Eosinophilic Pleocytosis in the Cerebrospinal Fluid following CAR-T Cell Therapy for Central Nervous System Lymphoma: A Case for Warning?

INTRODUCTION: Chimeric antigen receptor T (CAR-T) cell therapy, emerging as an efficient treatment option for patients with secondary central nervous system (CNS) lymphoma, is frequently complicated with immune effector cell-associated neurotoxicity syndrome (ICANS). CASE PRESENTATION: We report a case of a 64-year-old woman with transformed follicular lymphoma, developing high-grade ICANS with eosinophilic pleocytosis following third-line therapy with CAR-T cells (tisagenlecleucel). During bridging therapy, she declined neurologically and was diagnosed with secondary CNS lymphoma. She received methotrexate-cytarabine-thiotepa-rituximab regimen with clinical and radiological improvement. Post-CAR-T cell infusion she developed cytokine release syndrome grade II and ICANS grade III. Given the lack of response to steroids, anakinra was initiated with complete ICANS resolution. Cerebrospinal fluid (CSF) analysis, performed only on day +10 due to thrombocytopenia, revealed eosinophils, while infections were excluded. CONCLUSION: This report emphasizes the importance of CSF analysis in individuals with CAR-T-related neurotoxicity for elucidating the role of specific immune cells in such complications.

Outcomes of venous thromboembolism in patients with inherited thrombophilia treated with direct oral anticoagulants: insights from the RIETE registry.

While direct oral anticoagulants (DOACs) are frequently used to treat venous thromboembolism (VTE), the outcomes of patients with inherited thrombophilia (IT) receiving DOACs for VTE remain understudied. We used data from the international RIETE registry to compare the rates of VTE recurrences, major bleeding, and mortality during anticoagulant treatment in VTE patients with and without IT, grouped by the use of DOACs or standard anticoagulant therapy. Among 103,818 enrolled patients, 21,089 (20.3%) were tested for IT, of whom 8422 (39.9%) tested positive: Protein C deficiency 294, Protein S deficiency 726, Antithrombin deficiency 240, Factor V Leiden 2248, Prothrombin gene mutation 1434, combined IT 3480. Overall, 14,189 RIETE patients (6.2% with IT) received DOACs, and 89,629 standard anticoagulation (8.4% with IT), mostly with heparins followed by vitamin K antagonists. Proportions of patients receiving DOACs did not differ between IT-positive and IT-negative patients. Rates of VTE recurrence on anticoagulant treatment were highest in patients with AT deficiency (P < 0.01). Rates of on-treatment major bleeding and all-cause mortality were lowest among patients with Factor V Leiden (FVL) or PT G20210A mutations, compared with patients who tested negative. Patients with IT who received DOACs had lower rates of major bleeding than those receiving standard anticoagulation. Excluding FVL and Protein S deficiency, patients with IT had lower rates of VTE recurrence with DOACs than with standard anticoagulation. DOACs are equally safe and effective in VTE patients with IT, with lower bleeding rates than those on standard anticoagulation.

Outcome of Cancer-Associated Venous Thromboembolism Is More Favorable among Patients with Hematologic Malignancies than in Those with Solid Tumors.

