scholarly journals Novel Therapeutic Approaches to Familial HLH (Emapalumab in FHL)

2020 ◽  
Vol 11 ◽  
Author(s):  
Pietro Merli ◽  
Mattia Algeri ◽  
Stefania Gaspari ◽  
Franco Locatelli
Keyword(s):  
Progressive Disease ◽  
Interferon Γ ◽  
Line Treatment ◽  
Therapeutic Approaches ◽  
Front Line ◽  
Hematopoietic Stem ◽  
Fda Approval ◽  
Neutralizing Monoclonal Antibody ◽  
Life Threatening

Primary Hemophagocytic lymphohistiocytosis (pHLH) is a rare, life-threatening, hyperinflammatory disorder, characterized by uncontrolled activation of the immune system. Mutations affecting several genes coding for proteins involved in the cytotoxicity machinery of both natural killer (NK) and T cells have been found to be responsible for the development of pHLH. So far, front-line treatment, established on the results of large international trials, is based on the use of glucocorticoids, etoposide ± cyclosporine, followed by allogeneic hematopoietic stem cell transplantation (HSCT), the sole curative treatment for the genetic forms of the disease. However, despite major efforts to improve the outcome of pHLH, many patients still experience unfavorable outcomes, as well as severe toxicities; moreover, treatment-refractory or relapsing disease is a major challenge for pediatricians/hematologists. In this article, we review the epidemiology, etiology and pathophysiology of pHLH, with a particular focus on different cytokines at the origin of the disease. The central role of interferon-γ (IFNγ) in the development and maintenance of hyperinflammation is analyzed. The value of emapalumab, a novel IFNγ-neutralizing monoclonal antibody is discussed. Available data support the use of emapalumab for treatment of pHLH patients with refractory, recurrent or progressive disease, or intolerance to conventional therapy, recently, leading to FDA approval of the drug for these indications. Additional data are needed to define the role of emapalumab in front-line treatment or in combination with other drugs.

scholarly journals Endothelial cell dysfunction: a key determinant for the outcome of allogeneic stem cell transplantation

2021 ◽  
Author(s):  
Thomas Luft ◽  
Peter Dreger ◽  
Aleksandar Radujkovic
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Current Status ◽  
Sinusoidal Obstruction Syndrome ◽  
Hematopoietic Stem ◽  
Cell Dysfunction ◽  
Management Of Complications ◽  
Life Threatening

AbstractAllogeneic hematopoietic stem cell transplantation (alloSCT) carries the promise of cure for many malignant and non-malignant diseases of the lympho-hematopoietic system. Although outcome has improved considerably since the pioneering Seattle achievements more than 5 decades ago, non-relapse mortality (NRM) remains a major burden of alloSCT. There is increasing evidence that endothelial dysfunction is involved in many of the life-threatening complications of alloSCT, such as sinusoidal obstruction syndrome/venoocclusive disease, transplant-associated thrombotic microangiopathy, and refractory acute graft-versus host disease. This review delineates the role of the endothelium in severe complications after alloSCT and describes the current status of search for biomarkers predicting endothelial complications, including markers of endothelial vulnerability and markers of endothelial injury. Finally, implications of our current understanding of transplant-associated endothelial pathology for prevention and management of complications after alloSCT are discussed.

scholarly journals Monoclonal Antibody to CD14, TLR4, or CD11b: Impact of Epitope and Isotype Specificity on ROS Generation by Human Granulocytes and Monocytes

2020 ◽  
Vol 2020 ◽  
pp. 1-20
Author(s):  
Dmitry S. Kabanov ◽  
Sergey V. Grachev ◽  
Isabella R. Prokhorenko
Keyword(s):  
Cellular Response ◽  
Adaptive Immune System ◽  
Interferon Γ ◽  
Ros Generation ◽  
Ros Production ◽  
Therapeutic Approaches ◽  
Igg Antibody ◽  
Therapeutic Efficiency ◽  
Molecular Patterns

Lipopolysaccharides (LPSs or endotoxins) from Gram-negative bacteria represent pathogen-associated molecular patterns (PAMPs) that are recognized by CD14 and Toll-like receptor 4 (TLR4). Lipopolysaccharides prime polymorphonuclear leukocytes (PMNs) for substantial production of reactive oxygen species (ROS) during its response to secondary stimuli such as chemoattractants or pathogens. The excessive ROS production can damage surrounding host tissues, thereby amplifying the inflammatory reaction caused by pathogens. Today, specific antibodies against CD14, TLR4, and CD11b are being used as the essential tools to elucidate the role of these receptors in acute inflammation and some of these antibodies have advised as therapeutic agents for clinical use. Because each antibody has two antigen-binding arms [F(ab ′ )2] and one Fc arm, its effect on cellular response is much more complicated rather than simple blockage of target receptor. In fact, IgG antibody, once bound to target receptor, engages Fc receptors γ (FcγRs) and thereby is able to activate the adaptive immune system. The consequences of antibody-dependent binary heterotypic association of CD14, TLR4, or CD11b with FcγRs as well as homotypic one on ROS production are not well elucidated. Moreover, the consequences of antigenic recognition of CD14, TLR4, or CD11b by specific F(ab ′ )2 fragments are not always investigated. In this review, we will discuss known mechanisms underlying the therapeutic efficiency of CD14, TLR4, and CD11b/CD18 antibodies with a focus on LPS-dependent ROS or cytokine production by PMNs or monocytes. The impacts of F(ab ′ )2 as well as antibody IgG subclasses (isotypes) in therapeutic efficiency or agonistic potency of known antibodies against abovementioned receptors are presented. We also pay attention to how the efficiency of different IgG antibody subclasses is modulated during LPS-induced inflammation and by production of priming agents such as interferon γ (IFN-γ). Our review reinforces the molecular targets and therapeutic approaches to amelioration of harmful consequences of excessive activation of human pattern recognition receptors.

