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  • Author: Jan Styczyński x
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Abstract

Cytomegalovirus (CMV), the beta-human herpesvirus type 5 (HHV-5), is a major cause of morbidity in immunocompromised hosts, especially recipients of allogeneic hematopoietic cell transplantation (HCT) or solid organ transplantation. The standard-of-care approach to CMV prevention based on CMV surveillance-guided preemptive therapy is being challenged by the recent approval of letermovir (LMV) for primary prophylaxis. Real-word clinical data show dramatic improvement in the reduction of risk of CMV infection and any CMV viremia in all studies performed so far. LMV is the drug that is breaking the paradigm of preemptive therapy with shift to prophylaxis. A summary of reported data presented in 2019 annual meetings of American Society of Transplantation and Cellular Therapy (ASTCT), European Society for Blood and Marrow Transplantation (EBMT) and American Society of Hematology (ASH), as well as already published results, is presented in this review. A total number of 401 adult high-risk patients on primary prophylaxis after HCT were reported in 11 studies up to January 1, 2020. It was shown that fewer patients in the LMV arms had any CMV reactivation or need for CMV treatment compared with the any other prophylactic or preemptive approaches. In conclusion, LMV is much highly effective than CMV-guided preemptive therapy in preventing CMV infection and CMV disease. The use of LMV in prophylaxis results in an improvement in overall survival during the first 24 and 48 weeks. LMV has a favorable safety profile, as it does not cause myelotoxicity. Current guidelines of European Conference on Infections in Leukemia (ECIL7) recommend LMV for the use in prophylaxis of CMV infection in patients after allogeneic hematopoietic cell transplant.

Abstract

The most frequent and severe complications after chimeric antigen receptor T-cells (CAR-T cells) therapy include cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH), tumor lysis syndrome (TLS), followed by B-cell aplasia and hypogammaglobulinemia. With these immunologically related events, cytokine storm and immunosuppression, there is a high risk of sepsis and infectious complications. The objective of this review was to present current knowledge on incidence, risk factors, clinical characteristics, and outcome of infections in patients following CAR-T cells therapy, as well as to present current recommendations on prophylaxis of infections after CAR-T cells therapy. Comparable to hematopoietic cell transplantation setting, specific pre- and post-CAR-T cells infusion phases can be determined as early (from 0 to +30 days), intermediate (from +31 to +100 days), and late (beyond day +100). These phases are characterized by CAR-T cells therapy-related factors and immune system defects contributing to an increased risk of infections. It is recommended that in case of active infection, CAR-T cells infusion should be delayed until infection has been successfully treated. After CAR-T cells therapy, prophylaxis should be implemented (anti-bacterial, anti-viral, anti-fungal, anti-pneumocystis), as well as treatment of neutropenia and immunoglobulin replacement should be considered. No recommendations so far can be given on revaccinations after CAR-T cells therapy.

Abstract

Chimeric antigen receptors (CARs) are genetically engineered receptors that provide specific properties to an immune effector cell and these receptors gain the specificity of a monoclonal antibody targeted against specific tumor cells. T cells with engineered CARs acquire potent immunological properties and redirect the immune system in order to eliminate malignant cells. First-engineered T cells with chimeric molecule (CAR-T cells) were developed in 1989–1993 by Israeli immunologists Zelig Eshhar and Gideon Gross. The first clinical application of CAR-T cells was done in the University of Pennsylvania and Children’s Hospital in Philadelphia by the immunologist Carl June and hematologist David Porter to patients with chronic lymphocytic leukemia in 2011 and together with the pediatrician Stephan Grupp to patients with acute lymphoblastic leukemia (ALL) in 2012. The US Food and Drug Administration Agency (FDA) in 2017 and the European Medicines Agency (EMA) in 2018 have licensed two products of CAR-T cells: tisagenlecleucel for the use in children and young adults up to 25 years of age with B-cell ALL who do not respond to treatment or have relapsed two or more times and tisagenlecleucel and axicabtagene ciloleucel for the use in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Current progress in CAR technology includes the use in other hematological malignancies, solid tumors, the use of dual CAR-T cells and chimeric antigen receptor natural killer cells (CAR-NK cells).

Abstract

Infections are the main cause of morbidity and mortality in pediatric hematology and oncology (PHO) and hematopoietic cell transplantation (HCT) settings in children and adults. The analysis of incidence and outcome of bacterial, fungal, and viral infections in Polish PHO/ HCT centers was performed over a period of 72 months (2012–2017). The summary of infections in 5628 patients with newly diagnosed malignancy and 971 HCTs is presented in this paper. Additionally, data of 650 pediatric HCTs from 2012 to 2015 were compared with the data of 3200 HCTs in adults. The risk of any infection per patient was higher in HCT vs PHO patients (2062/971 vs 7115/5628; 2.1 vs 1.3; HR=1.7, p<0.0001). The incidence of bacterial infections was 34,2±0,6% in PHO vs 41,5±1,6% in HCT patients, and the outcome was better in PHO patients: 97,9±0,2% vs 91,8±1,0%. The incidence of patients with fungal infection was 8,8±0,4% vs 21,2±1,3%, and the outcome was better in PHO patients: 95,9±0,7% vs 85,8±2,3%. Incidence of viral infections was 5,0±1,0% in PHO setting, including part of previously transplanted patients, and 47,8±2,2% in HCT setting (60,9±2,3% allo-HCT; 5,6±1,3% auto-HCT). In children, the incidence was higher for bacterial (36.0% vs 27.6%), fungal (25.3% vs 6.3%), and viral (56.3% vs 29.3% allo-HCT; 6.6% vs 0.8% auto-HCT) infections than in adults (p<0.0001), and the outcome was better for bacterial (95.5% vs 91.4%), fungal (88.0% vs 74.9%), and viral (98.6% vs 92.3%) infections. In conclusion, the presented large studies have determined the incidence of infectious complications and their outcomes in HCT and PHO centers in Poland.