BACKGROUND: The natural history of patients with hematologic cancer and venous thromboembolism (VTE) has not been consistently evaluated. We aimed to compare the rates of symptomatic recurrent VTE, major bleeding, or death during anticoagulant therapy in patients with VTE associated with hematologic versus solid cancers. METHODS: Consecutive patients with active cancer recruited in RIETE were evaluated. Their baseline characteristics, treatments, and outcomes during the course of anticoagulation were compared. Univariate and multivariate competing-risk analyses were performed. RESULTS: As of December 2020, 16,694 patients with cancer and VTE were recruited. Of these, 1,062 (6.4%) had hematologic cancers. Hematologic patients were less likely to initially present with pulmonary embolism (46 vs. 55%) and more likely with upper extremity deep vein thrombosis (25 vs. 18%). They also were more likely to have severe thrombocytopenia at baseline (5.6 vs. 0.7%) or to receive chemotherapy (67 vs. 41%). During the course of anticoagulation (median, 150 vs. 127 days), 1,071 patients (6.4%) developed VTE recurrences, 806 (4.8%) suffered major bleeding, and 4,136 (24.8%) died. Patients with hematologic cancers had lower rates of recurrent VTE (rate ratio [RR]: 0.73; 95% confidence interval [CI]: 0.56-0.95), major bleeding (RR: 0.72; 95% CI: 0.53-0.98), or all-cause death (RR: 0.49; 95% CI: 0.41-0.57) than those with solid cancers. Patients with multiple myeloma showed the best outcomes. CONCLUSION: Patients with hematologic cancers, particularly multiple myeloma, and VTE had better outcomes than those with solid cancers. These findings are relevant for the interpretation of previous clinical trials and the design of future studies.

Humoral serological response to the BNT162b2 vaccine is abrogated in lymphoma patients within the first 12 months following treatment with anti-CD2O antibodies.

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.

Multicentric Castleman disease presenting as a chylous pleural effusion.

Castleman disease is a rare lymphoproliferative disorder presenting frequently with constitutional symptoms. Although pleural effusion is common, there is only one case report of an adult patient with chylous pleural effusion. We present the first case report of a hypervascular variant of Castleman disease presenting as a chylous pleural effusion and successfully treated with a combination of anti-interleukin-6 agent and steroids.

Outcome of patients with acute symptomatic pulmonary embolism and psychiatric disorders.

OBJECTIVE: To address the association between psychiatric disorders and short-term outcomes after acute symptomatic pulmonary embolism (PE). METHODS: We identified adults with PE enrolled in the RIETE registry between December 1, 2013, and January 31, 2019. Using multinomial regression, we assessed the association between a history of psychiatric disorders and the outcomes of all-cause mortality, PE-related mortality, and venous thromboembolism recurrence and bleeding rates through 30 days after initiation of treatment. We also examined the impact of depression on all-cause and PE-specific mortality. RESULTS: Among 13,120 patients diagnosed with acute PE, 16.1% (2115) had psychiatric disorders and 4.2% died within the first 30-days of follow-up. Patients with psychiatric disorders had increased odds for all-cause (adjusted odds ratio [OR] 1.50; 95% CI, 1.21 to 1.86; P < 0.001) and PE-related mortality (adjusted OR 1.64; 95% CI, 1.09 to 2.48; P = 0.02) compared to those without psychiatric disorders. Multinomial logistic regression showed a non-significant trend toward lower risk of recurrences for patients with psychiatric disorders (adjusted OR 0.49; 95% CI, 0.21 to 1.15; P = 0.10). Psychiatric disorders were not significantly associated with increased odds for major bleeds during follow-up (adjusted OR 1.09; 95% CI, 0.85 to 1.40; P = 0.49). Results were consistent in a sensitivity analysis that only considered patients with a diagnosis of depression. CONCLUSIONS: In patients with acute PE, history of psychiatric disorders might predict all-cause and PE-related death in the ensuing month after diagnosis.

