2 IgG antibody response level to the BNT162b2 (Pfizer BioNTech) mRNA vaccine after the first and second doses with the reported adverse events. This cohort study examined the adverse events profiles of people vaccinated with BNT162b2 in our institute between late 2020 and May 2021. Adverse events, age, and sex were reported using an electronic questionnaire, and their SARS-CoV-2 IgG antibody levels were retrieved from the hospital database. Between 20 December 2020 and 31 May 2021, the adverse events questionnaire was completed by 9700 individuals who received the first vaccine dose and 8321 who received the second dose. After the first and second doses, the average antibody levels were 62.34 AU/mL (mean 4–373) and 188.19 AU/mL (mean 20–392), respectively. All of the adverse events, except local pain, were more common after the second vaccine dose. Multivariate analysis showed that after the first vaccine dose, female sex and younger age (but not IgG titres) were associated with a higher probability of adverse events (OR 2.377, 95% CI, 1.607–3.515, p = 0.000; OR 0.959, 95% CI, 0.944–0.977, p £0.000; OR 1.002, 95% CI, 0.995–1.008, p £0.601; respectively); however, all three parameters were associated with the incidence of adverse events after the second dose (OR 2.332, 95% CI, 1.636–3.322, p = 0.000; OR 0.984, 95% CI, 0.970–0.999, p £0.039; OR 1.004, 95% CI, 1.001–1.007, p £0.022; respectively). Adverse events are significantly more common after the second BNT162b2 vaccine dose than after the first dose. We found an association between sex, age, and SARS-CoV-2 IgG antibody titre with the incidence of adverse events. [Display omitted] [ABSTRACT FROM AUTHOR]

Combination of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is regarded as standard care for diffuse large B-cell lymphoma (DLBCL) and upfront intensification of therapy is still controversial. The current study aimed to dertermine whether the addition of high-dose methotrexate (HDMTX) affects long-term outcomes and could also prevent central nervous system (CNS) relapse. Medical records of 480 patients with DLBCL treated between 1994 and 2013 at Rambam and Hadassah medical centers in Israel were reviewed; 130 (27%) had received HDMTX. Patients receiving HDMTX generally had higher International Prognostic Index (IPI) and CNS-IPI scores. HDMTX addition significantly improved progression free and overall survival (p =.001) and this advantage was maintained in multivariate analysis (HR for OS 0.3; 95% CI 0.19–0.47; p <.0001). Thirty-one (6.5%) patients had CNS relapse and in these cases high CNS-IPI, but not HDMTX treatment, was independently associated with CNS relapse (HR 1.2; 95% CI 1.2–11.5; p =.02). In conclusion, the addition of HDMTX to CHOP/RCHOP independently and significantly improved prognosis of patients with high-risk DLBCL, irrespective of their risk for CNS relapse. [ABSTRACT FROM AUTHOR]

Data regarding clinical characteristics, therapy, maternal and fetal outcomes of pregnancy-associated acute myeloid leukemia (PA-AML) are limited. This study (including 138 cases published between 1955 and 2013) provides comprehensive assessment of these clinical parameters and may serve as a platform for developing management recommendations. Most patients (58%) received anthracycline-cytarabine-based regimens (ACBRs), which were associated with significantly increased complete remission (CR: 91%). Yet, the maternal overall survival (OS: ~30%) was relatively low, probably reflecting reduced application of risk-adapted consolidation and allogeneic stem cell transplantation (allo-SCT). Fetal exposure to ACBRs resulted in a live birth rate of 87%, with complications (16%) diagnosed only in chemotherapy-subjected neonates. This study demonstrates safety and efficacy of ACBRs during pregnancy. Therapy and delivery schedule should allow early referral of high-risk patients to allo-SCT. Generation of a pool of high-quality data on PA-AML could contribute to providing evidence-based therapy and lead to improved maternal and fetal survival. [ABSTRACT FROM AUTHOR]

Cancer and pregnancy induce a procoagulant environment which may lead to maternal and fetal complications, such as venous thromboembolism, fetal growth restriction, and fetal loss. The incidence of hematological malignancies diagnosed during pregnancy is rising, and thrombotic events in such malignancies are not rare. Management of thrombosis during pregnancy poses a therapeutic challenge, that is further exacerbated by the impact of cancer. The available data on managing pregnant women with hematological malignancies are limited to those with myeloproliferative neoplasms, mainly essential thrombocythemia, and, to a lesser extent, polycythemia vera. Low-dose aspirin is recommended throughout pregnancy, and considering treatment with low-molecular-weight heparin and interferon formulations is advised for high-risk patients. Currently, guidelines for handling thrombotic events in pregnant women with lymphoma or leukemia are lacking, and their management is based on data extrapolated from retrospective studies, and guidelines for prevention and treatment of cancer-associated thrombosis. The present case-based review will focus on the complex issue of thrombotic risk in pregnant women with hematological malignancies, specifically myeloproliferative neoplasms, lymphomas, and leukemias. [ABSTRACT FROM AUTHOR]

