Overview of the Side-Effects of FDA- and/or EMA-Approved Targeted Therapies for the Treatment of Hematological Malignancies.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadIn the last decade there has been tremendous effort in offering better therapeutic management strategies to patients with hematologic malignancies. These efforts have ranged from biological to clinical approaches and resulted in the rapid development of new approaches. The main "problem" that comes with the high influx of newly approved drugs, which not only influences hematologists that frequently work with these drugs but also affects other healthcare professionals that work with hematologists in patient management, including intensive care unit (ICU) physicians, is they have to keep up within their specialty and, in addition, with the side-effects that can occur when encountering hematology-specific therapies. Nonetheless, there are few people that have an in-depth understanding of a specialty outside theirs. Thus, this manuscript offers an overview of the most common side-effects caused by therapies used in hematology nowadays, or that are currently being investigated in clinical trials, with the purpose to serve as an aid to other specialties. Nevertheless, because of the high amount of information on this subject, each chapter will offer an overview of the side-effects of a drug class with each reference of the section being intended as further reading. Keywords: hematological malignancies; life-threatening side-effects; novel therapies.MDPI A

Progress and trends in pediatric hematopoietic cell transplantation in Central-East European countries

Hematopoietic cell transplantation (HCT) is widely used as a treatment for acquired and congenital disorders. In recent years, a significant increase in transplant activity around the world has been observed, especially in Eastern European countries. This article aimed to assess progress and trends in pediatric HCT in Central-Eastern European countries between 2013 and 2018. Transplant activity survey in 2013 and 2018 in nine Central-Eastern European countries (Czech Republic, Croatia, Hungary, Lithuania, Poland, Romania, Slovakia, Slovenia, and Ukraine) was performed. The highest transplant rates in total were found in the Czech Republic and Hungary. When calculated per 10 million of the pediatric population, a 25.9% increase in the number of allo-HCT was observed with the highest in Croatia, Romania, Lithuania, and Poland; and a 12.2% increase in the number of auto-HCT was observed with the highest in Slovenia, Slovakia, Romania, Poland, Ukraine, and Croatia. We have shown, over the years 2013 and 2018, in some countries of Central-Eastern Europe that there was a significant increase in transplant activity, especially in those with the lower rates. This increase was observed mainly in centers already existing in 2013, especially in the allo-HCT setting. The rise of activity was significantly less influenced by the creation of new transplant centers or the increase in the number of pediatric transplant beds. In conclusion, our analysis indicates that in the Czech Republic, Hungary, Lithuania, and Slovenia, the actual infrastructure and the number of HCTs cover the needs, whereas in other countries, especially in Romania and Ukraine, the number of HCT needs to be increased

Continuous renal replacement therapy in cytokine release syndrome following immunotherapy or cellular therapies?

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadRecently, an increasing number of novel drugs were approved in oncology and hematology. Nevertheless, pharmacology progress comes with a variety of side effects, of which cytokine release syndrome (CRS) is a potential complication of some immunotherapies that can lead to multiorgan failure if not diagnosed and treated accordingly. CRS generally occurs with therapies that lead to highly activated T cells, like chimeric antigen receptor T cells or in the case of bispecific T-cell engaging antibodies. This, in turn, leads to a proinflammatory state with subsequent organ damage. To better manage CRS there is a need for specific therapies or to repurpose strategies that are already known to be useful in similar situations. Current management strategies for CRS are represented by anticytokine directed therapies and corticosteroids. Based on its pathophysiology and the resemblance of CRS to sepsis and septic shock, as well as based on the principles of initiation of continuous renal replacement therapy (CRRT) in sepsis, we propose the rationale of using CRRT therapy as an adjunct treatment in CRS where all the other approaches have failed in controlling the clinically significant manifestations.School of Doctoral Studies - Iuliu Hatieganu University Romanian Government Ion Chiricuta Oncology Institute Cluj Napoca Iuliu Hatieganu University of Medicine and Pharmacy Cluj Napoca European Economic Spac

