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Ben Varon,1 Netanel A Horowitz,1,2 Hazim Khatib1 1Department of Hematology and Bone Marrow Transplantation, Rambam Healthcare Campus, Haifa 3109601, Israel; 2Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3109601, IsraelCorrespondence: Ben Varon, Department of Hematology and Bone Marrow Transplantation, Rambam Healthcare Campus, Haifa, 3109601, Israel, Tel +972-4-7778026, Email b_varon@rambam.health.gov.ilAbstract: This article provides an overview of the novel treatments focusing on the class of bispecific T cell engagers (BiTEs) for the treatment of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), the two most prevalent subtypes of B cell non-Hodgkin lymphomas (B-NHL). After a brief outline of these diseases, the difficulties in the management of relapsed or refractory (R/R) disease are highlighted. There are currently 4 main BiTEs showing promise in treating R/R B-NHL—glofitamab, epcoritamab, mosunetuzumab, and odronextamab. Although the rational of their mechanism of action is similar, there are significant differences in their respective clinical trial design, reported outcomes, and the final FDA approvals. Considerations for selecting a specific BiTE therapy, including treatment duration, cost, administration route, adverse effects, and impact on quality of life, are also discussed. Patient preferences and shared decision making should be acknowledged by healthcare providers. Finally, the importance of personalized treatment strategies and ongoing research to optimize outcomes in the evolving landscape of R/R B-NHL therapy cannot be overstated.Keywords: bispecific, BiTE, glofitamab, epcoritamab, mosunetuzumab, odronextamab

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., (© 2024. The Author(s).)

Informal caregivers of cancer patients are known to experience extensive burdens, while this issue remains unresolved in the setting of hematological malignancies. Yet, these diseases are characterized by a prolonged course, numerous relapses and implementation of multi-line therapy, administered in outpatient facilities. The current study aimed to assess the factors contributing to burden and depressive symptoms in informal caregivers of patients with hematological malignancies, while concentrating on the role of medical visits. The study population comprised patients and their caregivers, recruited at the Rambam Hematology Ambulatory Unit. Participants completed validated questionnaires, including the Center for Epidemiologic Studies Depression Scale and Zarit Caregiver Burden Interview. The cohort (n=185) included 115 patients [average age 62.8+14.5 years; 54 males] and 70 caregivers. Among caregivers, 80% reported high psychological burden and 50% reported significant depressive symptoms. The burden was higher if caregivers were females, and if patients were less educated, less healthy and more depressed. The caregiver burden and depressive symptoms were significantly linked and the medical visit frequency predicted the level of both. The caregiver burden fully mediated the link between the independent variables of self-rated health and medical visits, and the dependent variable of caregiver depressive symptoms. Informal caregivers of ambulatory hemato-oncological patients experience high levels of psychological burden and depressive symptoms. This is partly attributed to the medical visit frequency. Hence, a decrease in the number and length of such visits via the implementation of advanced technology could essentially reduce burden and depressive symptoms of caregivers, without compromising patient outcomes., (Copyright © 2024 American Society of Hematology.)

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.

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., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

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., (© 2023 American Cancer Society.)

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.

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., Competing Interests: None declared., (Thieme. All rights reserved.)

