Total metabolic tumor volume as a survival predictor for patients with diffuse large B-cell lymphoma in the GOYA study

This retrospective analysis of the phase III GOYA study investigated the prognostic value of baseline metabolic tumor volume parameters and maximum standardized uptake values for overall and progression-free survival (PFS) in treatment-naïve diffuse large B-cell lymphoma. Baseline total metabolic tumor volume (determined for tumors >1 mL using a threshold of 1.5 times the mean liver standardized uptake value +2 standard deviations), total lesion glycolysis, and maximum standardized uptake value positron emission tomography data were dichotomized based on receiver operating characteristic analysis and divided into quartiles by baseline population distribution. Of 1,418 enrolled patients, 1,305 had a baseline positron emission tomography scan with detectable lesions. Optimal cut-offs were 366 cm3 for total metabolic tumor volume and 3,004 g for total lesion glycolysis. High total metabolic tumor volume and total lesion glycolysis predicted poorer PFS, with associations retained after adjustment for baseline and disease characteristics (high total metabolic tumor volume hazard ratio: 1.71, 95% confidence interval [CI]: 1.352.18; total lesion glycolysis hazard ratio: 1.46; 95% CI: 1.15-1.86). Total metabolic tumor volume was prognostic for PFS in subgroups with International Prognostic Index scores 0-2 and 3-5, and those with different cell-of-origin subtypes. Maximum standardized uptake value had no prognostic value in this setting. High total metabolic tumor volume associated with high International Prognostic Index or non-germinal center B-cell classification identified the highest-risk cohort for unfavorable prognosis. In conclusion, baseline total metabolic tumor volume and total lesion glycolysis are independent predictors of PFS in patients with diffuse large B-cell lymphoma after first-line immunochemotherapy

Punctual and kinetic MRD analysis from the Fondazione Italiana Linfomi MCL0208 phase III trial in mantle cell lymphoma

Minimal residual disease (MRD) analysis is a known predictive tool in mantle cell lymphoma (MCL). We describe MRD results from the Fondazione Italiana Linfomi phase III MCL0208 prospective clinical trial assessing lenalidomide maintenance vs observation after autologous transplantation (ASCT), in the first prospective comprehensive analysis of different techniques, molecular markers, and tissues (peripheral blood, PB, and bone marrow, BM), taken at well-defined timepoints. Among the 300 patients enrolled, a molecular marker was identified in 250 (83%), allowing us to analyze 234 patients and 4351 analytical findings from 10 timepoints. ASCT induced high rates of molecular remission (91% in PB and 83% in BM, by quantitative real-time PCR [RQ-PCR]). Nevertheless, the number of patients with persistent clinical and molecular remission decreased over time in both arms (up to 30% after 36 months). MRD predicted early progression and long-term outcome, particularly from 6 months after ASCT (6-month TTP HR 3.83, p<0.001). In single-timepoint analysis, BM outperformed PB, and RQ-PCR was more reliable, while nested PCR appeared applicable to a larger number of patients (234 vs 176). To improve MRD performance we developed a time-varying kinetic model, based on regularly updated MRD results and the Mantle Cell Lymphoma International Prognostic Index, showing an area under the ROC curve (AUROC) of up to 0.87 using BM. Most notably, PB reached an AUROC of up to 0.81: with kinetic analysis it was comparable to BM in performance. MRD is a powerful predictor over the entire natural history of MCL and suitable for models with continuous adaptation of patient risk. Study can be found in EudraCT N. 2009-012807-25 https://eudract.ema.europa.eu/

Tris(8-hydroxyquinolinato)gallium(III)-loaded copolymer micelles as cytotoxic nanoconstructs for cosolvent-free organometallic drug delivery

Therapeutically useful concentrations of the water-insoluble organometallic drug, tris(8-hydroxyquinolinato)gallium(III), are delivered to haematological cell lines without the need for toxic cosolvents. Delivery is by sequestration into aqueous micelles of a poly(ethylene glycol)/poly(propylene glycol)/poly(ethylene glycol) triblock copolymer using a facile method based on emulsion-mediated evaporation. The drug-loaded micelles function as a cell cycle inhibitor and cause cell death by a dose-dependent increase in apoptosis

Feasibility of Single-Port Laparoscopic Lymph Node Biopsy for Intra-Abdominal Lymphoma: A Case Series

Background: Laparoscopic lymph node biopsy through a multi-port access (MPLB) is a well-established technique for intra-abdominal lymphoma diagnosis. The aim of the current study is to assess the feasibility and the diagnostic accuracy of the single-port laparoscopic lymph node biopsy (SPLB) in intra-abdominal lymphoma. Materials and Methods: Between October 2016 and February 2019, 15 patients underwent SPLB to rule out or to follow the progression of a lymphoma. The clinical outcome and the pathology reports were analyzed retrospectively. Results: SPLB was completed laparoscopically in all cases. The total number of biopsies performed for each procedure was sometimes multiple (median: 2; range: 1-3). Duration of surgery was 85\u2009\ub1\u200932 minutes (range: 75-105 minutes). Length of hospitalization was 1.8\u2009\ub1\u20090.7 days (range: 1-3 days). No major postoperative complications occurred. A cutaneous infection managed conservatively was observed in a patient. In 10 patients, SPLB was used to establish a diagnosis whereas in 5 patients it was performed to follow a progression of a lymphoproliferative disease. In 93.3% of the cases, SPLB achieved the correct diagnosis and subsequent therapeutic decisions. Conclusion: SPLB has shown good procedure and postoperative outcomes as well as a high diagnostic yield, comparable to literature data on traditional MPLB. Therefore, our results show that this approach is safe and effective and can be an equally valid option to MPLB to obtain a diagnosis or to follow the progression of a lymphoproliferative disease. Further studies are necessary to support these results before its widespread adoption

