Endothelial injury and dysfunction with emerging immunotherapies in multiple myeloma, the impact of COVID-19, and endothelial protection with a focus on the evolving role of defibrotide.

Patients with multiple myeloma (MM) were among the groups impacted more severely by the COVID-19 pandemic, with higher rates of severe disease and COVID-19-related mortality. MM and COVID-19, plus post-acute sequelae of SARS-CoV-2 infection, are associated with endothelial dysfunction and injury, with overlapping inflammatory pathways and coagulopathies. Existing treatment options for MM, notably high-dose therapy with autologous stem cell transplantation and novel chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engaging antibodies, are also associated with endothelial cell injury and mechanism-related toxicities. These pathologies include cytokine release syndrome (CRS) and neurotoxicity that may be exacerbated by underlying endotheliopathies. In the context of these overlapping risks, prophylaxis and treatment approaches mitigating the inflammatory and pro-coagulant effects of endothelial injury are important considerations for patient management, including cytokine receptor antagonists, thromboprophylaxis with low-molecular-weight heparin and direct oral anticoagulants, and direct endothelial protection with defibrotide in the appropriate clinical settings.

Use of defibrotide in COVID-19 pneumonia: comparison of a phase II study and a matched real-world cohort control.

The coronavirus disease 2019 (COVID-19) pandemic led to an unprecedented burden on healthcare systems around the world and a severe global socioeconomic crisis, with more than 750 million confirmed cases and at least 7 million deaths reported by 31st December 2023. The DEFI-VID19 study (ClinicalTrials.gov NCT04335201), a phase II, single-arm, multicenter, open-label trial was designed in mid-2020 to assess the safety and efficacy of defibrotide in treating patients with COVID-19 pneumonia. Defibrotide was administered at a dose of 25 mg/kg/d intravenously, divided into four daily doses over a planned 14-day period for patients with COVID-19 pneumonia receiving non-invasive ventilation. The primary endpoint was Respiratory Failure Free Survival (RFFS); Overall Survival (OS), the number of post-recovery days, and adverse events were the secondary endpoints. For comparison, a contemporaneous control cohort receiving standard of care only was retrospectively selected by applying the eligibility criteria of the DEFI-VID19 trial. To adjust for the imbalance between the two cohorts in terms of baseline variable distributions, an outcome regression analysis was conducted. In adjusted analysis, patients receiving defibrotide reported a trend towards higher RFFS (HR=0.71[0.95CI: 0.34 to 1.29, P= .138]) and OS (HR=0.78[0.95CI: 0.33 to 1.53, P= .248]) and showed a significantly increased number of post-recovery days (difference in means: 3.61[ 0.95CI: 0.97 to 6.26, P= .0037]). Despite concomitant thromboprophylaxis with low molecular weight heparin, the safety profile of defibrotide proved to be favorable. Taken together, our findings suggest that defibrotide may represent a valuable addition to the COVID-19 therapeutic options.

Baseline circulating tumour DNA and interim PET predict response in relapsed/refractory classical Hodgkin lymphoma.

Reliable biomarkers for early identification of treatment failure in relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL) are lacking. Circulating tumour DNA (ctDNA) profiling has emerged as a powerful predictive and prognostic tool in several haemopoietic and non-haemopoietic malignancies and may guide rational treatment choices in r/r cHL. To assess the predictive and prognostic value of ctDNA, we performed a retrospective analysis on 55 r/r cHL patients treated with the bendamustine, gemcitabine and vinorelbine (BEGEV) regimen and additionally evaluated the potential utility of integrating ctDNA with interim [18 F]-FDG positron emission tomography (iPET). Baseline ctDNA genotyping in r/r cHL mirrored gene mutations and pathways involved in newly diagnosed cHL. We found that baseline ctDNA quantification and serial ctDNA monitoring have prognostic value in r/r cHL receiving salvage chemotherapy. Lastly, integrating ctDNA quantification with iPET evaluation may improve the early identification of patients at high risk of failing standard salvage therapy, who may benefit from an early switch to immunotherapeutic agents. Collectively, our results support the implementation of non-invasive methods to detect minimal residual disease in recurrent cHL and justify its prospective evaluation in appropriately designed clinical trials.

The antibody-drug conjugate loncastuximab tesirine for the treatment of diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a heterogenous subtype of non-Hodgkin lymphoma. Relapsed/refractory disease represents remains an unmet medical need, despite the introduction of novel cellular and targeted therapies. Loncastuximab tesirine is a cluster of differentiation19-targeting antibody-drug conjugate approved by the US Food and Drug Administration for relapsed DLBCL after 2 lines of systemic therapy based on a trial showing a 48.3% overall response rate. The spectrum of its clinical applications is expanding and is now being tested in other B-cell malignancies.

Chemotherapy after PD-1 inhibitors in relapsed/refractory Hodgkin lymphoma: Outcomes and clonal evolution dynamics.