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., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Introduction: The fourth SARS-CoV-2 vaccine dose was found to protect against infection and more importantly against severe disease and death. It was also shown that the risk of symptomatic or severe disease was related to the antibody levels after vaccination or infection, with lower protection against the BA.4 BA.5 Omicron variants. The aim of our study was to assess the impact of the fourth dose on infection and perception of illness seriousness among healthcare workers (HCWs) at a tertiary health care campus in Haifa, Israel, and to investigate the possible protective effect of antibody levels against infection., Methods: We conducted a prospective cohort study among fully vaccinated HCWs and retired employees at Rambam Healthcare Campus (RHCC), a tertiary hospital in northern Israel. Participants underwent serial serological tests at 1, 3, 6, 9, 12 and 18 months following the second BNT162b2 vaccine dose. Only a part of the participants chose to receive the fourth vaccine. A multivariable logistic regression was conducted to test the adjusted association between vaccination, and the risk of infection with SARS-CoV-2. Kaplan-Meier SARS-CoV-2 free "survival" analysis was conducted to compare the waning effect of the first and second, third and fourth vaccines. Receiver Operating Characteristic (ROC) curve was plotted for different values of the sixth serology to identify workers at risk for disease., Results: Disease occurrence was more frequent among females, people age 40-50 years old and those with background chronic lung disease. The fourth vaccine was found to have better protection against infection, compared to the third vaccine; however, it also had a faster waning immunity compared to the third vaccine dose. Antibody titer of 955 AU/mL was found as a cutoff protecting from infection., Conclusions: We found that the fourth vaccine dose had a protective effect, but shorter than the third vaccine dose. Cutoff point of 955 AU/mL was recognized for protection from illness. The decision to vaccinate the population with a booster dose should consider other factors, including the spread of disease at the point, chronic comorbidities and age, especially during shortage of vaccine supply.

Objectives: 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., Methods: 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., Results: 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)., Discussion: 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., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

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.

This study assessed humoral response to the third BNT162b2 dose among healthcare workers (HCW). This prospective cohort study of HCW tested for anti-spike antibodies (LIAISON SARS-CoV-2 S1/S2 IgG assay) at 1, 3, 6, 9, and 12 months after receiving the second BNT162b2 vaccine dose (tests 1, 2, 3, 4, and 5, respectively). A third (booster) vaccination dose was introduced before test 4. Linear regression model was used to determine the humoral response following vaccine doses. For each serology test, changes in log-transformed antibody concentrations over time, adjusted for age, sex, underlying diseases, steroid treatment, and smoking were described using the general linear mix model. Serology tests were performed at 3, 6, 9, and 12 months after the second vaccine dose in 1113, 1058, 986, and 939 participants, respectively. The third dose was received by 964 participants before the 9-month tests, 797 of whom participated in the 9- and 12-month serology tests. A significant inverse correlation was noted between time from third dose and antibody concentrations (Spearman correlation −0.395; p < 0.001). Age (p < 0.0001; CI 95% −0.005−−0.004), heart disease (p < 0.0001; CI 95% −0.177−−0.052), immunodeficiency (p < 0.0001; CI 95% 0.251−−0.106), and smoking (p < 0.0001; CI 95% −0.122−−0.040) were significantly associated with decreased antibody concentrations. Female sex (p = 0.03; CI 95% 0.013−0.066) was associated with increased antibody concentrations. The third booster dose had a better effect on immunogenicity, with higher antibody concentrations among tested HCW. Heart disease, smoking, and other known risk factors were associated with decreased antibody concentrations.

Background: 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., Methods: 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., Results: 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%., Conclusions: Significant CRT risk factors defined using the created model could be used for identification of high-risk newly-diagnosed AML patients requiring CRT prophylaxis., (Copyright © 2022. Published by Elsevier B.V.)

