Bendamustine and rituximab as first-line treatment for symptomatic splenic marginal zone lymphoma: long-term outcome and impact of early unmeasurable minimal residual disease attainment from the BRISMA/IELSG36 phase II study.

Not available.

A Multicentric Castleman Disease Associated with Mixed Warm and Cold Antibody-Mediated AHA Responsive to Siltuximab.

Castleman disease is non-clonal lymphoproliferative disorders defined by hypertrophy of lymph nodes. The multicentric form (MCD), in which multiple lymph node stations are involved, is not associated with HHV8 infection, but considered idiopathic, although IL-6 appears to play a central role in its pathogenesis. Here, we report the case of a patient who presented with mixed autoimmune hemolytic anemia (AIHA) and adenopathy that was very challenging to diagnose due to very low values of hemoglobin and refractoriness of obtaining any improvement of AIHA with standard first and second lines of therapy (steroids, rituximab, immunoglobulin, erythropoietin, and cyclosporine). When we safely proceeded to lymph node biopsy, a diagnosis of MCD was established. This permitted the treatment with siltuximab, an anti-IL-6 monoclonal antibody. After only 1 week, hemoglobin raised and he was discharged. After 1 year, he was still in remission. This case underlines the challenges in diagnosis of MCD, and the first case of response to siltuximab after the failure of rituximab to relieve mixed AIHA.

Erythrocyte deformability profile evaluated by laser diffractometry in patients with multiple myeloma: Re-examination of our cases.

BACKGROUND: Multiple myeloma is a complex pathology which represents about 10 % of all hematological neoplasms. It can often present changes in the hemorheological profile and, in relation to this last topic, our aim is to evaluate the hemorheological profile in a group of multiple myeloma patients, with reference to erythrocyte deformability. METHODS: We have examined the profile of the erythrocyte deformability in multiple myeloma enrolling 29 patients; this profile, expressed as elongation index at several shear stress, has been obtained using the diffractometric method. RESULTS: By comparing normal controls and MM patients, a significant decrease in erythrocyte deformability, especially at low shear stresses, but we did not observe any significant differences about this profile subdividing the whole group of MM patients according to the degree of bone marrow plasma cell infiltration, to the red blood cell distribution width and to the serum values of LDH. CONCLUSIONS: In this paper we have taken in consideration all the hypothesis for a possible explanation of the behaviour of this a reduced erythrocyte deformability in multiple myeloma. Erythrocyte deformability interferes with the physiological release of oxygen to tissues, with several clinical implications.

Molecular-Biology-Driven Frontline Treatment for Chronic Lymphocytic Leukemia: A Network Meta-Analysis of Randomized Clinical Trials.

The treatment of chronic lymphocytic leukemia (CLL) currently relies on the use of chemo-immunotherapy, Bruton's tyrosine kinase inhibitors, or BCL2 inhibitors alone or combined with an anti-CD20 monoclonal antibody. However, the availability of multiple choices for the first-line setting and a lack of direct head-to-head comparisons pose a challenge for treatment selection. To overcome these limitations, we performed a systematic review and a network meta-analysis on published randomized clinical trials performed in the first-line treatment setting of CLL. For each study, we retrieved data on progression-free survival (according to del17/P53 and IGHV status), overall response rate, complete response, and incidence of most frequent grade 3-4 adverse event. We identified nine clinical trials encompassing 11 different treatments, with a total of 5288 CLL patients evaluated. We systematically performed separated network meta-analyses (NMA) to evaluate the efficacy/safety of each regimen in the conditions previously described to obtain the surface under the cumulative ranking curve (SUCRA) score, which was subsequently used to build separated ranking charts. Interestingly, the combination of obinutuzumab with acalabrutinib reached the top of the chart in each sub-analysis performed, with the exception of the del17/P53mut setting, where it was almost on par with the aCD20 mAbs/ibrutinib combination (SUCRA aCD20-ibrutinib and O-acala: 93.5% and 91%, respectively) and of the safety evaluation, where monotherapies (acalabrutinib in particular) gave better results. Finally, considering that NMA and SUCRA work for single endpoints only, we performed a principal component analysis to recapitulate in a cartesian plane the SUCRA profiles of each schedule according to the results obtained in each sub-analysis, confirming again the superiority of aCD20/BTKi or BCL2i combinations in a first-line setting. Overall, here we demonstrated that: (1) a chemotherapy-free regimen, such as the combination of aCD20 with a BTKi or BCL2i, should be the preferred treatment choice despite biological/molecular characteristics (preferred regimen O-acala); (2) there is less and less room for chemotherapy in the first line treatment of CLL.

