Anti-CD19 monoclonal antibodies for the treatment of relapsed or refractory B-cell malignancies: a narrative review with focus on diffuse large B-cell lymphoma

Purpose: CD19 is a cell surface protein that is found on both healthy and malignant B cells. Accordingly, it has become an important target for novel treatments for non-Hodgkin lymphomas and B-cell leukaemia. Three anti-CD19 monoclonal antibodies with distinct mechanisms of action have been developed for the treatment of B-cell malignancies. Methods: We reviewed the preclinical and clinical data on the development of the newly approved anti-CD19 monoclonal antibodies blinatumomab, tafasitamab and loncastuximab tesirine, and consider their place in the treatment of relapsed or refractory B-cell malignancies. Results: Blinatumomab is a bispecific T-cell engager that binds to both CD19 on B cells and CD3 on T cells, facilitating antibody-dependent cytotoxicity. Blinatumomab significantly prolongs overall survival in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia, although cytokine release syndrome and severe neurotoxicity may necessitate discontinuation. Tafasitamab, which has modified anti-CD19 Fab and Fc regions, has significantly enhanced affinity for both CD19 and effector cell receptors compared with unmodified anti-CD19. In L-MIND, tafasitamab plus lenalidomide provided an overall response rate (ORR) of 57.5% in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in patients non-transplant eligible. Loncastuximab tesirine is an antibody–drug conjugate that has been studied as monotherapy and in combination with ibrutinib in 3L + relapsed or refractory DLBCL. The ORR was 48.3% in a phase II trial of loncastuximab tesirine. The optimal place of anti-CD19 monoclonal antibodies in therapy has yet to be determined, but the prospect of improved outcomes for at least some patients with treatment-resistant B-cell malignancies appears likely, particularly in those with limited therapeutic options and poor prognosis

Contested novel ecosystems: Socio-ecological processes and evidence from Italy

In the context of contemporary global climate and environmental change, both natural and social scientists have stressed the role green areas play in global warming adaptation strategies and in improving the healthiness of the urban environment. Indeed, in recent years these spaces have become central to institutional political debates and various policies have been designed for their valorization. However, little attention has been paid to rewilded urban spaces, recently defined as novel urban ecosystems, and to their socio-ecological complexity. By adopting an interdisciplinary approach that links natural and social science perspectives, this article aims to highlight the role of novel urban ecosystems in the reconfiguration of urban policies. Indeed, this contribution analyzes ecosystem services coupled with the hybrid, contested socio-ecological nature of four case studies in Italy characterized by grassroots socio-environmental mobilization. Data were collected through comparative quantitative and qualitative methods. The evidence shows that the specific ecological features of novel urban ecosystems are strategic in terms of actual and potential ecosystem service provision for cities and suggests that citizens play a fundamental role in recognizing and valorizing them. In parallel, these spaces, reconceptualized as contested novel ecosystems, emerge as controversial hybrid urban socio-natures that enable community empowerment and produce a heterogeneous, grassroots political space oriented towards urban commons and environmental-climate justice

New Treatment Options in Advanced Stage Follicular Lymphoma

Follicular lymphoma is one of the most common non-Hodgkin's lymphomas with an expected survival of more than 20 years for the majority of patients. This impressive outcome has been achieved with the introduction of immunochemotherapy, as first line treatment with remissions lasting over 8 years, followed by other treatment options at first or subsequent relapse. However, certain groups of patients still have a poor prognosis. In recent years the efficacy of chemotherapy regimens has been augmented by new compounds selectively targeting the cell surface, intracellular pathways, and/or the microenvironment. Some of these are beginning to change the therapeutic landscape. This review summarizes prognostic factors in follicular lymphoma in order to identify patients with greatest medical need for these new treatment options and reviews recent data from prospective clinical studies testing new agents in first-line and relapsed follicular lymphoma. Finally, we assess the current role of immunochemotherapy and discuss the requirements for future clinical trials

Management of chronic lymphocytic leukemia: practice guidelines from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation.