Non-Hodgkin lymphoma (NHL) is one of the most common hematologic malignancies worldwide. The incidence of NHL has been rising for several decades; however, in the last 20 years, it reached a plateau. NHL incidence among males is significantly higher than in females. In addition to gender itself, gravidity has a protective role against NHL occurrence. Gender also matters in terms of NHL clinical characteristics. For example, female predominance was found in three extra-nodal sites (the breast, thyroid, and the respiratory system) occasionally involved in NHL. The diagnosis of NHL during pregnancy is associated with a unique clinical behavior. It is usually diagnosed in the second or third trimester and in advanced stage. Furthermore, the histological subtype is highly aggressive, and reproductive organ involvement is common. The reduced rate of NHL among females may be explained by direct effects of estrogens on lymphoma cell proliferation or by its effect on anti-tumor immune response. Gender has an important role in responsiveness to standard B cell NHL treatment. Among older adults, women benefited more from the addition of the anti-CD20 antibody rituximab to standard chemotherapy regimens. This phenomenon can be explained by the difference in clearance rate of rituximab that was found to be significantly lower among older females than older males. In mantle cell lymphoma, women receiving lenalidomide have higher rates of response. An understanding of the mechanisms responsible for gender-associated NHL differences will ultimately improve the clinical approach, allowing for a more accurate assessment of prognosis and patient- tailored treatment. [ABSTRACT FROM AUTHOR]

In chronic lymphocytic leukemia (CLL), the immune system is skewed towards a suppressive milieu. Levels of thrombopoietin (TPO), promoting cellular immune regulatory activity in immune thrombocytopenic purpura, were shown to be elevated in CLL patients. This study explored TPO as a potential immunomodulator, supporting CLL progression. We evaluated CLL cell‐induced expression of TPO receptor (TPO‐R) on T‐cells and effects of its activation on T‐cell responses. CLL cell involvement in TPO generation was also assessed. Baseline TPO‐R expression on CD4 + T‐cells was found to be higher in CLL patients than in healthy controls (HC). Exposure of HC‐T‐cells to B‐cells, especially to CLL‐B‐cells stimulated with B‐cell activating molecules, resulted in enhanced TPO‐R expression on T‐cells. CLL‐T‐cell stimulation with TPO reduced their proliferation and expanded the regulatory T‐cell (Treg) population. At baseline, phosphorylation of STAT5, known to impact the Treg phenotype, was elevated in CLL‐T‐cells relative to those of HC. Exposure to TPO further enhanced STAT5 phosphorylation in CLL‐T‐cells, possibly driving the observed Treg expansion. The CLL immune milieu is involved in promotion of inhibitory features in T‐cells through increased TPO‐R levels and TPO‐induced intracellular signaling. TPO and its signaling pathway could potentially support immunosuppression in CLL, and may emerge as novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Herpesvirus 6 (HHV-6) infection is a common complication during immunosuppression. Its significance for multiple myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT) after treatment with novel agents affecting immune system remains undetermined. Data on 62 consecutive MM patients receiving bortezomib-dexamethasone (VD) (n = 41; 66%) or thalidomide-dexamethasone (TD) (n = 21, 34%) induction, together with melphalan 200 mg/m² autograft between 01.2005 and 09.2010, were reviewed. HHV-6 reactivation was diagnosed in patients experiencing postengraftment unexplained fever (PEUF) in the presence of any level of HHHV-6 DNA in blood. There were no statistically significant differences in patient characteristics between the groups, excluding dexamethasone dosage, which was significantly higher in patients receiving TD. Eight patients in TD and 18 in VD cohorts underwent viral screening for PEUF. HHV-6 reactivation was diagnosed in 10 patients of the entire series (16%), accounting for 35% of those screened; its incidence was 19.5% (n = 8) in the VD group versus 9.5% (n = 2) in the TD group. All patients recovered without sequelae. In conclusion, HHV-6 reactivation is relatively common after ASCT, accounting for at least a third of PEUF episodes. Further studies are warranted to investigate whether bortezomib has an impact on HHV-6 reactivation development [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Previous studies showed that the fourth SARS-CoV-2 vaccine dose has a protective effect against infection, as well as against severe disease and death. This study aimed to examine whether knowledge of a high-level antibody after the third dose may reduce compliance to the fourth booster dose among healthcare workers (HCWs). Methods: We conducted a prospective cohort study among HCWs vaccinated with the first three doses at Rambam Healthcare Campus, a tertiary hospital in northern Israel. Participants underwent a serological test before the fourth booster vaccine was offered to all of them, with results provided to participants. The population was divided into two groups, namely those with antibodies below 955 AU/mL and those with 955 AU/mL and higher, a cutoff found protective in a previous study. Multiple logistic regression was carried out to compare the compliance to the fourth booster between the two groups, adjusted for demographic and clinical variables. Results: After adjusting for the confounding variables, the compliance was higher in those with antibody levels below 955 AU/mL (OR = 1.41, p = 0.05, 95% CI 1.10–1.96). In addition, male sex and age of 60 years and above were also associated with higher vaccination rates (OR = 2.28, p < 0.001, 95% CI 1.64–3.17), (OR = 1.14, p = 0.043, 95% CI 1.06–1.75), respectively. Conclusions: Knowledge of the antibody status may affect compliance with the booster dose. Considering waning immunity over time, reduced compliance may affect the protection of HCWs who declined the fourth dose. [ABSTRACT FROM AUTHOR]

The advent of tyrosine kinase inhibitors (TKIs) has ushered in a new era in the management of patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph+ ALL). Although, as a group, these inhibitors have led to one of the most successful targeted therapies in leukemia, Ph+ ALL still remains a formidable disease. Unlike chronic myeloid leukemia (CML) where TKIs lead to dramatic long‐lasting responses as single agents, the biology of Ph+ ALL is far more complex and adjunctive therapies are mandatory. These may include corticosteroids, chemotherapy, antibody‐based therapies or, even, allogeneic hematopoietic cell transplantation. Clearly, other genes or mutations are in place that affect the outcome of Ph+ ALL. Additional chromosomal abnormalities are common in Ph+ ALL and have a varying impact on prognosis; some adverse, others less so. Genomic alterations have come into their own in the last decade and have increased our understanding of the mechanisms of resistance and differing responses to therapy. In this review, these genetic aberrations will be considered in some detail. In addition, innovations in current practice – including the use of immunological therapies – will be carefully reviewed. For the first time in decades, the long‐held imperative requiring an allogeneic transplant for a curative approach in adult Ph+ ALL is now being questioned and clinical trials are underway to resolve this issue. However, despite much progress in the past two decades, both in the biology and therapy of Ph+ ALL, this disease still presents a compelling challenge and much remains to be overcome. [ABSTRACT FROM AUTHOR]