Host-related factors and cancer: Malnutrition and non-Hodgkin lymphoma.

Assessment of host-related factors is a crucial aspect in the comprehensive management of cancer patients. A distinct nutritional disturbance linked to cancer has been recognized to be associated with negative outcomes. However, compared to solid tumors, only a limited number of studies have looked specifically at nutritional issues in the field of lymphoma. The aim of this review is to integrate the current knowledge on interactions between malnutrition and lymphoma and address most relevant and pertinent questions. We first provide a literature review on the mutual biological relationship between malnutrition and lymphoma. Next, we explore the overlap between malnutrition, sarcopenia, cachexia and frailty in lymphoma studies. In addition, we summarize the clinical assessment scales used to measure malnutrition in lymphoma subjects. Furthermore, we address the problem of nutritional interventions aimed at patients who are candidates for treatment for lymphoma. Malnutrition can arise as a consequence of lymphoma disease and can in turn promote lymphomagenesis, negatively affect the response to therapy and favor adverse event to treatment. There is increasing evidence that malnutrition, sarcopenia and cachexia in lymphoma are intimately inter-related and are a hallmark of frailty. A variety of different tools are recorded with the apparent ability to describe nutritional status and to impact prognosis in lymphoma patients. Finally, a network of prognostic host- and disease-related factors is proposed where malnutrition can interact with each other in complex ways.

Effects of B-Cell Lymphoma on the Immune System and Immune Recovery after Treatment: The Paradigm of Targeted Therapy.

B-cell lymphoma and lymphoproliferative diseases represent a heterogeneous and complex group of neoplasms that are accompanied by a broad range of immune regulatory disorder phenotypes. Clinical features of autoimmunity, hyperinflammation, immunodeficiency and infection can variously dominate, depending on the immune pathway most involved. Immunological imbalance can play a role in lymphomagenesis, also supporting the progression of the disease, while on the other hand, lymphoma acts on the immune system to weaken immunosurveillance and facilitate immunoevasion. Therefore, the modulation of immunity can have a profound effect on disease progression or resolution, which makes the immune system a critical target for new therapies. In the current therapeutic scenario enriched by chemo-free regimens, it is important to establish the effect of various drugs on the disease, as well as on the restoration of immune functions. In fact, treatment of B-cell lymphoma with passive immunotherapy that targets tumor cells or targets the tumor microenvironment, together with adoptive immunotherapy, is becoming more frequent. The aim of this review is to report relevant data on the evolution of the immune system during and after treatment with targeted therapy of B-cell lymphomas.

Isolated Nodal TBC Reactivation in a Patient with Post-Thrombocythemia Myelofibrosis Treated with Ruxolitinib: Case Report and Review of the Literature.

Ruxolitinib side effects include the most frequent hematological toxicity along with a more recently evidenced immunosuppressive activity, interfering both with the innate and adaptive immunity, and several cases of reactivation of latent infections by opportunistic agents in patients in treatment with ruxolitinib have been published in the last years. Several pathophysiological mechanisms may explain an association between ruxolitinib and opportunistic infections. From what we know, the only case of an isolated lymph node TBC reactivation in a ruxolitinib-treated myelofibrosis (MF) patient was reported by Patil et al. in 2016 [Int J Med Sci Public Health. 2017;6(3):1]. Other 10 cases describing TBC reactivations in MF patients assuming ruxolitinib and successfully treated with 4-drug anti-TBC therapy are available in the literature to date. The case we reported describes an isolated lymph nodal TBC reactivation in a patient with the diagnosis of post-essential thrombocythemia-MF during ruxolitinib treatment after a long course of interferon-a (IFN-α2b) assumed for the previous diagnosis of ET. The case we report teaches that lymphadenopathy with or without constitutional symptoms developing during ruxolitinib therapy should be considered as a possible manifestation of a TBC reactivation in patients with a previous positive TBC-exposure test. In these cases, Ziel-Nielsen testing on urine and sputum has to be performed to rule out infectiousness and eventually isolate the patient. Moreover, previous long-time exposition to IFN-α2b may be related with a higher risk for TBC reactivation in these subset of patients. We encourage reevaluation of the cohorts of patients treated with ruxolitinib in previous and current large prospective studies to study the possible correlation between previous exposition to IFN-α2b and TBC reactivation.