Direct Oral Anticoagulants for the Treatment of Acute Venous Thromboembolism Associated with Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: International guidelines have endorsed the use of edoxaban or rivaroxaban as an alternative to low-molecular-weight heparin (LMWH) for the treatment of acute venous thromboembolism (VTE) in cancer patients. Recently, a large randomized controlled trial of apixaban versus dalteparin in patients with cancer was completed. We performed an updated meta-analysis to assess the efficacy and safety of direct oral anticoagulants (DOACs) versus LMWH in patients with cancer-associated VTE. METHODS: MEDLINE, EMBASE, and CENTRAL (Cochrane Controlled Trials Registry) were systematically searched up to March 30, 2020 for randomized controlled trials comparing DOACs versus LMWH for the treatment of VTE in patients with cancer. The two coprimary outcomes were recurrent VTE and major bleeding at 6 months. Data were pooled by the Mantel-Haenszel method and compared by relative risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS: Four randomized controlled studies (2,894 patients) comparing apixaban, edoxaban, or rivaroxaban with dalteparin were included in the meta-analysis. Recurrent VTE occurred in 75 of 1,446 patients (5.2%) treated with oral factor Xa inhibitors and in 119 of 1,448 patients (8.2%) treated with LMWH (RR 0.62; 95% CI 0.43-0.91; I 2, 30%). Major bleeding occurred in 62 (4.3%) and 48 (3.3%) patients receiving oral factor Xa inhibitors or LMWH, respectively (RR 1.31; 95% CI 0.83-2.08; I 2, 23%). CONCLUSION: In patients with cancer-associated VTE, oral factor Xa inhibitors reduced the risk of recurrent VTE without a significantly higher likelihood of major bleeding at 6 months compared with LMWH.

Psychotropic Drugs and Outcome in Patients Receiving Anticoagulant Therapy for Venous Thromboembolism.

BACKGROUND: The influence (if any) of the use of psychotropic drugs on outcome in patients receiving anticoagulant therapy for venous thromboembolism (VTE) has not been consistently evaluated. METHODS: We used data from the RIETE (Registro Informatizado Enfermedad TromboEmbólica) database to compare the risk for VTE recurrences, major bleeding, or death during the course of anticoagulant therapy, according to the use of psychotropics at baseline. RESULTS: Among 49,007 patients with VTE enrolled from February 2009 to September 2019, total 5,230 (11%) were using psychotropics at baseline: antidepressants 3,273 (6.7%), antipsychotics 1,588 (3.2%), and anticholinesterases 369 (0.7%). During the course of anticoagulation, 1,259 patients developed VTE recurrences, 1,231 bled, and 3,988 died (fatal pulmonary embolism 269 and fatal bleeding 187). On multivariable analysis, patients using psychotropics at baseline had a similar risk for VTE recurrences (adjusted hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.58-1.12), a nonsignificantly higher risk for major bleeding (adjusted HR: 1.15; 95% CI: 0.97-1.35), and a higher risk for intracranial bleeding (adjusted HR: 1.83; 95% CI: 1.32-2.53) or death (adjusted HR: 1.44; 95% CI: 1.32-1.57) compared with those not using psychotropics. When separately analyzed, the highest risk for intracranial bleeding was found in patients using antidepressants (adjusted HR: 1.60; 95% CI: 1.08-2.37) or antipsychotics (adjusted HR: 2.02; 95% CI: 1.17-3.49) but not in those on anticholinesterases (adjusted HR: 1.69; 95% CI: 0.62-4.60). CONCLUSION: During the course anticoagulation for VTE, patients using psychotropics at baseline were at increased risk for intracranial bleeding.

Non-ST-Elevation Myocardial Infarction with Non-significant Coronary Artery Disease as a Symptom of Occult or New Malignancy.

BACKGROUND: Malignancy is a known risk factor for venous thromboembolism; however, the association with arterial thromboembolic events remains unclear. OBJECTIVES: To examine the association between non-ST-elevation myocardial infarction (NSTEMI) and non-significant coronary artery disease (CAD) and the presence of new or occult malignancy. METHODS: An observational cohort, single-center study was performed 2010-2015. Adult patients with NSTEMI, who underwent coronary angiography and had no significant coronary lesion, were included. Using propensity score matching, we created a 2:1 matched control group of adults with NSTEMI, and significant coronary artery disease. Risk factors for new or occult malignancy were assessed using multivariate backward stepwise logistic regression analysis. The primary outcome was new or occult malignancy, defined as any malignancy diagnosed in the 3 months prior and 6 months following the myocardial infarction (MI). RESULTS: During the study period, 174 patients who presented with MI with non-obstructive coronary arteries were identified. The matched control group included 348 patients. There was no significant difference in the group demographics, past medical history, or clinical presentation. The incidence of new or occult malignancy in the study group was significantly higher (7/174, 4% vs. 3/348, 0.9%, P = 0.019). NSTEMI with non-significant CAD was an independent risk factor for occult malignancy (odds ratio [OR] 4.6, 95% confidence interval [95%CI] 1.1-18.7). Other risk factors included active smoking (OR 11.2, 95%CI 2.5-49.1) and age (OR 1.1, 95%CI 1.03-1.17). CONCLUSIONS: NSTEMI with non-significant CAD may be a presenting or early marker of malignancy and warrants further investigation.