Design and preclinical testing of an anti-CD41 CAR T cell for the treatment of acute megakaryoblastic leukaemia

Funding Information: Adrian Bogdan Tigu and Catalin Constantinescu contributed equally to the current manuscript. Catalin Constantinescu is funded by an internal grant of the Iuliu Hatieganu University – School of Doctoral Studies. David Kegyes is funded by an internal grant of the Iuliu Hatieganu University – School of Medicine. Mareike Peters is funded by a national grant of the Romanian Society for Bone Marrow Transplantation. Ciprian Tomuleasa is also supported by a grant awarded by the Romanian National Ministry of Research, Innovation and Digitalization: PN‐III‐P4‐ID‐PCE‐2020‐1118 within PNCDI IV, Projects for Exploratory Medicine; Projects for Exploratory Medicine—PCE 225/2021; as well as a national grant awarded to Young Research Teams (PN‐III‐PI‐1.1‐TE‐2019‐0271 –‘Supporting a team of young researchers to create an independent research program based on the use of Sleeping Beauty protocol f or the development of CAR T Cells – SEATTLE’). Diana Gulei, Diana Cenariu, Adrian Bogdan Tigu, Jon Thor Bergthorsson and Victor Greiff are supported by an international collaborative grant of the European Economic Space between Romania and Iceland 2021–2023: ‘Cooperation strategy for knowledge transfer, internationalization and curricula innovation in the field of research education at the 3rd level of study –AURORA.’ Publisher Copyright: © 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.Acute megakaryoblastic leukaemia (AMkL) is a rare subtype of acute myeloid leukaemia (AML) representing 5% of all reported cases, and frequently diagnosed in children with Down syndrome. Patients diagnosed with AMkL have low overall survival and have poor outcome to treatment, thus novel therapies such as CAR T cell therapy could represent an alternative in treating AMkL. We investigated the effect of a new CAR T cell which targets CD41, a specific surface antigen for M7-AMkL, against an in vitro model for AMkL, DAMI Luc2 cell line. The performed flow cytometry evaluation highlighted a percentage of 93.8% CAR T cells eGFP-positive and a limited acute effect on lowering the target cell population. However, the interaction between effector and target (E:T) cells, at a low ratio, lowered the cell membrane integrity, and reduced the M7-AMkL cell population after 24 h of co-culture, while the cytotoxic effect was not significant in groups with higher E:T ratio. Our findings suggest that the anti-CD41 CAR T cells are efficient for a limited time spawn and the cytotoxic effect is visible in all experimental groups with low E:T ratio.Peer reviewe

Perspectives on the co-treatment with GnRHa in female patients undergoing hematopoietic stem cell transplantation

Outcomes after hematopoietic stem cell transplantation (HSCT) for patients with both malignant and nonmalignant diseases have improved significantly in recent years. However, the endocrine system is highly susceptible to damage by the high-dose chemotherapy and/or irradiation used in the conditioning regimen before HSCT. Ovarian failure and subsequent infertility are frequent complications that long-term HSCT survivors and their partners face with a negative impact on their QoL. Several meta-analyses of randomized clinical trials showed that gonadotropin-releasing hormone agonist (GnRHa) administration in advance of starting standard chemotherapy decreases the risk of gonadal dysfunction and infertility in cancer patients, but GnRHa use for ovarian protection in HSCT patients is not fully determined. In this review, we are discussing the potential preservation of ovarian function and fertility in pubertal girls/premenopausal women who undergo HSCT using GnRHa in parallel with conditioning chemotherapy, focusing on the current data available and making some special remarks regarding the use of GnRHa

Cardiotoxicity - the first cause of morbidity and mortality in pediatric patients survivors of acute lymphoblastic leukemia