Coexistence of Von Willebrand disease and gastrointestinal stromal tumor (G.I.S.T): Case report of a rare and challenge association.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is caused by a quantitative (type 1 and 3) or qualitative (type 2) defect of Von Willebrand factor (VWF). Bleeding from the gastrointestinal (GI) tract is not uncommon in VWD and is usually associated with angiodysplasia. We report herein on the management of a patient affected by VWD2B with severe GI bleeding secondary to gastrointestinal stromal tumor (GIST) complicated by deep vein thrombosis (DVT). The current case demonstrated that the hemostatic balance, in RBDs under specific circumstances, can range from a tendency toward a hemorrhagic to normal or prothrombotic state. In these patients, a close collaboration between hematologists and surgeons can guarantee appropriate management in high-risk clinical scenarios.

Buffy coat-derived platelets cryopreserved using a new method: Results from a pivotal clinical trial on thrombocytopenic patients with acute leukaemia.

The administration of cryopreserved platelets (PLTs) may overcome the limits of platelet shortage and availability, especially during some seasons or in specific contexts like rural areas. After in vitro validation studies, ad hoc prepared buffy coat-derived pooled platelet concentrates (BC-PLTs), treated with dimethyl sulphoxide (DMSO) and cryopreserved (CRY BC-PLTs) at -80 °C with a modified Valeri method, were transfused in patients with severe thrombocytopenia secondary to chemotherapy for acute leukaemia (AL). Five inpatients were enrolled in the pivotal clinical trial NCT02032134: 4 males and 1 female with a mean age of 71 years (range: 65-80). Four patients were diagnosed with acute myeloid leukaemia and 1 had acute lymphoblastic leukaemia.Transfusion of one Unit of CRY BC-PLTs resulted effective in active bleeding control in two patients without any adverse reaction or concomitant antihaemorrhagic therapies. CRY BC-PLTs met the currently accepted criteria for cryopreserved PLTs, their transfusion in patients with AL was safe. (Clinical trial: NCT02032134).

Management of Ponatinib in Patients with Chronic Myeloid Leukemia with Cardiovascular Risk Factors.

Cardiovascular (CV) adverse events are considered common complications of ponatinib treatment. Recently, it has been demonstrated that ponatinib dose reductions in definite settings can obtain optimal responses and lower ponatinib-related CV events. In this study, we describe the management of 5 patients with chronic myeloid leukemia treated with ponatinib, from second to fourth line of tyrosine kinase inhibitor therapy, carrying high pre-ponatinib CV risk, who obtained optimal molecular response and developed no CV adverse event during follow-up. Among these 5 patients, 2 had diagnosis of ischemic heart disease and underwent percutaneous angioplasty, 2 had type 2 diabetes and arterial hypertension, and 1 had only arterial hypertension. Median follow-up for ponatinib therapy is 1,039 days (34.6 months). Median dosage administered is 30 mg a day. SCORE charts were used to estimate risk of CV death in 10 years and Charlson Comorbidity Index was applied to estimate age-adjusted risk of death related to comorbidities. Strict cardiologic follow-up (complete evaluation every 3 to 6 months) and maximum effort in the control of CV modifiable risk factors are strongly recommended in the management of ponatinib treatment in patients at high risk for CV events and may allow the use of ponatinib in patients belonging to CV risk category.

Efficacy of bendamustine and rituximab in splenic marginal zone lymphoma: results from the phase II BRISMA/IELSG36 study.

