Hemato doi: 10.3390/hemato5020017

Authors: Sakditad Saowapa Natchaya Polpichai Manasawee Tanariyakul Thanathip Suenghataiphorn Narathorn Kulthamrongsri Maireigh McCullough Mariana Goncalves Damasceno Moreira Pharit Siladech Lukman Tijani

Background: Autoimmune disorders (ADs) are prevalent among patients with myelodysplastic syndrome (MDS), yet their impact on MDS outcomes, including overall survival (OS), mortality, and transformation to acute myeloid leukemia (AML), is not well defined. Methods: We conducted a systematic review of articles published up to April 2024, sourced from PubMed, Web of Science, Embase, and Google Scholar, focusing on the influence of ADs on survival and AML transformation rates in MDS patients. The methodological quality of each study was assessed using the Newcastle Ottawa Scale. Results: From 8 studies that met the inclusion criteria, ADs were present in 17.5% (3074/17,481) of MDS patients. Data analysis indicated mortality rates ranging from 15.3% to 67% in MDS patients with ADs and 12% to 69% in those without. The rate of AML transformation varied from 0% to 23% in patients with ADs compared to 4% to 30% in those without. Conclusions: The influence of ADs on survival and AML transformation in MDS patients appears variable. This systematic review highlights the need for further large-scale prospective studies to clarify the relationship between ADs and MDS outcomes.

Hemato doi: 10.3390/hemato5020016

Authors: Annunziata Gloghini Antonino Carbone

Classic Hodgkin lymphoma (cHL) is a B-cell lymphoma in which tumour cells, the so-called Hodgkin Reed–Sternberg (HRS) cells, are admixed with non-malignant cell types that are a functional part of the disease. Immune cells, fibroblasts, specialised mesenchymal cells, and microvasculature together make up the tumour microenvironment and have functional interactions with tumour cells. HRS cells are surrounded by T and B cells admixed with plasma cells, macrophages, eosinophils, and mast cells. A cross-talk occurs between HRS cells and immune cells of the TME. This cross-talk is mediated either by a large network of cytokines and chemokines expressed by HRS cells or molecules produced by different cell types of the TME, i.e., CD30/CD30L, CD40/CD40L, OX40L/OX40, Il- 3/Il-3R, CCR5/CCL5, CD74 macrophage migration inhibitory factor/macrophages, and PD-L1/PD-1. The over-expression of CD30 and CD40, members of the TNF receptor family, is a hallmark of HRS cells. This review highlights the current development of newer therapeutic strategies as a means of immune checkpoint blockade and suggests that further research should explore innovative molecules aimed at targeting components of HL that are involved in cancer cell growth and/or immune escape. Hopefully, this will influence sensitivity or resistance to checkpoint inhibitor therapy in an individual patient.

Hemato doi: 10.3390/hemato5020015

Authors: Gianluca Maiorana Giusy Antolino Giacinto La Verde Agostino Tafuri

Multiple Myeloma is a hematological neoplasm that, over the recent few years, has benefited from numerous therapeutic options. Among the latter, CAR-T stands out as the most recent and one of the most promising treatments currently available. Despite its recent introduction, multiple CAR-T products have already been approved, and research regarding cellular therapy is rapidly increasing. We conducted a comprehensive search and review of the available literature, including published studies and abstracts from recent meetings (ASH, ASCO, ASTCT, IMS), regarding Multiple Myeloma and CAR-T therapy. We describe the discovery and research regarding promising targets like the B-Cell Maturation Antigen (BCMA) and others, the origin and nature of CAR-T cells, and the recent introduction of anti-BCMA CAR-Ts Idecabtagene-vicleucel and Ciltacabtagene-autoleucel, which are currently the only approved CAR-T products for MM. Additionally, we discuss non-BCMA-targeting CAR-Ts and their clinical implications. Given the significant impact of cellular therapy, we provide an overview of its limitations and possible adverse implications, as well as related resistance mechanisms. Finally, we describe the current research aimed at improving CAR-T therapy in MM, including structural innovations and new therapeutic approaches, such as in the earlier lines of treatment and maintenance therapy.