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., Competing Interests: Conflict of interest None declared., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: We evaluated the antibody response to the BNT162B2 vaccine among healthcare workers (HCWs) to identify factors associated with decreased immunogenicity., Methods: This prospective cohort study included consenting HCWs who completed a questionnaire regarding background illnesses, medications, and post-vaccination allergic reactions or rash. All HCWs were tested for anti-spike antibodies (LIAISON SARS-CoV-2 S1/S2 IgG assay) 1 and 3 months after the second vaccine dose. A multivariate mixed linear model was adjusted to participants' data and fit to predict antibody levels after the second BNT162B2 vaccine dose, based on antibody levels at 1 month and the slope between 3 months and 1 month. Multivariate analyses identified factors associated with lower antibody levels., Results: In total 1506 HCWs were tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies. Older age was associated with lower mean antibody levels (-1.22 AU/mL, p < 0.001, 95%CI -1.43 to -1.01). In addition, male sex (-22.16 AU/mL, p < 0.001, 95%CI -27.93 to -16.39), underlying condition (-10.86 AU/mL, p 0.007, 95%CI -18.81 to -2.91) and immunosuppressive treatment (-28.57 AU/mL, p 0.002, 95%CI -46.85 to -10.29) were associated with significantly lower mean antibody levels. Allergic reactions after vaccine administration or peri-vaccination glucocorticosteroid treatment were not correlated with antibody levels., Conclusions: Most HCWs had measurable antibodies at 3 months. Risk factors for lower antibody levels were older age, male sex, underlying condition, and immunosuppressive treatment. These factors may be considered when planning booster doses during vaccine shortages., (Copyright © 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Patients with lymphoma, especially those treated with anti-CD20 monoclonal antibodies, suffer high COVID-19-associated morbidity and mortality. The goal of this study was to assess the ability of lymphoma patients to generate a sufficient humoral response after two injections of BNT162b2 Pfizer vaccine and to identify factors influencing the response. Antibody titers were measured with the SARS-CoV-2 IgG II Quant (Abbott ) assay in blood samples drawn from lymphoma patients 4 2 weeks after the second dose of vaccine. The cutoff for a positive response was set at 50 AU/mL. Positive serological responses were observed in 51% of the 162 patients enrolled in this cross-sectional study. In a multivariate analysis, an interval of <12 months between the last anti-CD20 monoclonal antibody dose and the second vaccine dose (odds ratio=31.3 [95% confidence interval: 8.4-116.9], P<0.001) and presence of active lymphoma (odds ratio=4.2 (95% confidence interval: 2.1- 8.2), P=0.006) were identified as negative response predictors. The rate of seropositivity increased from 3% in patients vaccinated within 45 days after the last monoclonal antibody administration to 80% in patients vaccinated >1 year after this therapy. The latter percentage was equal to that of patients never exposed to monoclonal antibodies. In conclusion, lymphoma patients, especially those recently treated with anti- CD20 monoclonal antibodies, fail to develop sufficient humoral response to BNT162b2 vaccine. While a serological response is not the only predictor of immunity, its low level could make this population more vulnerable to COVID-19, which implies the need for a different vaccination schedule for such patients.

Emerging studies have highlighted brain-derived neurotrophic factor (BDNF), a neuronal growth factor abundant in the peripheral blood, and its tyrosine kinase receptor TRKB, as onco-genes and proteins that support the survival of malignant hematological cells. In contrast, other researchers reported on a favorable association between BDNF blood levels and prognosis, chemotherapy response and neurological side effects in patients with hematological malignancies. Here, we review the accumulated data regarding the expression of BDNF and its receptors in normal hematopoietic and lymphatic cells and tissue. In addition, in-vitro experiments, animal models and human sample studies that investigated the role of BDNF and its receptors in hematological malignancies are discussed. Finally, directions for future research aimed at revealing the mechanisms underlying the protective effect of BDNF in patients with these diseases are suggested., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: 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., Methods: This retrospective study examined first vaccine dose effect on serology and investigated the associations between seroconversion and age or sex., Results: 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)., Conclusions: 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Bimiralisib is an orally bioavailable pan-phosphatidylinositol 3-kinase and mammalian target of rapamycin inhibitor which has shown activity against lymphoma in preclinical models. This phase I/II study evaluated the response rate to bimiralisib at 2 continuous dose levels (60 mg and 80 mg) in patients with relapsed/refractory lymphoma. Fifty patients were enrolled and started treatment. The most common histologies were diffuse large B-cell lymphoma (n = 17), follicular lymphoma (n = 9), T-cell lymphoma (n = 8), and others (mostly indolent). Patients had been treated with a median of 5 prior lines of treatment and 44% were considered refractory to their last treatment. Mean duration of treatment (and standard deviations) with 60 mg once daily (o.d.) was 1.3 ± 1.2 months, and with 80 mg o.d. 3.7 ± 3.9 months. On an intention to treat analysis, the overall response rate was 14% with 10% achieving a partial response and 4% a complete response. Thirty-six percent of patients were reported as having stable disease. No dose-limiting toxicities were observed during the phase I portion of the study. Overall, 70% of patients had a grade 3 treatment emergent adverse events (TEAE) and 34% had a grade 4 TEAE; 28% of patients discontinued treatment due to toxicity. The most frequent TEAEs grade ≥3 was hyperglycemia (24%), neutropenia (20%), thrombocytopenia (22%), and diarrhea (12%). Per protocol, hyperglycemia required treatment with oral antihyperglycemic agents in 28% and with insulin in 14%. At 60 mg or 80 mg continuous dosing, bimiralisib showed modest efficacy with significant toxicity in heavily pretreated patients with various histological subtypes of lymphoma., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

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.