Checkpoint inhibitors (CPIs) are routinely employed in relapsed/refractory classical Hodgkin lymphoma. Nonetheless, persistent long-term responses are uncommon, and one-third of patients are refractory. Several reports have suggested that treatment with CPIs may re-sensitize patients to chemotherapy, however there is no consensus on the optimal chemotherapy regimen and subsequent consolidation strategy. In this retrospective study we analysed the response to rechallenge with chemotherapy after CPI failure. Furthermore, we exploratively characterized the clonal evolution profile of a small sample of patients (n = 5) by employing the CALDER approach. Among the 28 patients included in the study, 17 (71%) were primary refractory and 26 (92%) were refractory to the last chemotherapy prior to CPIs. Following rechallenge with chemotherapy, response was recorded in 23 (82%) patients experiencing complete remission and 3 (11%) patients experiencing partial remission. The tumour evolution of the patients inferred by CALDER seemingly occurred prior to the first cycle of therapy and was characterized either by linear or branching evolution patterns. Twenty-five patients proceeded to allogeneic stem cell transplantation. At a median follow-up of 21 months, median PFS and OS were not reached. In conclusion, patients who fail CPIs can be effectively rescued by salvage chemotherapy and bridged to allo-SCT/auto-SCT.

Defibrotide: potential for treating endothelial dysfunction related to viral and post-infectious syndromes.

INTRODUCTION: Defibrotide (DF) is a polyribonucleotide with antithrombotic, pro-fibrinolytic, and anti-inflammatory effects on endothelium. These effects and the established safety of DF present DF as a strong candidate to treat viral and post-infectious syndromes involving endothelial dysfunction. AREAS COVERED: We discuss DF and other therapeutic agents that have the potential to target endothelial components of pathogenesis in viral and post-infectious syndromes. We introduce defibrotide (DF), describe its mechanisms of action, and explore its established pleiotropic effects on the endothelium. We describe the established pathophysiology of Coronavirus Disease 2019 (COVID-19) and highlight the processes specific to COVID-19 potentially modulated by DF. We also present influenza A and viral hemorrhagic fevers, especially those caused by hantavirus, Ebola virus, and dengue virus, as viral syndromes in which DF might serve therapeutic benefit. Finally, we offer our opinion on novel treatment strategies targeting endothelial dysfunction in viral infections and their severe manifestations. EXPERT OPINION: Given the critical role of endothelial dysfunction in numerous infectious syndromes, in particular COVID-19, therapeutic pharmacology for these conditions should increasingly prioritize endothelial stabilization. Several agents with endothelial protective properties should be further studied as treatments for severe viral infections and vasculitides, especially where other therapeutic modalities have failed.

The Many Facets of CD38 in Lymphoma: From Tumor-Microenvironment Cell Interactions to Acquired Resistance to Immunotherapy.

The CD38 antigen is expressed in several hematological malignancies, and the anti-CD38 monoclonal antibodies Daratumumab and Isatuximab have an established role in the therapy of multiple myeloma. However, data on the therapeutic utility of CD38 targeting in other lymphoid malignancies are limited. In chronic lymphocytic leukemia, the prognostic significance of CD38 expression is well accepted, and preclinical studies on the use of Daratumumab in monotherapy or combination therapy have demonstrated considerable efficacy. In other lymphoproliferative disorders, preclinical and clinical data have not been as compelling; however, CD38 overexpression likely contributes to resistance to checkpoint inhibitors, prompting numerous clinical trials in Hodgkin and non-Hodgkin lymphoma to investigate whether blocking CD38 enhances the efficacy of checkpoint inhibitors. Furthermore, due to its widespread expression in hematological tumors, CD38 represents an attractive target for cellular therapies such as CAR-T cells. The present review discusses current knowledge of CD38 expression and its implications in various lymphoid malignancies. Furthermore, it addresses current and future therapeutic perspectives, with a particular emphasis on the significance of CD38 interaction with immune cells of the tumor microenvironment. Lastly, results of ongoing studies using anti-CD38 antibodies will be reviewed.

Immune and Inflammatory Cells of the Tumor Microenvironment Represent Novel Therapeutic Targets in Classical Hodgkin Lymphoma.

Classical Hodgkin Lymphoma (cHL) is a B-cell malignancy that, typically, responds well to standard therapies. However, patients who relapse after standard regimens or are refractory to induction therapy have a dismal outcome. The implementation of novel therapies such as the anti-CD30 monoclonal antibody Brentuximab Vedotin and immune checkpoint inhibitors has provided curative options for many of these patients. Nonetheless, responses are rarely durable, emphasizing the need for new agents. cHL is characterized by a unique microenvironment in which cellular and humoral components interact to promote tumor survival and dissemination. Knowledge of the complex composition of cHL microenvironment is constantly evolving; in particular, there is growing interest in certain cell subsets such as tumor-associated macrophages, myeloid-derived suppressor cells and neutrophils, all of which have a relevant role in the pathogenesis of the disease. The unique biology of the cHL microenvironment has provided opportunities to develop new drugs, many of which are currently being tested in preclinical and clinical settings. In this review, we will summarize novel insights in the crosstalk between tumor cells and non-malignant inflammatory cells. In addition, we will discuss the relevance of tumor-microenvironment interactions as potential therapeutic targets.