Hemato doi: 10.3390/hemato5020014

Authors: Paula Rodriguez-Otero Thomas Martin

The treatment of relapsed and refractory multiple myeloma has improved substantially in the last 5–10 years based on the development and use of several novel classes of drugs and drug combinations. These advances have led to improvements in progression-free and overall survival as well as quality of life. The general tendency has been to advance drugs/combinations that have performed well in advanced disease to the earlier line settings (frontline, first/early relapse). There are several triplet drug combinations that, when used as part of first or early relapse, can provide remission durations of 3 years or longer. More recently, impressive responses have been seen with the use of targeted immunotherapeutics (chimeric antigen receptor T-cells and bispecific antibodies) in heavily pretreated patients with MM. These treatments, however, have been associated with some new and occasionally severe toxicities, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and severe infections, including opportunistic infections and profound cytopenias. These potential toxicities bring into question whether these immune-targeting drugs should remain as late-line therapeutics or whether the high single-agent overall response rates mandate that these agents be used in earlier line settings. Herein, the authors provide a point and counterpoint about the future use of these agents.

Hemato doi: 10.3390/hemato5020013

Authors: Elaine S. Jaffe Antonino Carbone

The World Health Organization (WHO) “Classification of Tumours of Haematopoietic and Lymphoid Tissues”, published in 2001 and subsequently updated in 2008 and 2017, defined disease entities based on morphologic and phenotypic characteristics, clinical features, and genomic findings. Recently, the criteria for the diagnosis of many lymphoma entities have been refined in a proposal by the International Consensus Classification (ICC). Some provisional categories have now been recognized as “definite” entities, while other categories have undergone major revision. This article reports on the major revisions in the criteria and definition of B- and T-/NK-cell lymphomas by the ICC system.

Hemato doi: 10.3390/hemato5020012

Authors: Paul G. Richardson

High-dose melphalan (HDM) plus autologous stem cell transplant (ASCT) remains a standard-of-care treatment approach for eligible patients with newly diagnosed multiple myeloma (NDMM) based on demonstrated superiority in terms of progression-free survival (PFS) versus nontransplant approaches. Very high rates of minimal residual disease (MRD)-negative responses are also being seen with novel triplet and quadruplet induction regimens plus HDM-ASCT. However, recent clinical trials have shown no overall survival benefit with transplant versus nontransplant approaches. Furthermore, HDM is associated with several important downsides, including acute and long-term toxicities, transient decreases in quality of life, the need for hospitalization, an increased mutational burden at relapse, and an elevated risk of second primary malignancies. In this context, given the highly heterogeneous nature of MM in the NDMM patient population, as well as the continued emergence of novel agents and treatment approaches, there is an increasing rationale for considering deferred HDM-ASCT approaches in selected patients. Approaches under investigation include MRD-adapted therapy and the use of novel immune-based therapies as alternatives to HDM-ASCT. Ongoing developments in understanding the pathobiology and prognostic factors in NDMM, plus immune profiling and routine MRD evaluation, will result in novel, HDM-sparing treatment paradigms, enabling further improvement in patient outcomes.

Hemato doi: 10.3390/hemato5020011

Authors: Joaquim Carreras Naoya Nakamura

Background: Artificial intelligence in medicine is a field that is rapidly evolving. Machine learning and deep learning are used to improve disease identification and diagnosis, personalize disease treatment, analyze medical images, evaluate clinical trials, and speed drug development. Methods: First, relevant aspects of AI are revised in a comprehensive manner, including the classification of hematopoietic neoplasms, types of AI, applications in medicine and hematological neoplasia, generative pre-trained transformers (GPTs), and the architecture and interpretation of feedforward neural net-works (multilayer perceptron). Second, a series of 233 diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab-CHOP from the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) was analyzed. Results: Using conventional statistics, the high expression of MYC and BCL2 was associated with poor survival, but high BCL6 was associated with a favorable overall survival of the patients. Then, a neural network predicted MYC, BCL2, and BCL6 with high accuracy using a pan-cancer panel of 758 genes of immuno-oncology and translational research that includes clinically relevant actionable genes and pathways. A comparable analysis was performed using gene set enrichment analysis (GSEA). Conclusions: The mathematical way in which neural networks reach conclusions has been considered a black box, but a careful understanding and evaluation of the architectural design allows us to interpret the results logically. In diffuse large B-cell lymphoma, neural networks are a plausible data analysis approach.