Objectives: Hematological malignancy (HM) patients treated with anti‐CD20 monoclonal antibodies are at higher risk for severe COVID‐19. A previous single‐center study showed worse outcomes in patients treated with obinutuzumab compared to rituximab. We examined this hypothesis in a large international multicenter cohort. Methods: We included HM patients from 15 centers, from five countries treated with anti‐CD20, comparing those treated with obinutuzumab (O‐G) to rituximab (R‐G) between December 2021 and June 2022, when Omicron lineage was dominant. Results: We collected data on 1048 patients. Within the R‐G (n = 762, 73%), 191 (25%) contracted COVID‐19 compared to 103 (36%) in the O‐G. COVID‐19 patients in the O‐G were younger (61 ± 11.7 vs. 64 ± 14.5, p = 0.039), had more indolent HM diagnosis (aggressive lymphoma: 3.9% vs. 67.0%, p < 0.001), and most were on maintenance therapy at COVID‐19 diagnosis (63.0% vs. 16.8%, p < 0.001). Severe‐critical COVID‐19 occurred in 31.1% of patients in the O‐G and 22.5% in the R‐G. In multivariable analysis, O‐G had a 2.08‐fold increased risk for severe‐critical COVID‐19 compared to R‐G (95% CI 1.13–3.84), adjusted for Charlson comorbidity index, sex, and tixagevimab/cilgavimab (T‐C) prophylaxis. Further analysis comparing O‐G to R‐G demonstrated increased hospitalizations (51.5% vs. 35.6% p = 0.008), ICU admissions (12.6% vs. 5.8%, p = 0.042), but the nonsignificant difference in COVID‐19‐related mortality (n = 10, 9.7% vs. n = 12, 6.3%, p = 0.293). Conclusions: Despite younger age and a more indolent HM diagnosis, patients receiving obinutuzumab had more severe COVID‐19 outcomes than those receiving rituximab. Our findings underscore the need to evaluate the risk–benefit balance when considering obinutuzumab therapy for HM patients during respiratory viral outbreaks. [ABSTRACT FROM AUTHOR]

Background: Elderly patients account for nearly 70% of all primary central nervous system lymphoma (PCNSL) cases. They cannot tolerate aggressive treatment and have poor prognosis with a median overall survival (OS) of less than 2 years and progression‐free survival (PFS) of 6–16 months. Ibrutinib penetrates the blood–brain barrier and has shown activity in PCNSL. Methods: This prospective study investigated whether ibrutinib maintenance is feasible, and whether it can benefit elderly PCNSL patients in terms of expected 2‐year PFS. It is an open label, phase 2 study in newly diagnosed PCNSL patients 60–85 years old who responded to first‐line high‐dose methotrexate (HDMTX)‐based treatment with partial or complete response. Ibrutinib maintenance (560 mg/d) was continued until disease progression or intolerable toxicity. Results: Twenty patients were enrolled, with a median age of 72 years (range, 61–80). Median time on ibrutinib maintenance was 12.5 (range, 2–46) months. Twelve patients stopped treatment: five due to central nervous system relapse and seven due to adverse events that were mainly grade 2. Five patients died (25%) all due to relapse. The 1‐ and 2‐year PFS are 90% and 72.6%, respectively, and the 2‐year OS is 89%. Conclusions: The study reached its primary end points and also showed that ibrutinib maintenance is tolerated reasonably well by the elderly. Therefore, this study supports the concept that ibrutinib maintenance should be further evaluated as an optional consolidation measure in the elderly. Ibrutinib maintenance following first‐line high dose methotrexate‐based chemotherapy in elderly patients with primary central nervous system lymphoma is feasible and probably also effective. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients suffering from multiple myeloma receive many lines of treatment including chimeric antigen receptor T cell (CART) therapy. Myeloma patients may develop devastating secondary malignancies such as myelodysplastic syndrome (MDS). The causative relationship between various anti-myeloma treatments and MDS is not fully understood. We report a study of five CART-treated patients myeloma patients who had MDS (four only after CART and one already prior to CART). We found that all these patients had all their MDS-related molecular changes (mutations) already prior to CART even if they did not have overt MDS in bone marrow evaluation before CART. No new mutations developed after CART, but the frequency of pre-existing mutations did increase. Our study presents evidence that anti-myeloma CART therapy may promote the expansion of pre-existing MDS clones rather than causing the development of new ones. Multiple myeloma (MM) is characterized by recurrent relapses. Consequently, patients receive multiple therapy lines, including alkylating agents and immune modulators, which have been associated with secondary malignancies such as myelodysplastic syndrome (MDS). Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T cell (CART) therapy is efficacious in patients with relapsed/refractory (R/R) MM. However, the long-term complications, particularly MDS, are not well understood. Whether CART therapy causes or promotes MDS has not been thoroughly investigated. In this study, we explored the causal relationship between MDS and CART therapy. We retrospectively examined the prevalence of MDS-related morphological and mutational changes before and after administration of CART therapy in five patients. Among them, four developed MDS after CART therapy, while one had pre-existing MDS prior to CART. None of the four patients who developed post-CART MDS showed morphological MDS changes prior to CART therapy. However, all four patients exhibited molecular alterations associated with MDS in their pre-CART as well as post-CART therapy bone marrow. No new mutations were observed. Our findings provide initial evidence suggesting that anti-BCMA CART therapy in MM may promote expansion of pre-existing MDS clones rather than causing development of new clones. [ABSTRACT FROM AUTHOR]