Objective: In response to the coronavirus disease 2019 (COVID-19) pandemic, the Israeli government strategy initially focused on containment. The Ministry of Health mandated isolation of COVID-19 patients in hospitals and instructed healthcare institutions to make necessary arrangements. As the second Israeli hospital to establish a COVID-19 department, this article describes our experience in its rapid establishment, while maintaining normal medical center activities., Setting: Establishing the COVID-19 department involved planning, set-up, and implementations phases, each one based on knowledge available regarding the pandemic and established medical standards for isolation and protection of patients and staff. Wherever possible, new innovative technologies were utilized to provide maximum protection for both patients and staff, together with special online training that was developed for medical teams., Results: A COVID-19 department was successfully established on the hospital campus, remote from other ongoing patient activities. A novel methodology of disease-adapted medicine was implemented successfully among the department's medical staff, who underwent training tailored to expected clinical scenarios. The COVID-19 department is receiving patients, with no contamination of medical personnel to date. A recent survey of COVID-19 patients revealed a very high patient satisfaction rate., Conclusion: Based on the experience described herein and lessons learned, the hospital is preparing for a potential large-scale COVID-19 wave, aimed at full readiness through utilization of a fortified underground emergency hospital to treat up to 900 COVID-19 patients, and establishment of versatile in-hospital infrastructure for quick conversion from standard conditions to COVID-19 appropriate conditions.

Competing Interests: Dr. Brenner reports personal fees from Pfizer, LEO Pharma, Sanofi, ROVI Laboratories, and Bayer Pharmaceuticals, outside the submitted work.

A B S T R A C T Thrombotic events are a major cause of morbidity and mortality in cancer. While the association of venous thromboembolic events with cancer is well documented, in recent years arterial events (i.e. acute myocardial infarction and ischemic strokes) have also emerged as relatively common complications among cancer patients. In hematological malignancies incorporating a heterogeneous group of diseases, the prediction of thrombosis occurrence and/or recurrence is challenging, due to unique disease characteristics. Furthermore, the treatment of thrombosis in these patients is often complicated because of disease- or therapy-related thrombocytopenia. In addition, patients with hematological cancers are poorly represented in randomized control clinical trials; hence, evidence-based guidelines are limited. This review will discuss the incidence of venous and arterial thrombotic events in common myeloid and lymphoproliferative diseases. Several new mechanisms contributing to cancer- associated thrombosis will be elaborated. The complicated issue of risk assessment and management of venous thrombosis in patients with hematological malignancies will be delineated., (© 2020 Elsevier Ltd. All rights reserved.)

Objective: This paper describes how a large academic medical center solved the challenges of war preparedness and subsequently adapted them for the COVID-19 pandemic., Setting: A 1,000-bed academic medical center in Northern Israel has faced two extreme challenges since 2006: operating under missile attack during the 2006 Second Lebanon War, and rapid establishment of a scalable infrastructure for COVID-19 patients. The first challenge led to construction of a dual-use facility: a parking lot during peacetime, and a fully functioning fortified underground emergency hospital (FUEH) in times of emergency. Several drills have confirmed readiness for various scenarios including conventional and unconventional warfare, and treating isolated patients during the Ebola and SARS threats., Results: The hospital achieved preparedness for patient care during the COVID-19 pandemic, including all facilities and personnel, including infrastructure, laboratories, and innovations, to maintain standard patient care and separate COVID-19 treatment facilities. The hospital's second challenge represented by the COVID-19 pandemic led to adaptation of the FUEH as a key strategic facility in Northern Israel for treating hundreds of COVID-19 patients. Each solution was supported by innovations targeted for specific purposes and needs., Conclusions: The function and unique mechanisms used to leverage use of a dual facility was proven viable for several emergency conditions, including the COVID-19 pandemic. Infrastructure and technological flexibility is essential when planning for handling different emergencies situations.

