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Fibrinogen-like protein 2 (FGL2) is a serine protease capable of converting prothrombin into thrombin (i.e., prothrombinase-like activity) while bypassing the classic coagulation cascade. It has been reported to be expressed by mononuclear blood cells and endothelial cells. There are multiple reports that FGL2 supports tumor development and metastasis. However, in the blood, the origin and functional significance of FGL2 has not been established. To determine if FGL2, a malignancy related enzyme, is present in platelets. Peripheral blood samples were collected in K2 EDTA tubes. Blood cells and platelets were separated and thoroughly washed to produce plasma-free samples. Procoagulant activity was measured in the cell lysates using a thrombin generation test or an adjusted prothrombin time (PT) test in plasma deficient of factor X. The findings were further supported by confocal microscopy, immunoprecipitation, flow cytometry, enzyme-linked immunosorbent assays and specific inhibition assays. FGL2 protein was readily detected in platelets. Also, despite being expressed by lymphocytes, FGL2 prothrombinase-like activity was solely detected in platelet samples, but not in white blood cell samples. Quiescent platelets were shown to contain the FGL2 protein in an active form. Upon activation, platelets secreted the active FGL2 into the milieu. Active FGL2 is found in platelets. This suggests another role for the involvement of platelets in malignancies.

Abstract BackgroundThe clinical value of FDG-PET/CT for staging and monitoring treatment response in patients with aggressive lymphoma is well established. Conversely, its role in the assessment and management of marginal zone lymphoma (MZL) is less conclusive. We aimed to assess clinical, laboratory, and pathological predictors for FDG uptake in these patients, in an attempt to identify MZL patients whose management will benefit from this imaging modality.MethodsIn this single-center, retrospective cohort study, we included all adult patients diagnosed with MZL at the Rabin Medical Center between January 2006 and December 2020 who underwent FDG-PET/CT at the time of diagnosis. Primary outcomes were FDG avidity (defined as a visual assessment of at least moderate intensity), SUVmax, and SUVliver. Variables such as advanced clinical stage, primary disease site, hemoglobin level (Hb), platelet count (Plt), serum albumin, LDH level, β-2 microglobulin, and Ki 67 index were evaluated univariate and multivariate analysis using logistic and linear regression models. Association between FDG avidity and progression-free and overall survival was evaluated using Kaplan–Meier curves and Cox regression analysis.ResultsA total of 207 MZL patients were included in this study, 76 of whom (36.7%) had FDG-avid disease. Baseline patients’ characteristics such as age, gender, and comorbid conditions were similar between patients with and without significant FDG uptake. In a multivariate logistic regression model, non-gastric MALT (OR 4.2, 95% CI 1.78–10), Ki 67 index ≥ 15% (OR 3.64, 95% CI 1.36–9.76), and elevated LDH level (OR 8.6, 95% CI 3.2–22.8) were all associated with positive FDG avidity. In a multivariate linear regression model, a combination of advanced clinical stage, specific disease subtypes, LDH level, and Ki 67 index predicted the value of SUVmax (P value < 0.001; adjusted R2 = 33.8%) and SUVmax/SUVliver (P value < 0.001; adjusted R2 = 27%). Baseline FDG avidity was associated to PFS and OS only in univariate analyses.ConclusionsIn this retrospective cohort study, we present prediction models for positive FDG uptake and SUVmax in MZL patients. These models aim to help clinicians choose patients suitable for incorporation of FDG-PET/CT for staging and monitoring disease and reduce the costs of redundant tests.

Background Cancer is characterized by accelerated glycolysis with enhanced glucose uptake and lactate production, a phenomenon termed Warburg effect (WE). We studied the incidence and clinical impact of Warburg‐driven lactic acidosis in lymphoma. Methods Patients admitted with newly diagnosed or relapsed/refractory lymphoma and documented lactate levels during the first week of admission were included. Patients with lactatemia were classified as secondary (with a recognizable cause for elevated lactate) or none (WE group). Results WE and secondary lactatemia were documented in 58 and 44 patients (15% and 12% of evaluable patients, respectively). Both WE and secondary lactatemia were associated with poor short‐term survival. WE at presentation correlated with tumor burden, with most patients having aggressive disease, advanced stage, and extranodal involvement. WE was associated with high rates of early death (26% and 43% at 30‐ and 60‐days, respectively). Higher lactate levels correlated with worse survival. Earlier initiation of chemotherapy was associated with a (nonsignificant) trend toward better outcomes, whereas steroid and/or thiamine therapy did not alter patient outcomes. Glucose administration was associated with worse survival. Conclusion WE‐driven lactatemia is associated with high tumor burden and increased short‐term mortality in lymphoma. Prompt initiation of anti‐lymphoma therapy may improve outcomes.