Hemato doi: 10.3390/hemato5020010

Authors: Salomon Manier Thierry Facon

Multiple myeloma (MM) presents unique challenges in the elderly population due to increased frailty and comorbidities. Balancing treatment efficacy, safety, and quality of life is essential in managing elderly patients. While two-drug regimens were often favored for elderly patients, recent studies show promising outcomes with anti-CD38 antibody-based therapies, particularly daratumumab and lenalidomide with minimal dexamethasone. Continuous low-intensity treatments have shown improved progression-free survival and overall survival, with significant benefits observed in elderly patients. The DRd combination has now emerged as the standard of care for elderly MM patients, offering a favorable balance of efficacy, safety, and convenience. Ongoing trials are evaluating the addition of bortezomib in an induction phase for fit patients. New-generation immunotherapies hold promise for further refining treatment approaches, potentially leading to treatment discontinuation in select patient populations with sustained minimal residual disease negativity.

Hemato doi: 10.3390/hemato5020009

Authors: Pilar Solves Ana Bataller Ana Belén Gálvez Pedro Asensi Cantó Marta Santiago María José Moreno Inés Gómez-Seguí Javier de la Rubia

Background: Selective IgA deficiency (IgA-D) has been historically considered a high-risk entity for developing allergic/anaphylactic reactions after blood transfusion (AATRs). However, it has been suggested that the IgA-D-related anaphylactic transfusion reaction is not evidence-based. Methods: We conducted three different approaches to collect evidence about epidemiology, AATRs, and transfusion management of patients with IgA-D at La Fe University Hospital. Firstly, we analysed the prevalence of IgA-D in a population of patients diagnosed with acute leukaemia, The second approach consisted of collecting transfusion data from IgA-D patients. Finally, we reviewed the IgA levels of patients recorded in the hemovigilance system suffering an AATR. Results: IgA-D prevalence was 1 in 334 patients. At least one blood component was transfused to 23 patients diagnosed with IgA-D. Plasma was transfused to eight IgA-D patients, while six patients received red blood cells, platelets, and plasma. No adverse reactions were reported in any patient. AATRs occurred in 325 men and 264 women with a median age of 52 years. Severe reactions occurred in 56 patients (1/14,520 components). Mean IgA levels were 215 mg/dL (4–5570) for mild reactions and 214 mg/dL (14–824) for severe reactions (p = ns). Washed platelets were administered to two patients who developed severe and repeated AATRs. Both had normal IgA levels. Conclusions: Since the AATRs related to IgA-D are extremely low, as reported in current hemovigilance systems, IgA-D should not be considered a high-risk entity to develop AATRs. On the contrary, our findings support standard transfusion management of IgA-D patients.

Hemato doi: 10.3390/hemato5010008

Authors: Michael Dennis Weaver Bianca Glass Chance Aplanalp Gauri Patel Jeshrine Mazhil Isabella Wang Samir Dalia

Eosinophils are a type of granulocyte key to immune system modulation seen in a number of disease processes. Nearly every major organ system can be connected to peripheral eosinophilia through a number of different disease processes, ranging from benign conditions to malignancy. In this paper, we review both common and rare causes of peripheral eosinophilia, their symptoms, and a framework for the workup of peripheral eosinophilia of unknown etiology.