Splenectomy in addition to immunotherapy with rituximab can provide quick and sometimes durable disease control in patients with splenic marginal zone lymphoma (SMZL). However, systemic chemotherapy is ultimately required in many cases. The BRISMA (Bendamustine-rituximab as first-line treatment of splenic marginal zone lymphoma)/IELSG (International Extranodal Lymphoma Study Group)36 trial is an open-label, single arm phase II study designed by the IELSG in cooperation with the Fondazione Italiana Linfomi and the lymphoma Study Association according to Simon's two-stage method. The primary endpoint was complete response rate. Fifty-six patients with SMZL diagnosis confirmed on central revision were treated with bendamustine (90 mg/m2  days 1, 2) and rituximab (375 mg/m2  day 1) every 28 days for six cycles (B-R). The overall response and CR rates were 91% and 73%, respectively. Duration of response, progression-free survival and overall survival at 3 years were 93% (95% confidence interval [CI] 81-98), 90% (95% CI 77-96) and 96% (95% CI 84-98), respectively. Toxicity was mostly haematological. Neutropenia grade ≥3 was recorded in 43% of patients; infections and febrile neutropenia in 5·4% and 3·6%. Overall, 14 patients (25%) experienced serious adverse events. Five patients (9%) went off-study because of toxicity and one patient died from infection. In conclusion, B-R resulted in a very effective first-line regimen for SMZL. Based on the results achieved in the BRISMA trial, B-R should be considered when a chemotherapy combination with rituximab is deemed necessary for symptomatic SMZL patients.

Lymphomas and thyroid: Bridging the gap.

The thyroid gland is often involved in the development of neoplastic diseases, including lymphoproliferative disorders. The aim of this paper is to provide a comprehensive overview of the multiple interactions between lymphoma and thyroid. Through an extensive research among the literature, the relationship between lymphomas and thyroid can be established at various levels, and the possible interconnections are here summarized in 5 points: (1) the greater risk of lymphoma development in some thyroid diseases; (2) the primary thyroid lymphoma, with focus on issues related to the diagnosis, differential diagnosis, and treatment; (3) the incidence of thyroid involvement in primitive nodal lymphomas or in extranodal lymphomas of the other sites; (4) thyroid changes after treatment of lymphoma, in relation to the effects of radiation therapy and immuno-chemotherapy; (5) the incidental findings of thyroid changes, on imaging, in patients with lymphoma, without a direct involvement of the gland in malignant disease. In conclusion, issues that until now have been dealt with separately will therefore be analyzed in a unique paper, allowing a global view of the topic and emphasizing the need of a multidisciplinary approach. Future learning areas in this topic mainly relate to rapidly increasing the knowledge of imaging studies together with expanding the armamentarium of novel biological and targeting agents in lymphoma patients.

Buffy coat-derived platelets cryopreserved using a new method: Results from in vitro studies.

Cryopreservation for the long-term storage of platelets (PLTs) is a useful method to overcome the limits of platelet shortage. This is an in vitro prospective study to evaluate the count, viability, and function of buffy coat-derived pooled platelet concentrates (BC-PLTs), treated with dimethyl sulphoxide (DMSO) and cryopreserved (CRY BC-PLTs) at -80 °C with a modified Valeri method. PLTs were stored in 6% DMSO with a patented kit. Overall, 49 BC-PLTs from 245 healthy volunteer donors were prepared, cryopreserved, and analysed before and after 3, 6, and 9 months of storage. In flow cytometry, a statistically significant reduction in CD 42b (92.7 ± 4.29% at T0 vs. 23.6 ± 27.5% at T3, 16.38 ± 12.54% at T6, and 17.3 ± 9.6% at T9) and PAC-1 (1.9 ± 1.34% at T0 vs. 0.62 ± 0.4% at T3, 0.63 ± 0.83% at T6, and 0.49 ± 0.48% at T9) was observed after storage. CRY BC-PLTs showed a good and stable endogenous thrombin generation potential (nM min): 529.25 ± 98.64 at T0 vs. 533.04 ± 103.15 at T9 months. CRY BC-PLTs showed a good viability in vitro, according to currently accepted criteria for cryopreserved PLTs.

Immunosenescence and lymphomagenesis.