Summary: Data for pregnancy-associated non-Hodgkin lymphoma are limited to case reports, making it difficult to define this disorder. We did a systematic search for articles published between 1967 and 2011 with the aim to determine the characteristics, management, and outcome of pregnancy-associated non-Hodgkin lymphoma. We identified 121 patients from 74 papers. Most patients with stage information available presented with stage IV disease (75%, 82 of 108 patients). Patients were classified into three clinical groups; those with indolent lymphomas accounted for 5% (five of 108), aggressive lymphomas (diffuse large B-cell lymphoma and T-cell lymphomas) made up 48% of patients (52 of 108), and highly aggressive lymphomas (Burkitt's lymphoma, immunoblastic lymphoma, and unspecified highly aggressive lymphomas) accounted for 47% of patients (51 of 108). Reproductive organ involvement (breast, ovary, uterus, placenta) was reported in 49% of 110 patients with information available on extranodal involvement, and prevailed in endemic Burkitt's lymphoma (100%, 19 of 19), followed by non-endemic Burkitt lymphoma (70%, 14 of 20), immunoblastic lymphoma (67%, two of three), peripheral T-cell lymphoma (46%, six of 13), and indolent (40%, two of five) and diffuse large cell lymphoma (23%, nine of 40). Most patients received antepartum (45%, 55 of 121) or postpartum therapy (45%, 54 of 121), resulting in 6-month survival of 53% for mothers and a livebirth rate of 83%. Pregnancy-associated non-Hodgkin lymphoma has unique clinical characteristics with frequent reproductive organ involvement. Collaborative prospective studies are needed to further characterise pathophysiological and clinical aspects of this complication. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the role of additional chemotherapy before autologous hematopoietic cell transplantation (HCT) in patients with relapse/refractory diffuse large B‐cell lymphoma (DLBCL) who achieve partial remission following first salvage therapy. Methods: We conducted a multicenter retrospective study of all adult patients with DLBCL who underwent HCT between 2008 and 2020 and achieved partial response (PR) after the first salvage and were either referred directly to HCT (n = 47) or received additional salvage therapy before HCT (n = 22). Results: Post‐HCT CR rate and progression‐free survival were comparable between the two groups (66% vs. 68%, p =.86 and median not reached vs. 10.2 months [95% confidence interval, CI 7.1–12.3], p =.27, respectively). Median overall survival (OS) and estimated 3‐year OS favored patients who were directly referred to HCT (105.8 [95% CI 63–148] months vs. 14.5 [95% CI 0–44] months, p =.035, and 65% [95% CI 51%–75%] vs. 40% [95% CI 21%–53%], p =.035, respectively). In Cox regression model, while International Prognostic Index and primary refractory versus relapse disease did not impact OS, allocation to a second salvage regimen and older age were both associated with inferior survival (hazard ratio [HR] = 2.57 95% CI 1.1–5.8, p =.023 and HR = 1.04 95% CI 0.99–1.2, p =.064, respectively). Conclusions: Referring patients with chemotherapy‐sensitive disease in PR directly to HCT is associated with better OS compared to those receiving additional lines of treatment. [ABSTRACT FROM AUTHOR]

Summary: Belantamab mafodotin, an immuno‐conjugate targeting B‐cell maturation antigen, showed single‐agent activity in phase 1 and 2 studies, and was recently approved for heavily pretreated relapsed/refractory multiple myeloma (RRMM) patients. Real‐world data and long‐term follow‐up are scarce. We conducted a multisite retrospective study aimed to assess safety and efficacy of belantamab mafodotin monotherapy administered via the GSK expanded access compassionate care programme. One‐hundred and six RRMM patients were treated with belantamab mafodotin between July 2019 and March 2021. The median age was 69.4 years. Patients were heavily pretreated with a median of six (range 2–11) prior therapy lines. Major adverse effects included ocular toxicity (keratopathy 68.4%, grade ≥3: 40.5%; blurred vision 36.8%, grade ≥3: 6.3%), thrombocytopenia (27.4%, grade ≥3: 17.9%) and infections (11.3%, grade ≥3: 7.5%). Median follow‐up time was 11.9 [95% confidence interval (CI) 10.0–13.8] months. Overall response rate was 45.5%. Median progression‐free survival was 4.7 (95% CI 3.5–5.9) months in the entire cohort and 8.8 (95% CI 6.6–10.9) months among responders. Median overall survival was 14.5 (95% CI 9.5–19.6) months, and not reached for responders. To conclude, in a real‐world setting, belantamab mafodotin monotherapy showed efficacy comparable with the prospective clinical trials, with a tolerable toxicity profile. [ABSTRACT FROM AUTHOR]

Solitary plasmacytoma (SP) is a rare plasma cell dyscrasia. In this retrospective multicenter study, 68 SP patients were included. Compared to solitary extramedullary plasmacytoma (SEP), patients with solitary bone plasmacytoma (SBP) were younger (57.3 vs. 70.9 years, p = 0.031), had larger plasmacytoma (median: 5.4 vs. 3 cm, p = 0.007) and higher median involved free light chain level (61 vs. 25.8 mg/L, p = 0.056). 92.6% of patients were treated by radiotherapy and 11.8% received systemic anti-myeloma treatment. With a median follow-up of 42 months, 45.6% of patients progressed (8.8% – recurrent SP, 36.8% – active myeloma). The median PFS was 58 months and the median OS has not been reached (10-year OS: 84.8%). Patients who received also anti-myeloma treatment had longer PFS compared to those who did not (median not reached vs. 48 months, p = 0.056). In conclusion, SBP and SEP appear to be different diseases. Radiotherapy is the cornerstone in the SP treatment. A large prospective trial is needed to evaluate the impact of adding systemic anti-myeloma treatment to local radiotherapy. [ABSTRACT FROM AUTHOR]