Hemato doi: 10.3390/hemato5010007

Authors: Natalia Wojciechowska Kaci Orr Karen Albritton Kenneth Heym Kelly Vallance Lauren Murray Rocio Aguilar Anish Ray

Immunotherapy has emerged as a promising treatment approach in oncology, as it is specifically designed to boost the strength and accuracy of the immune system, allowing it to target tumor cells but spare non-tumor tissue. This treatment not only demonstrates potential for improved clinical outcomes but may also be associated with fewer adverse effects compared to traditional therapies. Despite its early success, the application of immunotherapy has largely been limited to adult cancer patients, with slow adoption noted in the treatment of pediatric cancer patients. Our objective is to demonstrate a single institution’s experience with immunotherapy in pediatric cancer patients and to discuss the use of these treatment modalities in this unique patient population. We performed a retrospective chart review and identified patients who received immune checkpoint inhibitors (ICIs) and/or underwent immunohistochemistry (IHC) testing for programmed death ligand 1 (PD-L1), quantification of tumor mutational burden (TMB), and classification of microsatellite instability (MSI) status. In total, we identified seven pediatric cancer patients who received therapy with ICIs. Four of these patients demonstrated positive PD-L1 expression, high TMB, and/or MSI-high status. These patients were treated with nivolumab alone or in combination with ipilimumab or brentuximab. The diagnoses included: multifocal epithelioid and spindle cell hemangioma (n = 1); metastatic melanoma (n = 2); histiocytic sarcoma (n = 1); rectal adenocarcinoma in the setting of constitutional mismatch repair deficiency syndrome (CMMRD) (n = 1); and Hodgkin lymphoma (n = 2). The patients received between four and nineteen cycles of immunotherapy. Immunotherapy-related adverse events included: mild allergic reaction; prodromal symptoms; anemia; neutropenia; transaminitis; endocrinopathies; and self-limiting neuritis. Of the seven patients, three are still being treated with immunotherapy (the patients with rectal adenocarcinoma, metastatic melanoma, and multifocal epithelioid and spindle cell hemangioma) with positive treatment responses observed on imaging, one is being treated with other modalities (the patient with Hodgkin lymphoma), two have achieved remission (the patients with metastatic melanoma and Hodgkin lymphoma), and one has relapsed (the patient with histiocytic sarcoma). The three patients who completed their immunotherapy regimens have been followed for 1 month, 4 months, and 10 months, respectively. This report of a single-institution experience with immunotherapy in pediatric cancer patients highlights the positive impact immunotherapy can have, especially when utilized to treat relapsed/refractory malignancies, as tumor regression or stabilization of disease burden was achieved in six of the patients described (CR = 2; PR = 4). Further research is needed to accurately identify pediatric oncology patients who could benefit from immunotherapy.

Hemato doi: 10.3390/hemato5010006

Authors: Rabea Möller Katharina Kaiser Ulrich Baulain Björn Petersen Carsten Detering Mahnaz Ekhlasi-Hundrieser Richard Zimmermann Christian Mühlfeld Mario von Depka Prondzinski Christiane Pfarrer Stefanie Lehner

Pregnancy and the oestrus cycle are challenging for female patients suffering from von Willebrand disease (VWD). Therefore, our study aimed to investigate the changes in von Willebrand factor (VWF) and factor VIII (FVIII) during pregnancy and the oestrus cycle in our porcine model of von Willebrand disease compared with the wild-type. Plasma analyses regarding primary hemostasis, secondary hemostasis, and VWF multimers, as well as immunohistochemistry analyses of VWF in the uterus and ovary, were performed. For levels of VWF and FVIII activities, significant elevations were seen in the last trimester. Primary hemostasis improved towards the end of pregnancy. In the oestrus cycle, significantly lower VWF values can be seen in the immunohistochemistry of the ovaries during the oestrus, while values were highest in the metoestrus. VWF multimer patterns in pigs were similar to the ones in human VWD patients. In summary, the course of VWF and FVIII during pregnancy and the oestrus cycle in porcine VWD were investigated for the first time. The porcine model seems to be suitable for haemostaseological studies on VWD. This provides an advantage for investigating reproduction-related bleeding and understanding the underlying mechanisms of post-partum hemorrhage or miscarriage in women with VWD.