Early CAR- CD4+ T-lymphocytes recovery following CAR-T cell infusion: A worse outcome in diffuse large B cell lymphoma

CAR(-) CD4(+) T cell lymphopenia is an emerging issue following CAR-T cell therapy. We analyzed the determinants of CD4(+) T cell recovery and a possible association with survival in 31 consecutive patients treated with commercial CAR-T for diffuse large B-cell (DLBCL) or mantle cell lymphoma. Circulating immune subpopulations were characterized through multiparametric-flow cytometry. Six-month cumulative incidence of CAR(- )CD4(+) T cell recovery (&gt;= 200 cells/mu L) was 0.43 (95% confidence interval [CI]: 0.28-0.65). Among possible determinants of CD4(+) T cell recovery, we recognized infusion of a 4-1BB product (tisagenlecleucel, TSA) in comparison with a CD28 (axicabtagene/brexucabtagene, AXI/BRX) (hazard ratio [HR] [95% CI]: 5.79 [1.16-24.12] p = 0.016). Higher CD4(+) T cell counts resulted with TSA at month-1, -2 and -3. Moderate-to-severe infections were registered with prolonged CD4(+) T cell lymphopenia. Early, month-1 CD4(+ )T cell recovery was associated with a worse outcome in the DLBCL cohort, upheld in a multivariate regression model for overall survival (HR: 4.46 [95% CI: 1.12-17.71], p = 0.03). We conclude that a faster CAR(- )CD4(+) T cell recovery is associated with TSA as compared to AXI/BRX. Month-1 CAR(-) CD4(+) T cell subset recovery could represent a "red flag" for CAR-T cell therapy failure in DLBCL patients

Mitochondrial Generated Redox Stress Differently Affects the Endoplasmic Reticulum of Circulating Lymphocytes and Monocytes in Treatment-Naïve Hodgkin’s Lymphoma

Background. The redox stress caused by Hodgkin’s lymphoma (HL) also involves the peripheral blood mononucleated cells (PBMCs) even before chemotherapy. Here, we tested whether lymphocytes and monocytes show a different response to the increased mitochondrial generation of reactive oxygen species (ROS). Methods. PBMCs, isolated from the blood of treatment-naïve HL patients and control subjects, underwent assessment of malondialdehyde content and enzymatic activity of both hexose- and glucose-6P dehydrogenase (H6PD and G6PD) as well as flow cytometric analysis of mitochondrial ROS content. These data were complemented by evaluating the uptake of the fluorescent glucose analogue 2-NBDG that is selectively stored within the endoplasmic reticulum (ER). Results. Malondialdehyde content was increased in the whole population of HL PBMCs. The oxidative damage matched an increased activity of G6PD, and even more of H6PD, that trigger the cytosolic and ER pentose phosphate pathways, respectively. At flow cytometry, the number of recovered viable cells was selectively decreased in HL lymphocytes that also showed a more pronounced increase in mitochondrial ROS generation and 2-NBDG uptake, with respect to monocytes. Conclusions. PBMCs of HL patients display a selective mitochondrial and ER redox stress most evident in lymphocytes already before the exposure to chemotherapy toxicity

Long term follow-up of Rituximab plus Bendamustine and Cytarabine (R-BAC) in elderly patients with newly diagnosed MCL

: The combination of rituximab, bendamustine, and low dose cytarabine (R-BAC) has been studied in a phase 2 prospective multicenter study from the Fondazione Italiana Linfomi (FIL RBAC500). In 57 previously untreated elderly patients with mantle cell lymphoma (MCL), R-BAC was associated with complete remission rate of 91%, and 2-years progression free survival (PFS) of 81% (95%CI 68-89). Here, we report the long-term survival outcome, late toxicities, and results of minimal residual disease (MRD) evaluation. After a median follow-up of 86 months (57-107), the median overall survival (OS) and progression-free survival (PFS) were not reached. The 7-years PFS and OS rates were 55% (95%CI 41-67), and 63% (95%CI 49-74), respectively. Responding patients (n=53) had a 7-years PFS of 59% (95%CI 44-71), with no relapse or progression registered after the 6th year. At multivariate analysis blastoid/pleomorphic morphology was the strongest adverse predictive factor for PFS (p=0.04). Patients with an end of treatment negative minimal residual disease (MRD) had better, but not significant, outcomes for both PFS and OS than MRD positive patients (p=0,148 and p=0,162, respectively). There was no signal of late toxicity or increase of secondary malignancies during the prolonged follow-up. In conclusion, R-BAC, which was not followed by maintenance therapy, showed sustained efficacy over time in elderly patients with MCL. Survival outcomes compare favorably with other immuno-chemotherapy regimens (with or without maintenance), including combinations of BTK-inhibitors upfront