scholarly journals Redefining the role of etoposide in first-line treatment of peripheral T-cell lymphoma

2017 ◽  
Vol 1 (24) ◽  
pp. 2138-2146 ◽  
Author(s):  
Young Ae Kim ◽  
Ja Min Byun ◽  
Keeho Park ◽  
Gi Hwan Bae ◽  
Dukhyoung Lee ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Lymphoma ◽  
Line Treatment ◽  
First Line ◽  
Peripheral T Cell Lymphoma ◽  
Hematopoietic Stem ◽  
Asian Populations ◽  
Key Points ◽  
First Line Treatment

Key Points Etoposide addition/chemo-intensification has little role in first-line treatment of PTCL in Asian populations, regardless of subtype or age. Upfront hematopoietic stem-cell transplantation as consolidation seems like a legitimate choice in patients with PTCL.

scholarly journals Single Centre Experience of Managing Patients with Double Hit Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5868-5868
Author(s):  
Shankaranarayana Paneesha ◽  
Iman Qureshi ◽  
Malahat Saeed ◽  
Richard Lovell ◽  
Emmanouil Nikolousis ◽  
...  
Keyword(s):  
Overall Survival ◽  
Complete Remission ◽  
Progressive Disease ◽  
Salvage Chemotherapy ◽  
Line Treatment ◽  
First Line ◽  
Single Centre ◽  
Single Centre Experience ◽  
First Line Treatment

Abstract Double or triple hit Lymphomas (DHL) are characterized by translocation rearrangements of C-MYC with the addition of BCL2 and/or BCL 6, which are associated with a poor outcome due to their genetic complexity . Clinical controversies remain regarding the optimum treatment for patients with DHL due to lack of consensus regarding the optimal management and also age and frailty being a significant obstacle, limiting the role of dose-escalated or intensified therapy. Literature review suggests overall median survival for DHL patients is from 0.2-1.5years2. We report our single centre experience of treating this patient group. Materials & Methods: This single centre retrospective study evaluated the outcome of DHL patients who underwent various lines of treatment including standard R-CHOP chemotherapy, more intensive chemotherapy regimens and allogeneic stem cell transplantation (AlloSCT). Diagnosis of DHL was as per the 2008 WHO classification. Statistical analysis was performed by using SPSS 23®. Results: Our study included fourteen patients (9M; 5F) with a median age 60.5 years (range 33-65). 4 patients had stage 2B disease, 3 had stage 3B and 7 had 4B disease. R-CHOP chemotherapy only was commenced as first line treatment in 4 patients, R-CHOP plus intrathecal chemotherapy was given to 2 patients and 1 patient received R-CEOP. 5 patients received intensive chemotherapy with R-CODOX-M/R-IVAC where as one patient received EPOCH in a different centre prior to transfer. 1 patient received radiotherapy only. 10 patients were in complete remission following first line chemotherapy. One patient progressed following first line treatment and was managed palliatively. One patient relapsed whilst awaiting AlloSCT and was given mini-DEX BEAM salvage chemotherapy prior to transplant. One patient had a partial response to first line treatment and was given further rituximab but had progressive disease and was also managed palliatively. One patient had progressive disease and received GDP chemotherapy. 8 patients underwent AlloSCT with BEAM Alemtuzumab conditioning with cyclosporine as GvHD prophylaxis (6 unrelated and 2 sibling donors). The mean overall survival from starting treatment for DHL for the non-transplant cohort was 18.5 months (Range: 0.5 to 36.5) and the median OS was 8.3 months (Range: 4 to 12.6) as compared to mean overall survival of 44.2 months (Range: 22.2 to 66.35) in the transplant cohort with median overall survival not reached (p value: 0.46, Log Rank). In our patients, there was no progression after 3 months from Allo SCT. One patient progressed 6 weeks and died 8 weeks post AlloSCT, whereas two patients progressed 12 weeks and died 14 weeks post AlloSCT. In the cohort who did not undergo AlloSCT, 3 patients have died and two remain in complete remission and 1 patient is undergoing salvage chemotherapy for refractory disease. Conclusion: Our single centre experience of limited number of patients with DHL suggests AlloSCT as a consolidative treatment in first complete remission, may offer survival benefit as compared to no consolidation. Our data also shows no progression of DHL 3 months post AlloSCT highlighting the potential graft versus lymphoma effect. This requires further evaluation in a larger cohort to confirm our preliminary findings and identify potential biomarkers of best response. Confirmation of this result in larger cohort will identify the role of AlloSCT in DHL and enable to reach consensus in the DHL management. Disclosures Kishore: celgene: Other: travel grant.