Heparanase is an endoglycosidase that cleaves heparan sulfate side chains of proteoglycans, resulting in disassembly of the extracellular matrix underlying endothelial and epithelial cells and associating with enhanced cell invasion and metastasis. Heparanase expression is induced in carcinomas and sarcomas, often associating with enhanced tumor metastasis and poor prognosis. In contrast, the function of heparanase in hematological malignancies (except myeloma) was not investigated in depth. Here, we provide evidence that heparanase is expressed by human follicular and diffused non-Hodgkin's B-lymphomas, and that heparanase inhibitors restrain the growth of tumor xenografts produced by lymphoma cell lines. Furthermore, we describe, for the first time to our knowledge, the development and characterization of heparanaseneutralizing monoclonal antibodies that inhibit cell invasion and tumor metastasis, the hallmark of heparanase activity. Using luciferase-labeled Raji lymphoma cells, we show that the heparanase-neutralizing monoclonal antibodies profoundly inhibit tumor load in the mouse bones, associating with reduced cell proliferation and angiogenesis. Notably, we found that Raji cells lack intrinsic heparanase activity, but tumor xenografts produced by this cell line exhibit typical heparanase activity, likely contributed by host cells composing the tumor microenvironment. Thus, the neutralizing monoclonal antibodies attenuate lymphoma growth by targeting heparanase in the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Inflammation and coagulation are known to affect each other in many ways. Vasculitis represents a group of disorders where blood vessels (small, medium, large or variable) are infiltrated with inflammatory cells. Accumulating evidence in the literature suggests both clinical and physiological association between vasculitis and thrombosis. Vasculitis-associated thrombosis involves arteries and veins, and a tight connection has been reported between the activity of vasculitis and the appearance of thrombosis. Pathophysiology of these relations is complex and not completely understood. While thrombophilic factors are associated with vasculitis, it remains unclear whether a true association with clinical thrombosis is present. Furthermore, several factors leading to hemostasis, endothelial injury and induction of microparticles were described as possibly accounting for thrombosis. Management of thrombosis in vasculitis patients is challenging and should be further assessed in randomized controlled studies. The current review describes clinical manifestations, pathogenesis and management of thrombosis associated with different vasculitides. [ABSTRACT FROM AUTHOR]

Acquired idiopathic thrombotic thrombocytopenic purpura (I-TTP) is a life-threatening microangiopathic disorder usually treated with therapeutic plasma exchange (TPE). The current study assessed the role of rituximab in the treatment of complicated I-TTP. The sequence of TTP events was compared in a group of I-TTP patients treated with TPE and a cohort of refractory or relapsed patients who also received rituximab. This retrospective evaluation included 45 I-TTP patients, treated between January 2000 and October 2013, who underwent at least 3 TPE procedures and were followed up until December 2013 or death. Thirty-one patients with an uncomplicated course received TPE only. Fourteen patients had a complicated course due to either a primary refractory/exacerbated disease (n = 5) or relapse (n = 9) and received rituximab together with TPE. The median number of TPE procedures performed in the first TTP episode in the uncomplicated cohort and groups with primary refractory or relapsed TTP was 11, 27 and 45, respectively. The relapse rates per follow-up year in the uncomplicated I-TTP, primary refractory and relapsed I-TTP groups were 0.18, 0.2 and 0.6 episodes, respectively. After rituximab therapy this rate dropped to 0.2 per year in the relapsed subgroup. In conclusion, about a quarter of patients with I-TTP had a complicated course and experienced a major benefit from rituximab in terms of effectiveness and safety. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

• In newly diagnosed AML patients the catheter-related thrombosis (CRT) rate was >10%. • The study proposes simple models for CRT prediction in AML patients at diagnosis. • Acute promyelocytic leukemia (APL), prior VTE, high BMI and platelet counts are key risk factors. • Chronic obstructive pulmonary disease arose as a new CRT risk factor in non-APL AML. • CRT events are not associated with higher morality in newly diagnosed AML patients. Catheter-related thrombosis (CRT) is a common complication in cancer patients, that may lead to chemotherapy deferral, elevated risk for systemic infections and pulmonary embolism. This study aimed to assess CRT incidence and risk factors in newly-diagnosed acute myeloid leukemia (AML) patients and create predictive models potentially allowing to decrease CRT occurrence in this population. This retrospective single-center analysis included all AML patients treated at the Rambam Health Care Campus between 2006 and 2019. Patient clinical and laboratory data were collected to evaluate thrombosis occurrence and time from AML diagnosis to CRT development. Multivariate classification models were created using logistic regression (LR) and competing risk analyzes. The final analysis included 632 newly-diagnosed AML patients (mean age 54 ± 15 years). CRT incidence was 10.1% [confidence interval (CI) 7.7–12.9%], median time from AML diagnosis to CRT was 12.5 days [interquartile range 6–30]. In an LR multivariate model, prior history of venous thromboembolism [adjusted odds ratio (AOR) 12.046, p < 0.0001], acute promyelocytic leukemia (APL) (AOR 2.824, p = 0.015), a high body mass index and initial platelet counts <100 × 10E9/L (AOR 1.059 and 0.546; p = 0.011 and 0.040, respectively) were significantly associated with high CRT risk. Analysis of 587 non-APL patients demonstrated comparable results, with CRT incidence of 9.3% (CI 7.0%-12.1%) and emergence of chronic obstructive pulmonary disease (COPD) as a novel significant co-factor (AOR 34.491, p = 0.004). In both models, the area under curve (AUC) was ≥70%. Significant CRT risk factors defined using the created model could be used for identification of high-risk newly-diagnosed AML patients requiring CRT prophylaxis. [ABSTRACT FROM AUTHOR]