The Italian Society of Hematology (SIE) and two affiliate societies (SIES and GITMO) commissioned a project to develop clinical practice guidelines for the treatment of chronic lymphocytic leukemia (CLL). METHODS: Key questions in the management of patients with CLL were formulated by an Advisory Committee and approved by an Expert Panel of eight senior hematologists. After a systematic review of the literature, recommendations for disease-specific and supportive therapies were formulated and graded according to the supporting evidence. Explicit consensus methods were used for providing recommendations for questions with incomplete or potentially biased evidence. RESULTS: It is recommended that therapy is commenced in patients with CLL when at least one of the following are present: B-symptoms, progressive/obstructive lymphadenopathy or organomegaly, rapid lymphocyte doubling time, anemia or thrombocytopenia (of new onset, worsening or steroid-resistant). It is recommended that patients without co-morbidity should receive fludarabine plus cyclophosphamide, whereas elderly patients with co-morbidity should receive oral chlorambucil. Younger patients with unfavorable biological risk factors should be considered for high-dose chemotherapy and autologous or allogeneic stem cell transplantation within approved clinical trials. Patients either relapsing rapidly after, or non-responsive to, first-line chlorambucil should receive fludarabine-containing regimens. Patients either relapsing soon after or not responding to fludarabine-based chemotherapy should be considered for schedules including non-cross-reactive agents, such as alemtuzumab, possibly followed by high-dose chemotherapy and autologous transplantation in the context of a clinical trial or by allogeneic stem cell transplantation. CONCLUSIONS: We describe the results of a systematic literature review and an explicit approach to consensus techniques which resulted in recommendations for the key therapeutic decisions in patients with CLL

Consensus conference on the management of tumor lysis syndrome.

Tumor lysis syndrome is a potentially life threatening complication of massive cellular lysis in cancers. Identification of high-risk patients and early recognition of the syndrome is crucial in the institution of appropriate treatments. Drugs that act on the metabolic pathway of uric acid to allantoin, like allopurinol or rasburicase, are effective for prophylaxis and treatment of tumor lysis syndrome. Sound recommendations should regulate diagnosis and drug application in the clinical setting. The current article reports the recommendations on the management of tumor lysis syndrome that were issued during a Consensus Conference project, and which were endorsed by the Italian Society of Hematology (SIE), the Italian Association of Pediatric Oncologists (AIEOP) and the Italian Society of Medical Oncology (AIOM). Current concepts on the pathophysiology, clinical features, and therapy of tumor lysis syndrome were evaluated by a Panel of 8 experts. A consensus was then developed for statements regarding key questions on tumor lysis syndrome management selected according to the criterion of relevance by group discussion. Hydration and rasburicase should be administered to adult cancer patients who are candidates for tumor-specific therapy and who carry a high risk of tumor lysis syndrome. Cancer patients with a low-risk of tumor lysis syndrome should instead receive hydration along with oral allopurinol. Hydration and rasburicase should also be administered to patients with clinical tumor lysis syndrome and to adults and high-risk children who develop laboratory tumor lysis syndrome. In conclusion, the Panel recommended rasburicase for tumor lysis syndrome prophylaxis in selected patients based on the drug efficacy profile. Methodologically rigorous studies are needed to clarify its cost-effectiveness profile

Optimal Management of Adverse Events From Copanlisib in the Treatment of Patients With Non-Hodgkin Lymphomas

INTRODUCTION: Copanlisib is a phosphoinositol 3-kinase (PI3K) inhibitor approved for the third-line treatment of follicular non-Hodgkin lymphoma. Although the drug is generally well-tolerated, it can be associated with several unique and potentially serious adverse effects (AEs). Two of the most common toxicities not seen with other PI3K inhibitors include hyperglycemia and hypertension, which primarily occur during infusion and resolve shortly thereafter, and likely relate to targeting the PI3K alpha isoform. Other toxicities less commonly observed with copanlisib than with other approved drugs in this class include non-infectious pneumonitis, infections, diarrhea and colitis, and hepatobiliary toxicity. MATERIALS AND METHODS: A panel composed of experts in lymphoma, diabetes, and hypertension convened to develop guidance pertaining to the administration of copanlisib and the management of the AEs associated with copanlisib treatment. RESULTS: Recommendations were formulated pertaining to the management of AEs associated with copanlisib treatment, particularly infusion-related hyperglycemia and hypertension, noninfectious pneumonitis, infections, diarrhea, and colitis. The recommendations herein reflect the consensus of the members of this panel, all of whom contributed to these suggested approaches to patient supportive care. CONCLUSION: There are a number of challenges associated with the use of copanlisib. Infusion-related hypertension and hyperglycemia occur frequently, although they are transient, reversible, and rarely of clinical significance; this report provides guidance as to their management