scholarly journals Role of interferon-γ in immune-mediated graft failure after allogeneic hematopoietic stem cell transplantation

Haematologica ◽  
2019 ◽  
Vol 104 (11) ◽  
pp. 2314-2323 ◽  
Author(s):  
Pietro Merli ◽  
Ignazio Caruana ◽  
Rita De Vito ◽  
Luisa Strocchio ◽  
Gerrit Weber ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Graft Failure ◽  
Interferon Γ ◽  
Hematopoietic Stem ◽  
Immune Mediated

scholarly journals Front‐line treatment of ceritinib improves efficacy over crizotinib for Asian patients with anaplastic lymphoma kinase fusion NSCLC: The role of systemic progression control

2019 ◽  
Vol 10 (12) ◽  
pp. 2274-2281
Author(s):  
Shih‐Hao Huang ◽  
Allen Chung‐Cheng Huang ◽  
Chin‐Chou Wang ◽  
Wen‐Chen Chang ◽  
Chien‐Ying Liu ◽  
...  
Keyword(s):  
Anaplastic Lymphoma Kinase ◽  
Line Treatment ◽  
Front Line ◽  
Anaplastic Lymphoma ◽  
Asian Patients

scholarly journals Insights Into Genetics and Pathophysiology of Arrhythmogenic Cardiomyopathy

2021 ◽  
Author(s):  
Brenda Gerull ◽  
Andreas Brodehl
Keyword(s):  
Ventricular Arrhythmias ◽  
Disease Onset ◽  
Therapeutic Approaches ◽  
Arrhythmogenic Cardiomyopathy ◽  
Preclinical Research ◽  
Cellular Junctions ◽  
Genes Encoding ◽  
Life Threatening ◽  
Apparently Healthy

Abstract Purpose of Review Arrhythmogenic cardiomyopathy (ACM) is a genetic disease characterized by life-threatening ventricular arrhythmias and sudden cardiac death (SCD) in apparently healthy young adults. Mutations in genes encoding for cellular junctions can be found in about half of the patients. However, disease onset and severity, risk of arrhythmias, and outcome are highly variable and drug-targeted treatment is currently unavailable. Recent Findings This review focuses on advances in clinical risk stratification, genetic etiology, and pathophysiological concepts. The desmosome is the central part of the disease, but other intercalated disc and associated structural proteins not only broaden the genetic spectrum but also provide novel molecular and cellular insights into the pathogenesis of ACM. Signaling pathways and the role of inflammation will be discussed and targets for novel therapeutic approaches outlined. Summary Genetic discoveries and experimental-driven preclinical research contributed significantly to the understanding of ACM towards mutation- and pathway-specific personalized medicine.

scholarly journals Late-onset X-linked Chronic Granulomatous Disease in a Female Carrier: Therapeutic Role of Interferon-γ and Hematopoietic Stem Cell Transplantation

2021 ◽  
Author(s):  
Matteo Trevisan ◽  
Elizabeth Kang ◽  
Francesco Salton ◽  
Samuele Naviglio ◽  
Barbara Ruaro ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
X Chromosome ◽  
Late Onset ◽  
Interferon Γ ◽  
Granulomatous Disease ◽  
Hematopoietic Stem ◽  
Life Threatening ◽  
Skewed X Chromosome Inactivation

Abstract X-linked Chronic Granulomatous Disease (CGD) is a rare inherited immunodeficiency characterized by early life-threatening infections from bacteria and fungi in male children. Female carriers of X-linked CGD usually do not develop any manifestations of the disease, yet in rare cases they may present with CGD-related manifestations due to skewed X chromosome inactivation, even in advanced age. Here, we report the case of a 49-year-old woman with no history of previous frequent or severe infections, who presented acutely with life-threatening bilateral pneumonia caused by Nocardia asteroides and was eventually diagnosed with late-onset X-linked CGD due to skewed X chromosome inactivation in white blood cells. Treatment with interferon-γ as a rescue therapy resulted in normalization of the intensity of the oxidative burst in the residual positive cells and resolution of the infection, which was otherwise resistant to conventional treatments. After discharge, however, recurrent severe pulmonary infections despite prophylactic treatments as well as appearance of granulomatous colitis led to considering definitive treatment. Hematopoietic stem cell transplantation from unaffected HLA-identical brother using a non-myeloablative conditioning protocol with intravenous busulfan followed by high-dose peripheral blood stem cell graft and post-transplant cyclophosphamide was successfully performed. After three years of follow-up, white blood cell chimerism remained stable with about 60% donor cells in the myeloid lineage, with no further infections and no recurrence of inflammatory bowel disease.

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