One of the most important determinants of aging-related changes is a complex biological process emerged recently and called "immunosenescence". Immunosenescence refers to the inability of an aging immune system to produce an appropriate and effective response to challenge. This immune dysregulation may manifest as increased susceptibility to infection, cancer, autoimmune disease, and vaccine failure. At present, the relationship between immunosenescence and lymphoma in elderly patients is not defined in a satisfactory way. This review presents a brief overview of the interplay between aging, cancer and lymphoma, and the key topic of immunosenescence is addressed in the context of two main lymphoma groups, namely Non Hodgkin Lymphoma (NHL) and Hodgkin Lymphoma (HL). Epstein Barr Virus (EBV) plays a central role in the onset of neoplastic lymphoproliferation associated with immunological changes in aging, although the pathophysiology varies vastly among different disease entities. The interaction between immune dysfunction, immunosenescence and Epstein Barr Virus (EBV) infection appears to differ between NHL and HL, as well as between NHL subtypes.

Evaluation of the prognostic role of tumour-associated macrophages in newly diagnosed classical Hodgkin lymphoma and correlation with early FDG-PET assessment.

In Hodgkin Lymphoma (HL), about 20% of patients still have relapsed/refractory disease and late toxic effects rate continue to rise with time. 'Early FDG-PET' and tissue macrophage infiltration (TAM) emerged as powerful prognostic predictors. The primary endpoint was to investigate the prognostic role of both early FDG-PET and TAM; the secondary endpoint was to test if early FDG-PET positivity could correlate with high TAM score. A cohort of 200 HL patients was analysed. Induction treatment plan consisted of two to six courses of ABVD and, if indicated, involved field radiation therapy. All patients repeated CT scan and FDG-PET after two cycles and after the completion of therapy. TAM in diagnostic specimens was determined by immunohistochemistry with a monoclonal antibody (anti-CD68 KP1). Overall, early FDG-PET was negative in 163 patients (81.5%) and positive in 37 patients (18.5%), showing a significant correlation with the achievement of CR (p < 0.0001). After a median follow-up of 40 months, progression free survival (PFS) was significantly better for PET negative patients (p < 0.0001). CD68 expression was low, intermediate or high in 26 (13%), 100 (50%) and 74 (37%) cases, without difference in the distribution between responders and non-responders. PFS analysis showed no significant difference in any score group. TAM score did not show any correlation with early FDG-PET result. This study confirms that early FDG-PET has a high prognostic power, while TAM score does not seem to influence the outcome; in contrast to our original hypothesis, it does not correlate with FDG-PET assessment. Copyright © 2015 John Wiley & Sons, Ltd.

Thrombotic Risk and Calculated Whole Blood Viscosity in a Cohort of Patients With New Diagnosis of Multiple Myeloma.

The pathogenesis of venous thromboembolism in multiple myeloma is still poorly understood because multiple factors are involved. In particular, the increase in whole blood viscosity has a key role and, therefore, we performed an evaluation of some hemorheological determinants in multiple myeloma patients, putting them in relation to the thrombotic risk, with the aim to evaluate if an alteration of the hemorheological pattern was associated with a higher thrombotic risk. We performed an observational retrospective cohort study with data collected from January 2017 to September 2022. In a group of 190 patients with newly diagnosed multiple myeloma, we have examined the trend of calculated blood viscosity according to the Merrill formula, and we stratified the patients for the thrombotic risk in accordance with the IMWG/NCCN guidelines and with IMPEDE VTE score. Using the thrombotic risk stratification proposed by IMWG/NCCN any variation in calculated blood viscosity is evident, while, with the IMPEDE VTE score, we observed an increase in calculated blood viscosity in patients with "intermediate + high" risk. The calculated blood viscosity is higher in subjects presenting an "intermediate + high" thrombotic risk according to the IMPEDE VTE score. This association could therefore lay the groundwork for further research with the aim to confirm the role of hemorheological pattern in MM-related thrombotic risk.

Bone damage and health-related quality of life in Hodgkin lymphoma survivors: closing the gaps.

In the recent decades, remarkable successes have been recorded in the treatment of Hodgkin's lymphoma to the point that today it represents one of the neoplasms with the highest rates of cure and with the highest life expectancy. Nonetheless, this raises the concern for the health of long- term survivors. Late side effects of treatments in synergy with other risk factors expose survivors to increased morbidity and impaired quality of life. In the complexity of the topics concerning these last aspects, an area of growing interest is that of bone damage that follows Hodgkin Lymphoma and its treatments. In this narrative review, we conducted our work through assessment of available evidence focusing on several aspects linking bone damage and quality of life with Hodgkin lymphoma and its treatments. At present, the problem of osteopenia and osteoporosis in Hodgkin lymphoma survivors is a theme for which awareness and knowledge need to be implemented.