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.

Patients with RR DLBCL who have received ≥ 2 lines of therapy have limited treatment options and an expected overall survival (OS) of < 6 months. The SADAL study evaluated single-agent oral selinexor in patients with RR DLBCL and demonstrated an overall response rate (ORR) of 29.1% with median duration of response (DOR) of 9.3 months. The analyses described here evaluated a number of subpopulations in order to understand how response correlates with survival outcomes in order to identify patients who could most optimally benefit from selinexor treatment. Median age was 67 years; 44.8% of patients were ≥ 70 years of age. The median OS was 9.0 months (95% CI 6.2, 13.7) at a median follow-up of 14.8 months. The median OS was not reached in patients with a CR or PR, while patients who did not respond have a median OS of 4.9 months ( p  < 0.0001). Patients < 70 years had an OS of 11.1 months compared with 7.8 months in patients ≥ 70 years. Among patients with or without prior ASCT, the median OS was 10.9 and 7.8 months, respectively. Among patients with disease refractory to the most recent DLBCL treatment regimen, the median OS was 7.0 months compared with 11.1 months for disease not refractory to the most recent treatment. In a patient population in which survival is expected to be < 6 months, treatment with single-agent oral selinexor was associated with a median survival of 9 months. Increased median OS observed in patients responding to selinexor was consistent across subgroups regardless of age, prior ASCT therapy, or refractory status. Randomized studies of selinexor in combination with a variety of other anti-DLBCL agents are planned. This trial was registered at ClinicalTrials.gov (NCT02227251) on August 28, 2014. https://clinicaltrials.gov/ct2/show/NCT02227251 .

Aggressive B cell lymphoma often requires prompt steroid treatment, even before baseline 18f-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) and definitive treatment, to alleviate symptoms or prevent organ damage. Since lymphoma is a steroid-sensitive malignancy, there are concerns that steroids might affect the results of FDG PET/CT and decrease its diagnostic yield. The aim of the current study was to evaluate the effect of steroids administered before baseline PET/CT on the maximum standardized uptake value (SUVmax) and additional PET/CT parameters. Retrospective review of the database in a tertiary medical center yielded 178 patients newly diagnosed with aggressive B cell lymphoma between January 2017 and May 2020 who had an available baseline FDG PET/CT scan. The cohort was divided into patients who received steroids before PET/CT (n = 47) and those who did not (n = 131), and the groups were compared for SUVmax and additional PET/CT parameters. The steroid-treated group had a higher disease stage and lactate dehydrogenase level compared to the steroid-naïve group, with a trend toward a higher international prognostic index. There was no significant between-group difference in SUVmax (P = 0.61). This finding remained consistent across steroid treatment durations and dosage regimens. Further evaluation revealed a significantly larger mean tumor volume and a trend toward a higher tumor metabolic burden in the steroid-treated group, yet no between-group difference in SUV mean or other PET/CT parameters. In this retrospective analysis of patients with aggressive B cell lymphoma, steroid prophase prior to baseline PET/CT did not decrease the diagnostic yield of the scan. However, further studies are required to fully appreciate the impact of steroids on PET CT parameters.

Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas. ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1·8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1·4 mg/m2 and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152. Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48·2 months (95% CI 35·2–not evaluable) in the A+CHP group and 20·8 months (12·7–47·6) in the CHOP group (hazard ratio 0·71 [95% CI 0·54–0·93], p=0·0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group. Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile. Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center.

Patients with acute myeloid leukemia (AML) who progress after exposure to hypomethylating agents (HMA) have a dismal prognosis. We hypothesized that the addition of venetoclax, a BCL-2 inhibitor, to AML patients who previously failed HMA might overcome resistance. Adult patients (≥ 18 years) with AML were eligible if leukemia relapsed after, or was refractory to HMA. In general, in addition to venetoclax, patients continued HMA or other low-intensity therapies. Patients who previously underwent allogeneic hematopoietic cell transplantation (HCT) were also eligible. Data were analyzed in November 2018. Twenty-three patients were treated between October 2016 and October 2018 and were eligible for this study. Median age was 76 years and 6 patients had leukemia that relapsed post allogeneic HCT. None of the patients experienced tumor lysis syndrome and toxicities were as expected and manageable. Febrile neutropenia was the most common toxicity (78% of patients). Median hospitalization time was 13 days. Forty-three percent of the patients achieved CR/CRi. Overall survival (OS) was 74% at 6 months and median OS in patients who achieved remission was 10.8 months. Higher number of blasts in both bone marrow and peripheral blood was associated with lower chances of CR, while higher WBC, LDH, and bone marrow or peripheral blasts were associated with increased mortality rate. The addition of venetoclax to patients with HMA-refractory AML may result in a substantial anti-leukemic activity, specifically in those achieving complete remission. This should be further tested in a well-designed prospective trial.