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., (© 2019 by The American Society of Hematology.)

Background and Purpose: Brain-derived neurotrophic factor (BDNF) is a neuronal growth factor that plays an essential role in the maintenance of the nervous system. We have evaluated the peripheral blood protein levels of BDNF and the valine-to-methionine substitution at codon 66 (Val66Met) single-nucleotide polymorphism (SNP) as potential biomarkers for the early recognition of chemotherapy-induced peripheral neuropathy (CIPN) in non-Hodgkin lymphoma and multiple myeloma patients., Methods: CIPN was assessed in 45 patients at the diagnosis and during vincristine or bortezomib-based therapy using objective [reduced version of the Total Neuropathy Score (TNSr)] and subjective (FACT-GOG-NTx) tools. Depression was assessed using the Patient Health Questionnaire-9 (PHQ-9) questionnaire. BDNF protein levels and the Val66Met SNP were determined using ELISA and Sanger sequencing., Results: The pretreatment BDNF protein level was inversely correlated with the maximum TNSr, FACT-GOG-NTx, and PHQ-9 scores in both genotypes. BDNF patients with the Val/Val genotype demonstrated significantly higher maximum FACT-GOG-NTx and PHQ-9 scores than those with the Val/Met and Met/Met genotypes (Met-BNDF carriers). Correlations between PHQ-9 and TNSr score were found only in Met-BDNF carriers, suggesting that peripheral neuropathy and depression coincide in Met-BDNF carriers., Conclusions: Determining the BDNF protein levels before initiating chemotherapy might be a useful tool for CIPN risk assessment and preemptive dose modification. The present data should be validated in larger studies that include other neurotoxic agents., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2019 Korean Neurological Association.)

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.

Background: 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., Methods: We did a two-part, open-label, phase 1/2a study at 21 hospitals in Australia, Israel, Poland, Spain, Turkey, and the USA. The primary objective of part A (dose escalation) was to assess the safety of daily oral ibrutinib (420 mg or 560 mg) in combination with intravenous nivolumab (3 mg/kg every 2 weeks) to ascertain a recommended phase 2 dose in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, or diffuse large B-cell lymphoma. Dose optimisation was investigated using a modified toxicity probability interval design. The primary objective of the part B expansion phase was to establish the preliminary activity (the proportion of patients who achieved an overall response) of the combination of ibrutinib and nivolumab in four cohorts: relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, diffuse large B-cell lymphoma, and Richter's transformation. All participants who received at least one dose of treatment were included in the primary analysis and analyses were done by disease cohort. This trial is registered with ClinicalTrials.gov, number NCT02329847. The trial is ongoing., Findings: Between March 12, 2015, and April 11, 2017, 144 patients were enrolled in the study. Three patients died before receiving study treatment; thus, 141 patients were included in the analysis, 14 in part A and 127 in part B. One dose-limiting toxicity (grade 3 hyperbilirubinaemia) was reported at the 420 mg dose in the diffuse large B-cell lymphoma cohort, which resolved after 5 days. The combination of ibrutinib and nivolumab led to overall responses in 22 (61%) of 36 patients with high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma, 13 (33%) of 40 patients with follicular lymphoma, 16 (36%) of 45 patients with diffuse large B-cell lymphoma, and 13 (65%) of 20 patients with Richter's transformation. The most common all-grade adverse events were diarrhoea (47 [33%] of 141 patients), neutropenia (44 [31%]), and fatigue (37 [26%]). 11 (8%) of 141 patients had adverse events leading to death; none were reported as drug-related. The most common grade 3-4 adverse events were neutropenia (40 [28%] of 141 patients) and anaemia (32 [23%]). The incidence of grade 3-4 neutropenia ranged from eight (18%) of 45 patients with diffuse large B-cell lymphoma to 19 (53%) of 36 patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma; incidence of grade 3-4 anaemia ranged from five (13%) of 40 patients with follicular lymphoma to seven (35%) of 20 patients with Richter's transformation. The most common serious adverse events included anaemia (six [4%] of 141 patients) and pneumonia (five [4%]). The most common grade 3-4 immune-related adverse events were rash (11 [8%] of 141 patients) and increased alanine aminotransferase (three [2%])., Interpretation: The combination of ibrutinib and nivolumab had an acceptable safety profile and preliminary activity was similar to that reported with single-agent ibrutinib in chronic lymphocytic leukaemia or small lymphocytic lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. The clinical response in patients with Richter's transformation was promising and supports further clinical assessment., Funding: Janssen R&D., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Acute lymphoblastic leukemia (ALL) is a clonal disease of the hematopoietic system characterized by unique genetic characteristics. The significance of these genetic features has evolved over the past three decades. In the 1980s and 1990s, the primary interest was in excluding the Philadelphia chromosome; a finding more common in older adults which uniformly predicted for a rapidly fatal outcome. Areas covered: Over the past 15 years, much has evolved. Tyrosine kinase inhibitors completely changed the prognosis of Ph-positive ALL. In addition, the genetic characterization of Ph-negative ALL has significantly advanced through systematic progressive analyses of genetic data from large trial groups. These led to specific and more accurate prognostication, particularly at initial diagnosis. Expert commentary: These cytogenetic and molecular features will be reviewed in this paper and their ongoing significance will be critically analyzed in the era of minimal residual disease (MRD) determination, which has now superseded all the major known historic prognostic factors.