Calculated Whole Blood Viscosity and Albumin/Fibrinogen Ratio in Patients with a New Diagnosis of Multiple Myeloma: Relationships with Some Prognostic Predictors.

BACKGROUND: In this single center study, we retrospectively evaluated the calculated hemorheological profile in patients with a new diagnosis of multiple myeloma, with the aim to evaluate possible relationships with some prognostic predictors, such as ISS, albumin levels, beta2-microglobulin, red cell distribution width, and bone marrow plasma cell infiltration. METHODS: In a cohort of 190 patients, we examined the calculated blood viscosity using the de Simone formula, and the albumin/fibrinogen ratio as a surrogate of erythrocyte aggregation, and then we related these parameters to prognostic factors, using the Kruskal-Wallis and the Mann-Whitney tests, respectively. RESULTS: From our analysis, it emerged that the evaluated hemorheological pattern differed in the three isotypes of multiple myeloma, and the whole blood viscosity was higher in IgA and IgG isotypes with respect to the light chain multiple myeloma (p < 0.001). Moreover, we observed that, as the ISS stage progressed, the albumin/fibrinogen ratio was reduced, and the same hemorheological trend was traced in subgroups with lower albumin levels, higher beta2-microglobulin and red cell distribution width RDW values, and in the presence of a greater bone marrow plasma cell infiltrate. CONCLUSIONS: Through the changes in blood viscosity in relation to different prognostic factors, this analysis might underline the role of the hemorheological pattern in multiple myeloma.

Hemophagocytic lymphohistiocytosis secondary to histoplasmosis: A case report in a patient with AIDS and recent SARS-CoV-2 infection and minireview.

Here, we describe the case of a naïve HIV late presenter female African patient with progressive disseminated histoplasmosis and a severe life-threatening clinical picture in a non-endemic area. She had not visited Africa in the past decade. She developed a reactive hemophagocytic lymphohistiocytosis and an acute psychiatric disorder. Histoplasmosis was diagnosed after two bone marrow biopsies. Therapy with liposomal amphotericin B resulted in rapid and progressive improvements in blood examinations and clinical conditions, including the disappearance of psychiatric disorders. The characteristics of our case were compared with those of all other cases of hemophagocytic syndrome secondary to histoplasmosis in HIV-positive patients reported in PubMed. In conclusion, clinicians outside endemic areas should evaluate histoplasmosis as a cause of severe clinical picture, especially in a patient with a travel history to an endemic area, even after many years, considering the possible reactivation of latent infection.

EBF1, MYO6 and CALR expression levels predict therapeutic response in diffuse large B-cell lymphomas.

Background: Diffuse large B-cell lymphoma (DLBCL) is a hematological malignancy representing one-third of non-Hodgkin's lymphoma cases. Notwithstanding immunotherapy in combination with chemotherapy (R-CHOP) is an effective therapeutic approach for DLBCL, a subset of patients encounters treatment resistance, leading to low survival rates. Thus, there is an urgent need to identify predictive biomarkers for DLBCL including the elderly population, which represents the fastest-growing segment of the population in Western countries. Methods: Gene expression profiles of n=414 DLBCL biopsies were retrieved from the public dataset GSE10846. Differentially expressed genes (DEGs) (fold change >1.4, p-value <0.05, n=387) have been clustered in responder and non-responder patient cohorts. An enrichment analysis has been performed on the top 30 up-regulated genes of responder and non-responder patients to identify the signatures involved in gene ontology (MSigDB). The more significantly up-regulated DEGs have been validated in our independent collection of formalin-fixed paraffin-embedded (FFPE) biopsy samples of elderly DLBCL patients, treated with R-CHOP as first-line therapy. Results: From the analysis of two independent cohorts of DLBCL patients emerged a gene signature able to predict the response to R-CHOP therapy. In detail, expression levels of EBF1, MYO6, CALR are associated with a significant worse overall survival. Conclusions: These results pave the way for a novel characterization of DLBCL biomarkers, aiding the stratification of responder versus non-responder patients.