Flow-cytometry (FC) is a powerful tool that can assist in lymphoma diagnosis in lymph node (LN) specimens. Although lymphoma diagnosis and classification are mainly based on tumor cell characteristics, surrounding cells are less employed in this process. We retrospectively investigated alterations in the ploidy status, proliferative cell fraction (PF) and the percentages of surrounding immune cells in 62 consecutive LN specimens with B-Cell Non-Hodgkin Lymphoma (B-NHL) that were submitted for FC evaluation between 2019–2022. Compared with indolent B-NHLs, aggressive B-NHLs show increased DNA aneuploidy and PF, increased monocytes, immature-granulocytes, mature granulocytes, CD8+ T-cells, Double-Negative-T-cells and Double-Positive-T-cells, and decreased total CD45+ cells, total lymphocytes, CD4+ T-cells and CD4/CD8 ratio. Receiver operating characteristic analysis determined PF > 6.8% and immature-granulocytes > 0.9% as optimal cutoffs with highest specificity and sensitivity in differentiating aggressive and indolent B-NHLs. These findings further strength the diagnostic value of DNA content analysis by FC and suggest the utilization of tumor surrounding immune cells in NHL diagnosis and classification. [ABSTRACT FROM AUTHOR]

Polatuzumab (Pola)-based regimens and chimeric antigen receptor T (CAR T) cells provide superior outcome compared to conventional chemoimmunotherapy in patients with relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL). Choosing between these strategies remains controversial. The efficacy of CAR T versus Pola-rituximab(R) /Pola-bendamustine(B)-R in R/R DLBCL patients after failing ≥2 lines of treatment was compared in a retrospective, 'real-world' study. Propensity score matching, for age, lymphoma category (de-novo/transformed), number of prior lines, Eastern Cooperative Oncology Group performance status and lactate dehydrogenase level, was applied to control for differences in patients' characteristics. Response rate, progression-free survival (PFS) and overall survival (OS) were analyzed. A total of 82 patients, treated with CAR T (n=41) or Pola-based regimens (n=41), were included. No treatment-related deaths occurred with CAR T vs. 3 (7.3%) with Pola. The overall and complete response rates were 83% and 58% with CAR T vs. 66% and 44% with Pola-based-regimens (p=0.077 and p=0.18, respectively). At a median follow-up of 9 months (range 1-19.2) and 16 months (range 0.7-25.3) for the CAR T and Pola arm respectively, the median PFS has not been reached for CAR T vs. 5.6 months for Pola (95% CI 3.6-7.6, p=0.014). Median OS has not been reached for CAR T vs. 10.8 months (95% CI 2.2-19.4) for Pola (p=0.026). To conclude, in a real-world setting, treatment with CAR T achieved superior PFS and OS compared to Pola-based regimens in patients with R/R DLBCL. [ABSTRACT FROM AUTHOR]

Purpose: Primary mediastinal B-cell lymphoma (PMBCL) is a rare subtype of diffuse large B-cell lymphoma (DLBCL). Despite its aggressive course, PMBCL is considered curable. While in recent years dose-adjusted (DA) EPOCH-R (rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) has become widely endorsed as first-line therapy for newly-diagnosed PMBCL, the optimal treatment for this disease and the role of radiotherapy (RT) remains unclear. DA-EPOCH-R provides good clinical outcomes, albeit is associated with short-and long-term toxicity. To address this issue, the current retrospective bi-icenter analysis compared efficacy and toxicity of DA-EPOCH-R and a less toxic R-CHOP/R-ICE regimen used for the treatment of newly-diagnosed PMBCL. Patients and Methods: The study included all patients with a histologically confirmed PMBCL diagnosis treated with DA-EPOCH-R or R-CHOP/R-ICE between 01/2013-12/2020 at two tertiary medical centers. Patient demographic and clinical data were derived from institutional electronic medical records. The analysis included 56 patients: 31 received DA-EPOCH-R and 25 -R- CHOP/R-ICE. Results: At a median follow-up of 1.9 years (IQR 3.1 years), similar progression-free survival (2.1 versus 2.4 years; p = 0.7667), overall survival (2.5 versus 2.7 years; p = 0.8047) and complete response (80%) were observed in both groups. However, DA-EPOCH-R was associated with significantly longer hospitalization required for its administration (p < 0.001) and a trend for higher frequency of infections, stomatitis, thrombotic complications and febrile neutropenia-related hospitalizations. Conclusion: DA-EPOCH-R and R-CHOP/R-ICE provide similarly encouraging outcomes in newly-diagnosed PMBCL patients. R-CHOP/R-ICE is associated with lower toxicity and significantly reduced hospitalization. Our findings suggest that this regimen may be considered as an alternative to DA-EPOCH-R in this patient population. [ABSTRACT FROM AUTHOR]