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.

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 + CD25 hi FOXp3 + 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.

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.

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., (© 2017 John Wiley & Sons Ltd.)

Allogeneic hematopoietic cell transplantation for acute lymphoblastic leukemia (ALL) offers curative therapy for patients who are in complete remission. Historically, there was great hesitation to offer this modality to patients with ALL due to the high attendant morbidity and mortality. Furthermore, the outstanding results in childhood ALL led many to believe that significant long-term survival could be achieved using chemotherapy-based regimens alone. The International ALL Study jointly conducted by ECOG and MRC completely changed perceptions indicating, surprisingly to many, that transplantation - particularly for patients at standard risk - offered a significant survival advantage. There followed trials of more intensive chemotherapy demonstrating improved results that may obviate the need for allogeneic transplantation. While a certain controversy reigns, there are unequivocal high-risk scenarios where allogeneic transplantation still forms the core of curative therapy. Such transplants should be performed as early as possible in the course of the disease once remission has been obtained., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

With increase of maternal age, the incidence of haematological malignancies during pregnancy is rising and posing diagnostic and treatment challenges. Lymphoma is the fourth most common malignancy diagnosed in pregnancy; Hodgkin lymphoma is more frequent in pregnant women than non-Hodgkin lymphoma (NHL). The proportion of highly aggressive lymphomas in pregnant women is significantly higher than in non-pregnant women of reproductive age. Reproductive organ involvement is observed in almost half of pregnant women with NHL. The association of acute leukaemia and pregnancy is infrequent and it is assumed that pregnancy does not accelerate the disease course. Both cancer and pregnancy induce a procoagulant state which can lead to maternal venous thromboembolism (VTE) and placental occlusion. Pregnancy in woman with myeloproliferative neoplasms (MPN) promotes thrombotic environment, associating with an augmented risk of placental thrombosis, intrauterine growth retardation or loss and maternal thrombotic events.Haematological malignancies during pregnancy often require urgent diagnosis and management and are associated with potential adverse fetal outcomes. Most chemotherapeutic agents are teratogenic and should be avoided during the first trimester. Their use during the second and third trimesters may cause intrauterine growth restriction, premature birth and intrauterine fetal death. All chemotherapeutic drugs should be administered only after a detailed discussion with the patient and with close fetal monitoring. Chemotherapy and biological agents might also augment thrombotic risk. Guidelines for VTE prophylaxis in pregnant women with hematologic malignancies, apart from MPN, are currently unavailable, and therefore, clinical judgment should be made in each case.

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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)