Streszczenie

Powiększenie węzłów chłonnych (limfadenopatia) jest jednym z najczęstszych objawów klinicznych, zwłaszcza u dzieci. U ok. 50% zdrowych dzieci dochodzi do powiększenia węzłów chłonnych; najczęściej w wieku 2-10 lat. Celem pracy jest przedstawienie zasad postępowania diagnostycznego u pacjenta z limfadenopatią, jak również omówienie jej przyczyn, zasad rozpoznawania oraz przedstawienie rekomendacji postępowania klinicznego u pacjenta z powiększeniem węzłów chłonnych. Etiologię limfadenopatii u dzieci i dorosłych oraz związane z tym ukierunkowanie diagnostyki różnicowej można określić wg kilku reguł przedstawionych akronimami w języku angielskim: MIAMI, CHICAGO, wg liter alfabetu lub lokalizacji. W postępowaniu diagnostycznym obowiązuje czteroetapowy proces: (1) badanie podmiotowe (wywiad) i przedmiotowe; na tym etapie najczęściej zapada decyzja o hospitalizacji; (2) badania laboratoryjne; (3) badania obrazowe: USG i/lub tomografia komputerowa; (4) otwarta biopsja węzła. W chwili obecnej otwarta biopsja węzła i badanie histopatologiczne są złotym standardem diagnostycznym limfadenopatii u dzieci. Ze względu na ryzyko maskowania lub opóźnienia rozpoznania chłoniaka lub białaczki do czasu ustalenia jednoznacznej diagnozy nie należy podawać steroidów. U dzieci z ostrym jednostronnym powiększeniem przednich węzłów chłonnych szyjnych oraz z objawami ogólnymi powinna zostać zastosowana antybiotykoterapia empiryczna.

Abstract

Viruses are a form of life that possess genes but do not have a cellular structure. Viruses do not have their own metabolism, and they require a host cell to make new products; therefore, they cannot naturally reproduce outside a host cell. The objective of this paper is to present the basic practical clinical roles of viruses in patients with hematological diseases including malignancies and non-malignan- cies, as well as those undergoing hematopoietic cell transplantation (HCT), with the focus on herpesviruses causing latent infections in severely immunocompromised patients. From the hematologist point of view, viruses can play a major role in four conditions: causing infections; causing lymphoproliferations and/or malignancies; causing (pan)cytopenia; and used as vectors in treatment (e.g., gene therapy, CAR-T cells). Taking into account the role of viruses in hematology, infection is the most frequent condition. Among DNA viruses, the highest morbidity potential for human is expressed by Herpesviridiae (herpesviruses), Adenoviridae (adenovirus; ADV), Polyomavirus (BKV, JCV), and Bocavirus. RNA viruses can play a role in pathogenesis of different clinical conditions and diseases: lymphoproliferative disorders and malignancy, possibly causing NHL, AML, MDS, and others (HCV, HIV, and others); pancytopenia and aplastic anemia (HIV, HCV, Dengue virus); respiratory infections (community-acquired respiratory virus infections; CARV) caused by Orthomyxoviruses (e.g. influenza A/B), Paramyxoviruses (e.g. human parainfluenza virus PIV-1, -2, -3, and -4; respiratory syncytial virus RSV-A and -B), picornaviruses (e.g., human rhinovirus), coronaviruses (e.g., human coronavirus), Pneumoviridiae (e.g., human metapneumovirus), and potentially other viruses.

Streszczenie

Reaktywacja zakażenia HBV jest istotnym problemem u chorych poddawanych terapiom, które poprzez działanie immunomodulujące wpływają na upośledzenie odporności przeciwwirusowej, takim jak: leczenie biologiczne (np. przeciwciała monoklonalne powodujące deplecję limfocytów CD20, przeciwciała anty-TNF), chemioterapia, leczenie immunosupresyjne (np. kortykosteroidy, cyklosporyna, azatiopryna). Ryzyko reaktywacji wiąże się również z nowymi terapiami stosowanymi w leczeniu nowotworów hematologicznych, takimi jaki inhibitory kinaz tyrozynowych, inhibitory proteasomu czy przeciwciało anty-CD38, daratumumab. Populacją szczególnie zagrożoną są chorzy poddawani transplantacji komórek krwiotwórczych, w szczególności chorzy po transplantacji allogenicznej, u których prowadzone jest leczenie immunosupresyjne. W pracy przedstawiono epidemiologię, czynniki ryzyka reaktywacji oraz aktualne zasady postępowania dotyczące profilaktyki reaktywacji zakażenia HBV.

Streszczenie

Zakażenia są jednym z największych zagrożeń dla chorych w trakcie i po leczeniu chorób nowotworowych. Dla dzieci z nieonkologicznymi schorzeniami hematologicznymi infekcje wiążą się ze zwiększonym ryzykiem powikłań, a także mogą być czynnikiem spustowym wystąpienia lub zaostrzenia problemu zdrowotnego. Jedynym skutecznym i bezpiecznym sposobem zapobiegania zakażeniom są szczepienia ochronne. Zalecenia odnośnie do ich realizacji zmieniają się w czasie, w zależności od aktualnej sytuacji epidemiologicznej, dostępu do szczepionek, a także danych dotyczących bezpieczeństwa ich stosowania w grupach ryzyka. Prezentowana praca przedstawia aktualne rekomendacje Polskiego Towarzystwa Hematologii i Onkologii Dziecięcej, dotyczące zasad immunizacji dzieci z chorobami nowotworowymi i schorzeniami hematologicznymi.