Hemostasis and Thrombosis in the Oldest Old.

There is a growing proportion of the elderly population in the Western world, and these individuals require special considerations regarding a broad variety of aspects, including treatment approaches to illnesses that affect all age groups. The hemostatic system in individuals changes considerably with aging. Specifically, changes in levels of procoagulant and natural anticoagulant factors along with thrombopathy simultaneously create a hypercoagulable state and hemostatic difficulties. Underlying morbidities, such as congestive heart failure, chronic obstructive pulmonary disease, diabetes mellitus, and cancer, increase the risk for venous and arterial thrombosis. This population is also increasingly affected by acquired bleeding disorders, including acquired hemophilia and acquired von Willebrand syndrome, as well as mild congenital bleeding disorders. Real-life data demonstrate that recurrent and fatal venous thromboembolism is the major hemostatic concern in the elderly. The fact that treatment of thrombotic complications increases the bleeding risk also has to be taken into consideration, particularly in the older age group. This remains true in the era of direct oral anticoagulants. In conclusion, maintaining a delicate balance between thrombosis and bleeding risks is the key issue in providing qualified treatment to elderly patients.

Arterial Ischemic Events Are a Major Complication in Cancer Patients with Venous Thromboembolism.

BACKGROUND: Venous thromboembolism is common in patients with malignancies, affecting up to 10% of this patient population. The association between arterial ischemic events and venous thromboembolism also has been established. However, the influence of arterial ischemic events on outcomes in cancer patients with venous thromboembolism has not been fully determined. METHODS: The current study analyzed clinical characteristics, time course, risk factors, incidence and severity of venous thromboembolism recurrences, arterial ischemic events and major bleeding in 5717 patients with active cancer and venous thromboembolism recruited into RIETE (multi-center prospective registry of patients with objectively confirmed venous thromboembolism). RESULTS: During the anticoagulation course (median 7.3 months), 499 (8.7%) patients developed venous thromboembolism recurrences, 63 (1.1%) developed arterial events, and 346 (6.1%) suffered from major bleeding. Overall, major bleeding and arterial events appeared earlier (median 35 and 36 days, respectively) than venous thromboembolism recurrences (median 97 days). Thirty-day mortality rates after each event were: 20% after recurrent pulmonary embolism, 13% after recurrent deep vein thrombosis, 41% after major bleeding, 40% after myocardial infarction, 64% after ischemic stroke, and 83% after lower limb amputation. Bleeding was the leading cause of death (67 fatal bleeds), whereas cumulative mortality due to arterial ischemic events (n = 27) was similar to that related to pulmonary embolism recurrences (n = 26). CONCLUSIONS: In this study, arterial ischemic events and major bleeding appeared early after venous thromboembolism in patients with active cancer and were among frequent causes of their deaths. The risk and severity of arterial events need to be considered in this clinical setting.

Gender-related differences in the outcome of patients with venous thromboembolism and thrombophilia.