Primary follicular and marginal-zone lymphoma of the breast: clinical features, prognostic factors and outcome: a study by the International Extranodal Lymphoma Study Group

Background: Primary breast lymphoma (PBL) of low-grade histology is a rare disease. This multicentric retrospective study was carried out to determine clinical features, prognosis and relapse. Patients and methods: Patients with histologically proven, previously untreated follicular or marginal-zone PBL (MZL PBL) diagnosed from 1980 to 2003 were included in the study. Major end points were progression-free survival (PFS), overall survival (OS) and potential prognostic factors. Results: We collected data on 60 cases of PBL [36 follicular and 24 marginal-zone lymphoma (MZL)]. Stage was IE or IIE in 57 patients and IVE in three patients due to bilateral breast involvement. Surgery, chemotherapy and radiotherapy (RT), alone or in combination, were used as first-line treatments in 67%, 42% and 52% of patients, respectively. Overall response rate was 98%, with a 93% complete response rate. Five-year PFS were 56% for MZL and 49% for follicular PBL (P = 0.62). Relapses were mostly in distant sites (18 of 23 cases); no patients relapsed within RT fields. Conclusions: Our data showed an indolent behaviour of MZL PBL, comparable to other primary extranodal MZL. Conversely, patients with follicular PBL had inferior PFS and OS when compared with limited-stage nodal follicular non-Hodgkin's lymphomas, suggesting an adverse prognostic role of primary breast localisation in this histological subgrou

Effect of the extent of ethanol removal on the volatile compounds of a Chardonnay wine dealcoholized by vacuum distillation

“Beverages obtained from the partial dealcoholization of wine” are those drinks whose final alcoholic degree after dealcoholization is lower than that of a wine and higher than or equal to 0.5% v/v. When the total alcoholic degree is lower than 0.5% v/v the denomination is “Beverages obtained from the dealcoholization of wine”. The practices to be authorized for the production of these drinks with the dealcoholized wine fractions are currently being studied at OIV. The characterization of the composition of these fractions is essential to identify the necessary corrective practices. The present work was aimed at monitoring the losses of the main volatile compounds of a Chardonnay wine with the proceeding of the dealcoholization process by vacuum distillation. The wine was subjected to total dealcoholization, and during the process the evaporated fractions, re-condensed at 9 ∘C, were collected in aliquots of 1.25 L each. The ethanol content of each fraction was measured, and for the first 20 fractions the content in volatile compounds was determined with GC-MS. The results show that the losses of volatile compounds during the dealcoholization process follow different trends depending on the molecules considered. The most volatile compounds, generally with the lowest perception thresholds, were mainly present in the first evaporated fractions. The greatest losses concerned isoamylacetate, ethyl hexanoate and ethyl octanoate. Conversely, a greater number of molecules were present at similar concentrations in the different fractions, and their losses followed a linear or sometimes exponential trend: in particular, these compounds included n-hexanol, 2-phenylethanol, diethyl succinate and medium chain fatty acids (hexanoic, octanoic and decanoic acids). In the wine dealcoholized at 3.36% v/v (loss of ethanol equal to 7.43% v/v, corresponding to the 20th and last recondensed fraction), some volatile compounds were no longer detectable or quantifiable; in particular, these compounds were isoamylacetate, ethylhexanoate, hexylacetate, n-hexanol and other alcohols with 6 carbon atoms and ethyl octanoate. Other compounds, such as hexanoic, octanoic and decanoic acids, and, in particolar, β-phenylethanol, benzylic aalcohol and γ-butyrolactone, underwent lower percentage losses than those of ethanol. The dealcoholization process can therefore deeply modify the original aromatic profile of the wines, intervening on the absolute concentration and on the relative ratios of the single molecules