Real-life experience with the combination of polatuzumab vedotin, rituximab, and bendamustine in aggressive B-cell lymphomas.

Transplant-ineligible relapsed/refractory (rr) diffuse large B-cell lymphoma (DLBCL) patients represent an unmet medical need. Polatuzumab vedotin (Pola), an anti-CD79b antibody-drug-conjugate (ADG), with bendamustine- rituximab(BR) has recently gained approval for these patients, both in the USA and Europe, based on the GO29365 phase IIb trial. Real-life data with Pola are extremely limited. We report the outcomes of 61 Greek patients, who received Pola-(B)R mainly within a compassionate use program. Treatment was given for up to six 21-day cycles. Bendamustine was omitted in three cases due to previous short-lived responses. Fourty-nine rrDLBCL(efficacy cohort-EC) and 58 rr aggressive B-NHL (safety cohort-SC) patients received at least 1 Pola-BR cycle. Twenty-one (43%) patients of the EC responded with 12/49 (25%) CR and 9/49 (18%) PR as best response. Median progression-free survival, overall survival and duration of response were 4.0, 8.5, and 8.5 months respectively, while 55% of patients experienced a grade ≥3 adverse event, mainly hematologic. Treatment discontinuations and death during treatment were mainly due to disease progression. Twenty-two (41%) patients received further treatment; 11/22 are still alive, including one after CAR-T cells, and two after stem cell transplantation. Our data confirm that Pola-BR is a promising treatment for rrDLBCL patients, inducing an adequate response rate with acceptable toxicity. Pola-BR could be used as bridging therapy before further consolidative treatments.

Immunoglobulin and B-cell disturbances in patients with chronic idiopathic neutropenia.

Chronic idiopathic neutropenia (CIN) is a granulocytic disorder associated with presence of activated, myelosuppressive T-lymphocytes. In the present study we have evaluated constituents of humoral immunity in CIN patients (n=48) compared to healthy controls (n=52). CIN patients displayed lower serum IgG levels due to a reduction in IgG1, IgG3, IgG4 but not IgG2, lower IgA and increased IgM levels compared to controls. The proportion of CD19+ cells did not differ between patients and controls; however the proportion of the naïve IgD+/CD27- B-cells was increased and the proportion of class-switched memory IgD-/CD27+ B-cells was decreased in the patients. The percentage of CD40+ B-cells did not differ between patients and controls and no aberrations in the CD40-meadiated signal transduction pathway or in CD40-gene polymorphisms were identified. These data provide further evidence that immune disturbances are associated with the pathophysiology of CIN and point out for the first time the implication of the B-cell system.

Monitoring anti-Xa levels in elderly medical patients undergoing thromboprophylaxis: A prospective cohort study.

INTRODUCTION: Given the rising incidence of venous thromboembolism (VTE) and insufficient thromboprophylaxis dosing evidence in certain patients, the precise monitoring of anti-Xa (aFXa) levels is crucial. The aim of this study is to investigate the achievement of prophylactic aFXa levels in medical inpatients who were receiving parenteral anticoagulant and to evaluate the impact of various factors on aFXa levels. METHODS: This is a single-center observational cohort study conducted on patients admitted to the Department of Internal Medicine at the University Hospital of Heraklion, Greece, from March to August 2023. These individuals received low-molecular-weight heparins thromboprophylaxis owing to an increased risk of VTE. Data regarding demographics, past medical history, and somatometric and laboratory findings were recorded. The established range for peak prophylactic aFXa levels was defined as 0.2-0.5 IU/mL. RESULTS: In this study, we enrolled 150 individuals [91 (60.7%) women] with a mean age of 80.0 ± 14.1 years. Sixty-two (41.4%) patients exhibited non-prophylactic peak aFXa levels. Supratherapeutic levels were observed in all underweight patients and subtherapeutic levels in 12 of 13 obese patients in class II and III. A multivariate linear regression analysis revealed that body weight, cancer, and the Charlson Comorbidity Index (CCI) were independent factors influencing aFXa levels. CONCLUSIONS: Our study reveals a substantial portion of medical elderly inpatients on thromboprophylaxis with non-prophylactic aFXa levels, with a notable prevalence among underweight and severely obese patients. Body weight, cancer, and CCI were identified as independent factors influencing aFXa levels, advocating for tailored thromboprophylaxis strategies. Further research is warranted to validate personalized dosing approaches and to enhance clinical decision-making. Geriatr Gerontol Int 2024; 24: 587-594.

T-cell receptor Vß repertoire analysis in patients with chronic idiopathic neutropenia demonstrates the presence of aberrant T-cell expansions.