BACKGROUND: In patients with venous thromboembolism (VTE) and factor V Leiden (FVL) or prothrombin 20210G-A mutation (PTM), the influence of gender on outcome has not been consistently studied. METHODS: We used the RIETE (Registro Informatizado Enfermedad TromboEmbolica) database to assess the existence of gender differences in the rate of VTE recurrences (deep vein thrombosis [DVT] or pulmonary embolism [PE]) or major bleeding during the course of anticoagulation and after its discontinuation in FVL and PTM carriers. RESULTS: From March 2001 to September 2016, 11,224 VTE patients underwent thrombophilia testing. Of these, 1,563 were FVL carriers (863 men and 700 women) and 1,231 were PTM carriers (659 men and 572 women). During the course of anticoagulant therapy, men with FVL had a 6-fold higher rate of VTE recurrences than major bleeds (31 vs. 5 events). In women with FVL, the rate of VTE recurrences was 2-fold higher (16 vs. 8), as was in men (17 vs. 8) or women (17 vs. 9) with PTM. After discontinuing anticoagulation, men with FVL had a 3-fold higher rate of DVT recurrences than women (hazard ratio [HR]: 3.13; 95% CI: 1.79-5.67), with no differences in PE recurrences. Among patients with PTM, there were no gender differences in the rate of DVT (HR: 1.89; 95% CI: 1.00-3.65) or PE recurrences (HR: 1.82; 95% CI: 0.83-4.12). CONCLUSIONS: During the anticoagulation course, men with FVL are at a much higher risk for VTE recurrences than bleeding. After discontinuing anticoagulation, men with FVL are at an increased risk for DVT recurrences.

Outcome of Patients with Venous Thromboembolism and Factor V Leiden or Prothrombin 20210 Carrier Mutations During the Course of Anticoagulation.

BACKGROUND: Individuals with factor V Leiden or prothrombin G20210A mutations are at a higher risk to develop venous thromboembolism. However, the influence of these polymorphisms on patient outcome during anticoagulant therapy has not been consistently explored. METHODS: We used the Registro Informatizado de Enfermedad TromboEmbólica database to compare rates of venous thromboembolism recurrence and bleeding events occurring during the anticoagulation course in factor V Leiden carriers, prothrombin mutation carriers, and noncarriers. RESULTS: Between March 2001 and December 2015, 10,139 patients underwent thrombophilia testing. Of these, 1384 were factor V Leiden carriers, 1115 were prothrombin mutation carriers, and 7640 were noncarriers. During the anticoagulation course, 160 patients developed recurrent deep vein thrombosis and 94 patients developed pulmonary embolism (16 died); 154 patients had major bleeding (10 died), and 291 patients had nonmajor bleeding. On multivariable analysis, factor V Leiden carriers had a similar rate of venous thromboembolism recurrence (adjusted hazard ratio [HR], 1.16; 95% confidence interval [CI], 0.82-1.64), half the rate of major bleeding (adjusted HR, 0.50; 95% CI, 0.25-0.99) and a nonsignificantly lower rate of nonmajor bleeding (adjusted HR, 0.66; 95% CI, 0.43-1.01) than noncarriers. Prothrombin mutation carriers and noncarriers had a comparable rate of venous thromboembolism recurrence (adjusted HR, 1.00; 95% CI, 0.68-1.48), major bleeding (adjusted HR, 0.75; 95% CI, 0.42-1.34), and nonmajor bleeding events (adjusted HR, 1.10; 95% CI, 0.77-1.57). CONCLUSIONS: During the anticoagulation course, factor V Leiden carriers had a similar risk for venous thromboembolism recurrence and half the risk for major bleeding compared with noncarriers. This finding may contribute to decision-making regarding anticoagulation duration in selected factor V Leiden carriers with venous thromboembolism.

Development of a Risk Prediction Score for Occult Cancer in Patients With VTE.

BACKGROUND: The benefits of a diagnostic workup for occult cancer in patients with VTE are controversial. Our aim was to provide and validate a risk score for occult cancer in patients with VTE. METHODS: We designed a nested case-control study in a cohort of patients with VTE included in the RIETE (Registro Informatizado Enfermedad TromboEmbólica) registry from 2001 to 2014. Cases included cancer detected beyond the first 30 days and up to 24 months after VTE. Control subjects were defined as patients with VTE with no cancer in the same period. RESULTS: Of 5,863 eligible patients, 444 (7.6%; 95% CI, 6.8%-8.2%) were diagnosed with occult cancer. On multivariable analysis, variables selected were male sex, age > 70 years, chronic lung disease, anemia, elevated platelet count, prior VTE, and recent surgery. We built a risk score assigning points to each variable. Internal validity was confirmed using bootstrap analysis. The proportion of patients with cancer who scored ≤ 2 points was 5.8% (241 of 4,150) and that proportion in those who scored ≥ 3 points was 12% (203 of 1,713). We also identified scores divided by sex and age subgroups. CONCLUSIONS: This is the first risk score that has identified patients with VTE who are at increased risk for occult cancer. Our score needs to be externally validated.

