Tumor-associated and immunochemotherapy-dependent long-term alterations of the peripheral blood NK cell compartment in DLBCL patients

Natural Killer (NK) cells are a key component of tumor immunosurveillance and thus play an important role in rituximab-dependent killing of lymphoma cells via an antibody-dependent cellular cytotoxicity (ADCC) mechanism. We evaluated the phenotypic and functional assets of peripheral blood NK cell subsets in 32 newly-diagnosed diffuse large B-cell lymphoma (DLBCL) patients and in 27 healthy controls. We further monitored long-term modifications of patient NK cells for up to 12 months after rituximab-based immunochemotherapy. At diagnosis, patients showed a higher percentage of CD56dim and CD16C NK cells, and a higher frequency of GrzBC cells in CD56dim, CD56bright, and CD16C NK cell subsets than healthy controls. Conversely, DLBCL NK cell killing and interferon g (IFNg) production capability were comparable to those derived from healthy subjects. Notably, NK cells from refractory/relapsed patients exhibited a lower “natural” cytotoxicity. A marked and prolonged therapy-induced reduction of both “natural” and CD16- dependent NK cytotoxic activities was accompanied by the down-modulation of CD16 and NKG2D activating receptors, particularly in the CD56dim subset. However, reduced NK cell killing was not associated with defective lytic granule content or IFNg production capability. This study firstly describes tumor-associated and therapy-induced alterations of the systemic NK cell compartment in DLBCL patients. As these alterations may negatively impact rituximab-based therapy efficacy, our work may provide useful information for improving immunochemotherapeutic strategies

Efficacy of residual site radiation therapy (ISRT) in patients with primary mediastinal lymphoma with Deauville Score 4 following R-CHT: results of a retrospective mono institutional study

Background: In order to evaluate the efficacy of residual site radiation therapy (RSRT) in terms of progression-free survival (PFS) and overall survival (OS) in patients with primary mediastinal lymphoma (PMBCL) with Deauville Score 4 (DS 4) following rituximab and chemotherapy treatment (R-ICHT). Methods: Thirty-one patients with PMBCL were recruited. After completion of R-ICHT, patients were staged with 18F-fluorodeoxyglucose positron-emission tomography, showing DS 4, and were treated with adjuvant RSRT. The chosen techniques for RT delivery were intensity-modulated radiation therapy (IMRT) or three-dimensional conformal RT (3D-CRT). Most patients underwent the first one using cone-beam computed tomography (CBCT). All patients were evaluated every 3 months for the first 2 years and every 6 months afterwards for a period of at least 5 years, with clinical and radiological procedures as required. Results: All patients received RSRT with a dose of 30 Gy in 15 fractions. The median follow-up time of 52.7 months (IQR: 26–64.1 months). The 5-year OS rate was 100%. The 2-year and 5-year PFS rates were 96.7% and 92.5%, respectively. Patients with relapsed disease had been treated with high-dose chemotherapy (HDC) and autologous stem cell transplantation (auto-SCT). Conclusion: RSRT in patients with PMBCL treated with ICHT and DS 4 did not impact unfavorably on patient survival

Residual Site Radiotherapy After Immunochemotherapy in Primary Mediastinal B-Cell Lymphoma: A Monoinstitutional Retrospective Study

Aim: To evaluate the efficacy of residual site radiation therapy (RSRT) on local control (LC), progressionfree (PFS) and overall (OS) survival in patients with primary mediastinal lymphoma (PMBCL), following rituximab and chemotherapy treatment (ICHT). Patients and Methods: The study included 34 patients with PMBCL treated between 2006 and 2014 with ICHT with/without autologous stem cell transplantation and RSRT. Between the end of ICHT/stem cell transplantation and RSRT, patients were evaluated with F-18-fluorodeoxyglucose positron-emission tomography. The gross tumor volume included morphological mediastinal residual disease after ICHT/SCT. The percentage of LC, PFS and OS were assessed. Results: All patients received RSRT with a median dose of 30 Gy. Median follow-up was 82 months. One patient out of 34 (3%) showed progressive disease 9 months from diagnosis. The 10-year PFS and OS were 97% and 97% respectively. Conclusion: RSRT in patients with PMBCL treated with ICHT did not impact unfavorably on LC and patient survival

Arrhythmias and cardiogenic shock: a rare disease presentation of diffuse large B-cell lymphoma with cardiac involvement

Extranodal involvement of non-Hodgkin lymphoma (NHL) has been reported in 20–40% of patients and has been typically observed in the skin, bones, gastrointestinal tract, liver and brain. Cardiac involvement has been reported in up to 20% of autopsy cases of patients with NHL and accounts for about 2% of all cardiac malignancies. Here, we report a peculiar case of a secondary cardiac diffuse large B-cell lymphoma (DLBCL), occurring with an abrupt hemodynamic instability, characterized by a sudden ventricular tachycardia and cardiogenic shock. The patient promptly started the first cycle of chemotherapy and was admitted to the cardiac intensive care unit (CICU) of our institution to prevent potential cardiovascular complications during treatment. We applied a fractionated treatment approach, progressively reaching standard doses, to decrease the risk of early death and ensure a successful management