• Serological testing was performed 21 days after first BNT162b2 dose of 1898 Healthcare Workers. • Younger age (<60) was associated with increased likelihood of seroconversion. • Positive serology among females was greater than males. • Delayed second BNT162b2 dose in under 60 s population may be justified if necessary. The coronavirus disease 2019 (COVID-19) pandemic has led to worldwide vaccination development efforts. In December 2020 the Pfizer BNT162b2 vaccine was approved in the United States. This study describes the first BNT162b2 vaccine dose effect on a large cohort. This retrospective study examined first vaccine dose effect on serology and investigated the associations between seroconversion and age or sex. Serological blood tests were performed on 1898 participants following first vaccine dose; 81% were tested on day 21, before receiving the second dose (mean age 47.5 ± 12.45; median 47.7, range 18–90). Positive serology was found in 92.7% of day 21 tests. Overall positivity was 86.8%, with rates increasing from 2.5% within 1–14 days to 89.8% (14–20 days), 92.7% (21 days), and 95.9% (>21 days). Mean antibody levels 21 days after first dose were 64.3 ± 33.01 AU/ml, (range 15–373 AU/ml, median 61 AU/ml). Seropositivity was greater in females than males (88.3%. vs 83.3% respectively, p < 0.001; OR1.515; 95% CI 1.152–1.994). Older age > 60 years was associated with decreased likelihood of seropositivity (p < 0.001; OR 0.926; 95% CI 0.911–0.940). Longer time between first vaccination and serology tests was associated with increased likelihood for seropositivity (p < 0.001; OR 1.350; 95% CI 1.298–1.404). The high seroconversion rate following first BNT162b2 dose among individuals < 60 may justify delayed delivery of the second dose, potentially help relieve the worldwide vaccination supply shortage, enable vaccination of twice this population within a shorter period, and ultimately reduce COVID-19 contagion. [ABSTRACT FROM AUTHOR]

• Inferred viral shedding (cycle threshold [Ct] values) was not different between first variants and Omicron. • No viable SARS-CoV-2 virus was detected in air samples taken in proximity to patients. • No viable SARS-CoV-2 virus was detected in surface samples taken near patients. • Omicron-enhanced transmissibility was not a result of acquiring airborne infectivity. SARS-CoV-2 Omicron strain emergence raised concerns that its enhanced infectivity is partly due to altered spread/contamination modalities. We therefore sampled high-contact surfaces and air in close proximity to patients who were verified as infected with the Omicron strain, using identical protocols applied to sample patients positive to the original or Alpha strains. Cumulatively, for all 3 strains, viral RNA was detected in 90 of 168 surfaces and 6 of 49 air samples (mean cycle threshold [Ct]=35.2±2.5). No infective virus was identified. No significant differences in prevalence were found between strains. [ABSTRACT FROM AUTHOR]

The article discusses a study that describes alterations of bortezomib-induced peripheral neuropathy (BIPN) in patients with multiple myeloma (MM). It shows that reduced soluble brain-derived neurotrophic factor (sBDNF) levels in the plasma concomitant with elevated BDNF content in platelets of MM patients that developed BIPN. It unveils that the patients who developed BIPN had undetectable subclinical disease-related neuropathy before starting treatment.

Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma. Patients with stage I disease are usually treated with radiotherapy (RT). In previous studies, mostly from the pre positron emission tomography-computed tomography (PET-CT) era, the 5 year progression-free survival (PFS) and overall survival (OS) rates of stage I disease were 60-80% and 80-93%, respectively. This study retrospectively evaluated the outcome of stage I FL which was treated with involved field RT in the PET-CT era between 2002 and 2015. Ninety-one patients were enrolled. Five year PFS and OS rates were 73% and 97%, respectively. Relapse occurred in 19 (21%) patients, 74% occurring outside the radiation field. In conclusion, PET-CT staging of clinical stage I FL may contribute to the improved prognosis in patients treated with RT compared to historical cohorts, possibly due to better identification of “genuine” stage I disease. [ABSTRACT FROM AUTHOR]

Circulating chronic lymphocytic leukemia (CLL) cells share phenotypic features with certain subsets of regulatory B-cells (Bregs). The latter cells have been reported to negatively regulate immune cell responses, mostly by provision of IL-10. The purpose of the current study was to identify and delineate Breg properties of CLL cells. B-cells and T-cells were obtained from the peripheral blood of untreated CLL patients diagnosed according to the 2008 Guidelines of the International Workshop on Chronic Lymphocytic Leukemia. Co-culture assays were used to examine the ability of CLL cells to suppress autologous T-cell immune responses. IL-10 potency of CLL cells was assessed following stimulation with activators of the toll-like receptor 9 (TLR9) or CD40 and was correlated with the inhibitory activity of the cells. TLR9-activated CLL cells were found to increase the frequency of CD4+CD25hiFOXp3+ regulatory T-cells (Tregs) and to inhibit autologous CD4+ T-cell proliferation. This signaling cascade proved to control IL-10 generation in CLL cells, which in turn promoted the inhibition of T-cell proliferation by CLL cells. However, CD40 activation of CLL cells, while exhibiting a similar ability to augment Treg frequency, did not either affect IL-10 generation or T-cell proliferation. In conclusion, CLL cells demonstrate a unique clonal quality of adopting Breg properties which promote modulation of T-cell characteristics. TLR9 appears to be a potent activator of regulatory abilities in CLL cells, possibly contributing to preferential immune escape of TLR9-responsive cells. [ABSTRACT FROM AUTHOR]