Age-Adjusted Cutoff D-Dimer Level to Rule Out Acute Pulmonary Embolism: A Validation Cohort Study.

BACKGROUND: The diagnosis of pulmonary embolism in the Emergency Room setting is challenging. Multiple patients have to undergo radiologic assessment with its inherent shortcomings. The D-dimer test with accepted cutoff level of 500 µg/L is associated with a high proportion of false-positive results. The present study aimed to validate the advantages of using an age-adjusted D-dimer cutoff level, compared with 500-µg/L value in the diagnosis of acute pulmonary embolism. METHODS: This study evaluated patients admitted to the Rambam Emergency Room between 2011 and 2014 with a suspected diagnosis of pulmonary embolism. Patient data, D-dimer plasma levels, and imaging results were collected. The study cohort was subdivided according to the D-dimer levels below and above 500 µg/L. The group with levels above 500 µg/L was further assessed using the newly suggested age-adjusted D-dimer cutoff level, defined as age multiplied by 10. RESULTS: Files of 1241 patients were reviewed; 654 patients with low or intermediate risk for pulmonary embolism had a D-dimer level above 500 µg/L. Two hundred eight (208) patients had a D-dimer level above 500 µg/L but below the age-adjusted cutoff value; one of them was diagnosed with pulmonary embolism (0.48% [95% confidence interval 0%-2.6%]). Four hundred forty-six (446) patients had a D-dimer level above the age-adjusted cutoff value, and 28 of them were diagnosed with pulmonary embolism (6.28% [95% confidence interval 4.2%-8.9%]), representing a negative predictive value of 99.5% for the age-adjusted cutoff level. CONCLUSIONS: An age-adjusted D-dimer cutoff level may be safely used to exclude pulmonary embolism in patients with a low or intermediate probability for acute pulmonary embolism, alleviating the need to perform unnecessary imaging evaluations.

Disease dynamics in patients with acute myeloid leukemia: new biomarkers.

Acute myeloid leukemia (AML) is characterized by rapid growth of leukemic blast cells. Extracellular vesicles (EVs), shedding from various cells, express antigens, reflecting their cellular origin. The current study was designed to explore the role of circulating EVs as potential biomarkers of AML activity and predictors of thrombogenicity in patients with this malignancy. Blood samples were collected from healthy controls and patients with newly diagnosed AML at three time points: diagnosis, nadir, and remission. EV concentration, cell origin, and expression of coagulation proteins were characterized using fluorescence-activated cell sorting. EV cytokine contents were evaluated by protein array. Procoagulant activity was assessed using Factor Xa chromogenic assay. Forty-two AML patients were enrolled in the study. Total EV numbers were higher in patients in first remission compared with controls, whereas blast EV counts were higher in patients at diagnosis compared with controls and patients in remission. Blast EV levels were significantly lower in patients who achieved remission and were alive at 3-year follow up compared with their succumbed counterparts. At all three time points, percentage of endothelial EVs was higher in patients compared with controls. EV procoagulant activity was elevated at diagnosis and in remission, and, unlike controls' EVs, patients' EVs increased endothelial cell thrombogenicity. EVs of AML patients express membrane proteins of blast cells and might serve as biomarkers of leukemia dynamics and presence of minimal residual disease. Increased levels of endothelial EVs and their procoagulant activity may indicate a vascular injury associated with a hypercoagulable state in AML.