Very long-lasting remission of refractory T-large granular lymphocytes leukemia and myeloma by lenalidomide treatment

Background: Large granular lymphocyte leukemias (LGLLs) represent a spectrum of biologically distinct lymphoproliferative diseases originating from either mature T cells (CD3+) or natural killer (NK) cells (CD3-). Both T-cell and NK-cell LGL leukemia can manifest as indolent or aggressive neoplasia. These rare lymphoproliferative disorders are often associated with autoimmune diseases and impaired hematopoiesis. Symptomatic patients are treated with immunosuppressive drugs. The co-association of T-LGLL with clonal B-cell disorders is reported in more than 10% of patients. Case presentation: We describe the case of a 57-yr-old white male patient with no history of autoimmune disorders, with refractory T-LGLL and myeloma who was treated with bortezomib and subsequently with lenalidomide. After 30months of on-going lenalidomide therapy, the patient is in partial remission from myeloma and in continuous complete hematological remission from T-LGLL. Conclusions: As far as we know, this is the first report of a patient with refractory T-LGLL treated with bortezomib and lenalidomide. As refractory T-LGLL is a challenging condition, we think that lenalidomide and bortezomib deserve further investigation

Angioimmunoblastic T-Cell Lymphoma with Exuberant CD30-Positive Follicular Dendritic Cell Proliferation in a SARS-CoV-2 Patient: The Role of Mutational Analysis to Exclude an Associated Follicular Dendritic Cell Sarcoma

Follicular dendritic cell (FDC) proliferation in angioimmunoblastic T-cell lymphoma (AITL) is still not well defined, challenging the accurate differential diagnosis between the AITL with expanded follicular dendritic cell meshwork and the combined AITL and follicular dendritic cell sarcoma (FDCS). Herein, we reported the case of a 58-year-old male with coexisting SARS-CoV-2 infection and AITL with an exuberant CD30-positive FDC proliferation, in which genetic analysis identified mutations of genes commonly involved in AITL but not in FDC sarcoma (i.e., RHOA, TET2, DNMT3A, and IDH2), thus supporting the reactive nature of the CD30-positive FDC expansion

Selective phenotypical and functional alterations of peripheral blood immune cells in neo-diagnosed patients with Diffuse Large B cell Lymphoma (DLBCL)

PURPOSE: To investigate the impact of lymphoid tumor presence on the asset of the systemic immune compartment. METHODS: Multiparameter FACS analysis and in vitro cytotoxicity assay were used to evaluate: 1) natural and CD16-mediated NK cytotoxic functions; 2) relative and absolute frequency, and 3) cytotoxic and IFN γ production capabilities of the main leukocyte subsets, in a cohort of 32 DLBCL patients at diagnosis and 27 healthy, age- and sex-matched controls. RESULTS: Patients showed a higher absolute monocyte number, and a lower lymphocyte count, mostly due to the selective diminution of CD4+ T cells (but not of Treg), and B lymphocytes. Accordingly, lymphocyte/monocyte and CD4/CD8 ratios decreased, while NK percentage increased. The phenotypically skewed profile of PBL associated with functional alterations, as: 1) IFN γ+ cells were increased among CD4+ and CD8+ T cell subsets, but not in CD56+ T and CD3-CD56+ NK cell populations; 2) a higher frequency of Granzyme B+ cells characterized (CD4+ and CD8+) T and (CD56bright and CD56dim) NK cell subsets; noteworthy, natural and CD16-dependent NK cytotoxic activities were unchanged. IL-6 and IL-10 plasma levels were significantly higher in DLBCL. Selected alterations of patients' immunological profile differently correlated with the DLBCL Germinal Center B (GCB) vs non GCB-type and with the presence of bulky disease or the involvement of extra-nodal sites. DISCUSSION: Our findings show a deeply altered phenotypic and functional PBMC profile in newly-diagnosed DLBCL patients, with the lymphocyte compartment showing traits of chronic activation; moreover, distinct immunological alterations correlated with tumor histological subtype and clinical features. CONCLUSION: These results suggest that tumor presence deeply affects the immune status of the host, at the systemic level, in the context of the immune system/tumor cross-talk; they could be of relevance in the perspective of chemoimmunotherapeutical strategies.PURPOSE: To investigate the impact of lymphoid tumor presence on the asset of the systemic immune compartment. METHODS: Multiparameter FACS analysis and in vitro cytotoxicity assay were used to evaluate: 1) natural and CD16-mediated NK cytotoxic functions; 2) relative and absolute frequency, and 3) cytotoxic and IFN γ production capabilities of the main leukocyte subsets, in a cohort of 32 DLBCL patients at diagnosis and 27 healthy, age- and sex-matched controls. RESULTS: Patients showed a higher absolute monocyte number, and a lower lymphocyte count, mostly due to the selective diminution of CD4+ T cells (but not of Treg), and B lymphocytes. Accordingly, lymphocyte/monocyte and CD4/CD8 ratios decreased, while NK percentage increased. The phenotypically skewed profile of PBL associated with functional alterations, as: 1) IFN γ+ cells were increased among CD4+ and CD8+ T cell subsets, but not in CD56+ T and CD3-CD56+ NK cell populations; 2) a higher frequency of Granzyme B+ cells char