Chronic idiopathic neutropenia (CIN) is a bone marrow (BM) disorder characterized by presence of activated T-lymphocytes in peripheral blood (PB) and BM. We investigated the pattern of T-cell responses in CIN by analyzing the T-cell receptor ß-chain variable (Vß) gene repertoire. Compared to controls, CIN patients displayed different patterns of Vß gene usage in PB CD3(+), CD4(+) and CD8(+) cells. The frequency of Vß skewing and the number of expanded Vß families per subject were higher in patients compared to controls in all cell subpopulations. Skewing was more profound within the CD8(+) cells. The number of Vß expansions per patient was higher in BM compared to PB. The majority of patients displayed a skewed oligoclonal/monoclonal pattern within the PB and/or BM CD8(+) cells and a polyclonal profile within the CD4(+) cells. We concluded that aberrant T-cell expansions are invariably detected in CIN patients and may have a role in the disease pathogenesis.

Effect of lenalidomide therapy on hematopoiesis of patients with myelodysplastic syndrome associated with chromosome 5q deletion.

BACKGROUND: Lenalidomide improves erythropoiesis in patients with low/intermediate-1 risk myelodysplastic syndrome and interstitial deletion of the long arm of chromosome 5 [del(5q)]. The aim of this study was to explore the effect of lenalidomide treatment on the reserves and functional characteristics of bone marrow hematopoietic progenitor/precursor cells, bone marrow stromal cells and peripheral blood lymphocytes in patients with low/intermediate-1 risk myelodysplastic syndrome with del(5q). DESIGN AND METHODS: We evaluated the number and clonogenic potential of bone marrow erythroid/myeloid/megakaryocytic progenitor cells using clonogenic assays, the apoptotic characteristics and adhesion molecule expression of CD34(+) cells by flow cytometry, the hematopoiesis-supporting capacity of bone marrow stromal cells using long-term bone marrow cultures and the number and activation status of peripheral blood lymphocytes in ten patients with low/intermediate-1 risk myelodysplastic syndrome with del(5q) receiving lenalidomide. RESULTS: Compared to baseline, lenalidomide treatment significantly decreased the proportion of bone marrow CD34+ cells, increased the proportion of CD36(+)/GlycoA(+) and CD36(-)/GlycoA(+) erythroid cells and the percentage of apoptotic cells within these cell compartments. Treatment significantly improved the clonogenic potential of bone marrow erythroid, myeloid, megakaryocytic colony-forming cells and increased the proportion of CD34(+) cells expressing the adhesion molecules CD11a, CD49d, CD54, CXCR4 and the SLAM antigen CD48. The hematopoiesis-supporting capacity of bone marrow stroma improved significantly following treatment, as demonstrated by the number of colony-forming cells and the level of stromal-derived factor-1 alpha and intercellular adhesion molecule-1 in long-term bone marrow culture supernatants. Lenalidomide treatment also increased the proportion of activated peripheral blood T lymphocytes. CONCLUSIONS: The beneficial effect of lenalidomide in patients with lower risk myelodysplastic syndrome with del(5q) is associated with significant increases in the proportion of bone marrow erythroid precursor cells and in the frequency of clonogenic progenitor cells, a substantial improvement in the hematopoiesis-supporting potential of bone marrow stroma and significant alterations in the adhesion profile of bone marrow CD34(+) cells.

Risk factors for cardiovascular disease mortality in patients with myelodysplastic syndromes: A nationwide, registry-based cohort study.

Cardiovascular disease (CVD) emerges as a major cause of death in patients with myelodysplastic syndrome (MDS), but predictors of fatal CVD and the effect of MDS-specific treatments on CVD mortality remain largely unknown. In an analysis involving 831 patients with MDS with known causes of death, we noted an independent association of lower risk MDS, age >70 years, pre-existing CVD, and treatment with erythropoiesis-stimulating agents with a higher risk of death from CVD. If externally validated, these simple risk factors could increase clinicians' awareness toward CVD complications and guide early introduction of intensive monitoring and preventive interventions in MDS patients.

The -509C/T polymorphism of transforming growth factor-beta1 is associated with increased risk for development of chronic idiopathic neutropenia.

OBJECTIVE: Impaired granulopoiesis in chronic idiopathic neutropenia (CIN) has been associated with an inflammatory bone marrow (BM) microenvironment consisting of pro-inflammatory and pro-apoptotic mediators, such as tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1, and Fas-Ligand (Fas-L). In this study, we evaluated the frequency of TNF-alpha, TGF-beta1 and Fas-L gene polymorphisms in CIN patients and explored their role in excessive cytokine production and their association with CIN development. METHODS: The TNF-alpha-308G/A, TGF-beta1 -509C/T, +869T/C, +915G/C, and Fas-L -844T/C polymorphisms were studied in 57 CIN patients, and 100 healthy controls from Crete, a well-defined area with genetically homogeneous population, using a polymerase chain reaction-based restriction fragment length polymorphism assay. RESULTS: The mutant genotype C/T or T/T of TGF-beta1 -509C/T polymorphism was more common in CIN patients than in controls (P = 0.033). Compared to wild-type genotype, the TT genotype was associated with increased risk for CIN development (OR: 5.7; 95% CI: 1.18-27.26; P = 0.033). Compared to controls, patients with CT and TT genotypes displayed increased TGF-beta1 levels in serum (P < 0.0001 and P = 0.0002, respectively) and BM (P < 0.0001 and P = 0.0002, respectively). No significant difference was found between patients and controls in the frequency of TNF-alpha-308G/A, TGF-beta1 +869T/C and +915G/C and Fas-L -844T/C polymorphisms. CONCLUSIONS: The TGF-beta1 -509C/T polymorphism is associated with increased risk for CIN and contributes to the pathophysiology of the disorder by inducing TGF-beta1 overproduction. This is the first study providing evidence that genetic factors may predispose to CIN and may have a role in the pathophysiology of the disorder.