The development of Bruton Tyrosine Kinase inhibitors (BTKis) has revolutionized the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). However, increased infection rates have been reported in patients receiving BTKis in multiple clinical trials. This study aimed to evaluate the risk of infections associated with BTKis compared to other therapeutic regimens in CLL/SLL patients. A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted. We included trials comparing BTKi-containing regimens (e.g., BTKi alone or combined with anti-CD20 or venetoclax) to other therapeutic regimens, as well as studies comparing different BTKis or BTKi combinations. Primary outcomes were the risk of any infection and grade 3–4 infections. Secondary outcomes included pneumonia, sepsis, septic shock, COVID-19, fungal infections, fatal infections, bacteremia, and febrile neutropenia. Pooled risk ratios (RR) with 95% confidence intervals (CIs) were estimated using fixed or random effects models based on heterogeneity. Eighteen trials encompassing 8,324 patients were included. BTKi-containing regimens, either as monotherapy or combined with anti-CD20 or venetoclax, were not associated with a significantly increased risk of any infection compared to other regimens [BTKi + anti-CD20 or venetoclax: RR 0.93 (95% CI: 0.79–1.09, I 2  = 46%), 3 trials; BTKi monotherapy: RR 1.12 (95% CI: 0.94–1.34, I 2  = 73%), 3 trials]. Similarly, BTKi monotherapy was not associated with an increased risk of grade 3–4 infections [RR 1.05 (95% CI: 0.76–1.44, I 2  = 61%), 5 trials]. The risk of sepsis was not significantly increased with BTKi regimens [BTKi + anti-CD20: RR 0.48 (95% CI: 0.12–1.84, I 2  = 69%), 4 trials; BTKi monotherapy: RR 0.50 (95% CI: 0.25–1.01, I 2  = 0%), 5 trials]. However, pneumonia risk was increased in the BTKi + anti-CD20 vs other regimens, [RR 2.18; 95% CI 1.29–3.70; I 2  = 3%, 4 trials]. The risk of febrile neutropenia was reduced in trials comparing BTKi-containing regimens to other therapies. BTKi-containing regimens were not associated with an increased risk of overall infections or grade 3–4 infections compared to other regimens. However, an elevated risk of pneumonia was observed with BTKi combinations, highlighting the need for careful consideration when selecting treatment regimens for CLL/SLL patients.

Glofitamab, a CD20-directed CD3 T-cell engager, was recently FDA-approved after demonstrating a 52% overall response rate (ORR) and a 39% complete response (CR) rate in heavily pretreated diffuse large B-cell lymphoma (DLBCL) patients. However, real-world data on its efficacy and safety remain limited. This study evaluated glofitamab’s performance in clinical practice. We conducted a retrospective multicenter study of adults with relapsed/refractory (R/R) DLBCL treated via a national compassionate use program. Patients received at least one dose of glofitamab after failing ≥ 2 prior therapies. Recruitment spanned September 2020–January 2023. Outcomes included ORR, CR (per Lugano criteria), progression-free survival (PFS), and overall survival (OS). Adverse events were classified per ASTCT 2019 criteria, and risk factors for PFS and OS were assessed via logistic regression. Thirty-five patients from six Israeli centers were included (median age: 67 years; 66% male). The median number of prior therapies was 5, with 43% being primary refractory and 91% post-CAR-T therapy. ORR was 34%, with 14% achieving CR. Median PFS and OS were 2 and 4 months, respectively. Treatment was prematurely discontinued in 86%, mainly due to disease progression (46%) and to infections in responding patients (17%). Male sex was a significant risk factor for poor PFS and OS. In this real-world cohort, glofitamab’s efficacy was lower than in clinical trials, likely due to a more heavily pretreated population. However, its manageable toxicity supports its potential role in r/r DLBCL treatment.