Acute lymphoblastic leukemia is the most common hematological malignancy at pediatric age. Cardiotoxicity holds the first place among the causes of morbidity and mortality in these patients. Anthracyclines are cytostatic drugs frequently associated with cardiotoxicity. Early diagnosis of cardiac impairment during the treatment of pediatric patients is extremely important, both for modulating future chemotherapy and for administering cardioprotective agents. Long term monitoring after chemotherapy helps to identify the risk of late cardiotoxicity among cancer survivors. There are several biomarkers, already in use or still under study, which may represent an operator-independent alternative for echocardiography in the diagnosis of cardiotoxicity. In case of cardiac damage, the clinician has options for treating or limiting the progression, either with the use of already approved agents, such as Dexrazoxane, or by administrating other cardioprotective drugs. International experts are still attempting to establish the best algorithm for early detection of cardiotoxicity, as well as the most efficient treatment plan in case of already existing myocardial damage in these patients. We present a review on treatment-related cardiotoxicity, including mechanisms of development, useful biomarkers and treatment options, after carefully analyzing specialty literature

2014-2017 RETROSPECTIVE STUDY ON THE ANALYSIS OF CAUSES OF DEATH, OTHER THAN DISEASE PROGRESSION, IN CHILDREN DIAGNOSED WITH ACUTE LYMPHOBLASTIC LEUKAEMIA – EXPERIENCE OF THE PAEDIATRIC DEPARTMENT OF FUNDENI CLINICAL INSTITUTE

Introduction. Acute lymphoblastic leukemia (ALL) is the most common form of cancer in the pediatric population (1). The survival rate has increased in recent years due to the continuous adjustment of therapeutic protocols (2). Despite all the efforts made alongside the evolution of new therapeutic protocols, the treatment related mortality (TRM) is around 2-4% in the Western European countries (3,4). Materials and methods. This retrospective is an analytical, observational and cohort-type study, the first of this kind in Romania, performed in a single pediatric hematology center, Clinical Institute Fundeni, between 2014 and 2017. It assesses the incidence of global mortality, the incidence of mortality due to any cause other than progression of disease (NRM = Non Relapse Mortality) and the main cause of death in children diagnosed with ALL. Results. We included 142 patients diagnosed between January 2014 and June 2017, with follow-up of 48 months post-diagnosis. The overall mortality of the cohort is 10.5% (15/142). The mortality rate for any other cause except disease progression (NRM) is 7.04% (10/15). These ten patients, in molecular remission, have as main cause of death complications that occurred during treatment (TRM= treatment related mortality with / without IRM = infection related mortality). The study showed increased percentages of IRM 6.3%, over value of other studies, explaining and increasing also the value of NRM and also the value of global mortality; In contrast to TRM 2.1%, this being in the reference range (12,17,19,20). The most common cause of NRM was Clostridium difficile infection (4/10). Conclusion. There are important to note the high percentage of achievement of complete remission (98%) and impressive global survival at 4 years (89.4%)

Decision making in pediatric oncology: Views of parents and physicians in two European countries

Decision making is a highly complex task when providing care for seriously ill children. Physicians, parents, and children face many challenges when identifying and selecting from available treatment options

Dynamics of CL-P1 in ischemia/reperfusion

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The Significance of CD20 Intensity Variance in Pediatric Patients with B-Cell Precursor Acute Lymphoblastic Leukemia

B-cell precursor acute lyphoblastic leukemia (ALL) is a common pediatric malignancy and patients may have significant benefits from monoclonal antibodies therapy with increased survival rates. Positive CD20 expression is identified in about half of these patients and its presence may serve as a prognostic factor in disease evolution. We performed a retrospective study including 114 patients diagnosed with B-ALL and evaluated the expression of CD20 through flow cytometry at diagnosis and on day 15. Additional immunophenotypic analyses as well as cytogenetic and molecular genetic analyses were also performed. We observed an increase in the mean fluorescence intensity (MFI) of CD20 between diagnosis—1.9 (1.2–3.26) and day 15: 6.17 (2.14–27.4), (p 8.08 at diagnosis and >28.65 at day 15. In conclusion, CD20 expression appears to be a poor prognostic feature of B-ALL in pediatric patients. In this study, stratification of the outcome by the intensity of CD20 has implications concerning the allocation to rituximab-based chemotherapy and may offer new, potentially useful information for pediatric patients with B-ALL