Transforming growth factor-beta1 affects interleukin-10 production in the bone marrow of patients with chronic idiopathic neutropenia.

BACKGROUND: Chronic idiopathic neutropenia (CIN) is a bone marrow (BM) failure syndrome characterized by accelerated apoptosis of myeloid progenitor cells because of a local imbalance between pro-inflammatory and anti-inflammatory cytokines. In this study, we investigated the interplay among transforming growth factor-beta1 (TGF-beta1), interleukin-10 (IL-10), and soluble flt-3 ligand (sFL) within the BM of CIN patients and probed the role of these cytokines in the pathophysiology of CIN. DESIGN: We used long-term BM cultures (LTBMC) to evaluate TGF-beta1, IL-10, and sFL levels in CIN patients (n = 70) and healthy subjects (n = 35). Cytokine levels in LTBMC supernatants were correlated with the number of circulating neutrophils and the proportion of BM CD34+/CD33+ myeloid progenitor cells. RESULTS: CIN patients had increased TGF-beta1 and sFL levels in LTBMCs compared with controls and individual cytokine values were found to be correlated inversely with the number of neutrophils and the proportion of CD34+/CD33+ cells. Patients displayed low supernatant IL-10 levels compared with controls and cytokine values were found to be correlated positively with the number of neutrophils and the proportion of CD34+/CD33+ cells. The levels of TGF-beta1 were found to be inversely correlated with IL-10 and positively with sFL values in LTBMC, supernatants suggesting a possible interplay among these cytokines in CIN BM. Neutralization of TGF-beta1 in LTBMCs increased IL-10 levels significantly in patients but not in controls, while neutralization had no effect on sFL levels. CONCLUSION: Excessive production of TGF-beta1 within the BM microenvironment of CIN patients results in downregulation of IL-10 and reduction of myeloid progenitor cells. Overexpression of sFL probably represents a compensatory mechanism to the low myeloid progenitor cells.

Cytogenetic evaluation of mesenchymal stem/stromal cells from patients with myelodysplastic syndromes at different time-points during ex vivo expansion.

Mounting evidence suggests that in myelodysplastic syndromes (MDSs) bone marrow (BM) mesenchymal stem/stromal cells (MSCs) possess abnormal characteristics and are actively involved in disease pathogenesis. Nevertheless, it is controversial whether these cells harbor clonal cytogenetic aberrations. To probe more deeply into this issue, in the present study we used conventional G-banding and FISH analysis to assess the clonal chromosomal abnormalities of hematopoietic cells (HCs) and cultured MSCs, from 29 MDS patients and 25 healthy individuals, at early, intermediate and late passage. Variable clonal cytogenetic aberrations were detected in HCs from 31% and in MSCs from 34% of MDS patients. Clonal chromosomal abnormalities in MSCs were detected even in patients without aberrations in HCs. They were mostly numerical and always differed from those in HCs from the same individual. Clonal chromosomal abnormalities did not seem to confer a proliferative and/or survival advantage to MSCs. HCs from normal donors harbored no cytogenetic abnormalities, whereas trisomy of chromosome 5 was detected in MSCs from 16% of healthy individuals, in line with other studies. Our results suggest that MDS-derived BM-MSCs are genetically unstable. The significance of this observation in the biology of MSCs and MDS pathogenesis is still unknown and warrants further evaluation.

Pro-inflammatory bone marrow milieu in patients with chronic idiopathic neutropenia is associated with impaired local production of interleukin-10.

The levels of interleukin-10 (IL-10) were evaluated in long-term bone marrow (BM) culture supernatants from 54 patients with chronic idiopathic neutropenia (CIN) and 30 healthy volunteers using enzyme-linked immunoabsorbent assay. Cytokine levels were significantly reduced in patients, compared with controls, and strongly correlated with peripheral blood neutrophil counts. Low levels of supernatant IL-10 were associated with increased values of supernatant IL-1beta, tumour necrosis factor-alpha, IL-6 and transforming growth factor-beta(1). We suggest that the pro-inflammatory milieu in the BM of CIN patients may be causatively related to the impaired production of IL-10, a cytokine normally displaying strong anti-inflammatory properties.