This multicentre study evaluated 5-year progression-free ( PFS) and overall survival ( OS) in early and advanced Hodgkin lymphoma ( HL), where therapy was individualized based on initial prognostic factors and positron emission tomography-computed tomography performed after two cycles ( PET-2). Between September 2006 and August 2013, 359 patients aged 18-60 years, were recruited in nine Israeli centres. Early- HL patients initially received ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) ×2. Depending on initial unfavourable prognostic features, PET-2-positive patients received additional ABVD followed by involved-site radiotherapy ( ISRT). Patients with negative PET-2 and favourable disease received ISRT or ABVD ×2; those with unfavourable disease received ABVD ×2 with ISRT or, alternatively, ABVD ×4. Advanced- HL patients initially received ABVD ×2 or escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone; EB) ×2 based on their international prognostic score (≤2 or ≥3). PET-2-negative patients further received ABVD ×4; PET-2-positive patients received EB ×4 and ISRT to residual masses. With a median follow-up of 55 (13-119) months, 5-year PFS was 91% and 69% for PET-2-negative and positive early- HL, respectively; 5-year OS was 100% and 95%, respectively. For advanced- HL, the PFS was 81% and 68%, respectively ( P = 0·08); 5-year OS was 98% and 91%, respectively. PET-2 positivity is associated with inferior prognosis in early- HL, even with additional ABVD and ISRT. Advanced- HL patients benefit from therapy escalation following positive PET-2. EB can be safely de-escalated to ABVD in PET-2-negative patients. [ABSTRACT FROM AUTHOR]

The article discusses the preliminary studies which show a possible link between chemotherapy-induced peripheral neuropathy (CIPN) and blood levels of brain-derived neurotrophic factor (BDNF), pointing to BDNF as a potential biomarker for CIPN. It states that vincristine is a chemotherapeutic agent that is associated with CIPN.

COVID-19 exerts deleterious cardiopulmonary effects, leading to a worse prognosis in the most affected. This retrospective multi-center observational cohort study aimed to analyze the trajectories of key vitals amongst hospitalized COVID-19 patients using a chest-patch wearable providing continuous remote patient monitoring of numerous vital signs. The study was conducted in five COVID-19 isolation units. A total of 492 COVID-19 patients were included in the final analysis. Physiological parameters were measured every 15 min. More than 3 million measurements were collected including heart rate, systolic and diastolic blood pressure, cardiac output, cardiac index, systemic vascular resistance, respiratory rate, blood oxygen saturation, and body temperature. Cardiovascular deterioration appeared early after admission and in parallel with changes in the respiratory parameters, showing a significant difference in trajectories within sub-populations at high risk. Early detection of cardiovascular deterioration of COVID-19 patients is achievable when using frequent remote patient monitoring. [ABSTRACT FROM AUTHOR]

Summary Therapeutic options for progressive multifocal leukoencephalopathy (PML) caused by reactivation of John Cunningham virus (JCV) are limited and inefficient in preventing neurological progression and death. The current study investigated the course of JCV reactivation resulting in PML in patients undergoing allogeneic stem cell transplantation (allo-SCT) and assessed the feasibility and potential significance of preemptive JCV detection in peripheral blood, enabling early cessation of immunosuppressive therapy and immune restoration. Two allografted patients were diagnosed with PML at 188 and 808 days post-allo-SCT. Stored DNA samples of both patients, originally obtained for quantitative cytomegalovirus PCR analysis since transplantation, were evaluated for JCV. JCV reactivation in peripheral blood was found to precede the appearance of neurological symptoms by 126 and 105 days. JCV blood levels were found to be highly correlated with the steroid dosage administered for treating graft-versus-host disease (GVHD). In one patient, the cessation of immunosuppression, including steroids, led to the disappearance of JCV in peripheral blood, with a remarkable improvement in neurological symptoms. In conclusion, the current study suggests the feasibility of early detection of JCV reactivation in blood. Immune restoration at that point may prevent PML development; however prospective studies are warranted to elucidate these issues. [ABSTRACT FROM AUTHOR]

Background: BDNF is a neuronal growth factor essential for nervous system maintenance. Objective: We have evaluated peripheral neuropathy (PN) and depression in patients with type 2 diabetic mellitus and looked for an association with serum protein levels of BDNF and the BDNF-Val66Met-SNP. Methods: Symptoms of PN were clinically assessed and graded using Total Neuropathy Score (TNSr) scale. Small nerve fiber testing was performed using the Q-sense device. Depression was assessed using PHQ9 questionnaire. BDNF protein levels and Val66Met-SNP were determined with ELISA and Sanger sequencing respectively. Results: 42 patients, 18 non-insulin treated (NIT) and 24 insulin treated (IT) were included. Albeit similar disease duration, the IT group show increased HbA1c and glucose levels as compared to NIT group, suggesting a more aggressive disease in the IT group. Higher TNSr-sensory and autonomic scores and low sensitivity thresholds to cold, warm and hot-pain signals were found in the IT group. Likewise, PHQ9 score was higher in the IT group. Serum BDNF protein levels were lower in the IT group. Met-BDNF proportion among female patients was lower relative to male patients (23.5% vs. 76.5% respectively, Prob>ChiSq=0.01). Of note, Met-BDNF female patients were all in the IT group and show a trend of increased TNSr and PHQ9 score as compared to Val-BDNF female patients. Correlations between patients' PHQ9 score and TNSr score or Q-sense cold and warm sensitivity thresholds were found only in Met-BDNF carriers, suggesting that PN and depression are coincided in Met-BDNF carriers. Conclusion: A diminished peripheral BDNF resource in our IT patients is associated with uncontrol diabetes and underlined augmented symptoms of PN and depression. The negative effect of Met-BDNF in female patients and the correlation of depression and PN in Met-BDNF should be further studied. Disclosure: A. Bashkin: None. A. Safadi: None. B. Gross: None. N.A. Horowitz: None. R. Sharon: None. E. Shaoul: None. M. Nodelman: None. D. Azoulay: None. Funding: D-Cure [ABSTRACT FROM AUTHOR]