Hemato doi: 10.3390/hemato5010005

Authors: Elpis Mantadakis Sonia Alexiadou Panagiota Zikidou

Iron deficiency (ID) is by far the most common nutritional disorder in developing and developed countries. When left untreated, ID leads to anemia. Although the usually recommended treatment for iron deficiency anemia (IDA) is oral iron therapy with countless products, such therapy necessitates administration for >3–6 months with questionable patient compliance since most oral iron products have an unpleasant metallic aftertaste and cause intestinal side effects. In addition, in certain gastrointestinal conditions, such as inflammatory bowel diseases or untreated gluten-sensitive enteropathy, oral iron therapy is contraindicated or unsuccessful. Intravenous iron is considered safe in adults, where adverse events are mild and easily managed. The experience with parenteral iron in children is much more limited, and many pediatricians appear reluctant to use it because of uncorroborated fears of serious anaphylactic reactions. In the current article, we thoroughly review the available pediatric literature on the use of all commercially available parenteral iron products except ferumoxytol, which was recently removed from the market. We conclude that parenteral iron appears to be safe in children; it works faster than oral iron, and the newer third-generation products allow replacement of the total iron deficit in a single sitting.

Hemato doi: 10.3390/hemato5010004

Authors: Aditi Sharma Amit Dahiya Asif Alavi Indryas Woldie Aditya Sharma Jeffrey Karson Vijendra Singh

Background: Transfusional iron overload causes significant morbidity and mortality in sickle cell disease (SCD). Nevertheless, red blood cell transfusions continue to be essential in its management. This study describes the transfusion patterns among SCD hospitalizations. Methods: Hospitalizations for SCD in the 2017–2018 Nationwide Readmissions Database were divided into two groups based on whether they received transfusions. Descriptive analysis was performed to compare their demographics and complications. Multivariable logistic regression was performed to determine the factors associated with transfusions. Results: Out of 109,783 hospitalizations, 28,300 were transfused, and 81,483 were not transfused. Females and older individuals were higher in the transfused category than the non-transfused category (59.49% vs. 53.52% and 28.86% vs. 21.27%, respectively; p < 0.001 for both). The wealthiest population was more likely to be in the transfused category (11.27% vs. 8.34%; p < 0.001). Admissions to teaching hospitals, large metropolitan hospitals, and highest-volume hospitals were higher in the non-transfused category vs. transfused category (79.89% vs. 72.17%; p < 0.001, 69.26% vs. 65.35%; p 0.003 and 74.71% vs. 63.51%; p < 0.001, respectively). Most admissions were transfused once, with three or more transfusions being given more in the non-teaching hospitals than the teaching hospitals (1.27% vs. 0.41%; p 0.01). Furthermore, a higher proportion of early transfusions occurred in the non-teaching hospitals (65.6% vs. 57.82% for admission days 1 and 2; p < 0.001). Admission to a teaching hospital was associated with lower blood transfusion odds than a non-teaching hospital. Conclusion: A quarter of admissions for SCD receive a blood transfusion. In addition to performing more frequent and early transfusions, the odds of being transfused are higher in non-teaching hospitals.

Hemato doi: 10.3390/hemato5010003

Authors: Alessandro Cellini Andrea Visentin Alessandro Salvalaggio Mario Cacciavillani Sergio Ferrari Chiara Briani

The dysregulation of the immune system in Chronic Lymphocytic Leukemia (CLL) often allows for the development of immune-mediated diseases. Among them, autoimmune cytopenias are the most common, but cases of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have been reported. We herein report on a patient who developed a CIDP while undergoing ibrutinib treatment for CLL, prompting drug discontinuation. Steroid treatment and a rituximab course proved to be ineffective at obtaining long-term control of CIDP, but therapy with venetoclax and rituximab, which was started due to CLL progression, led to the progressive amelioration of the symptoms up to complete remission of the neurological disease.

Hemato doi: 10.3390/hemato5010002

Authors: Francisco Alejandro Lagunas-Rangel Venice Chávez-Valencia

Acute lymphoblastic leukemia (ALL), a remarkable cancer that mainly affects children, has seen commendable advances in its treatment. However, the occurrence of relapses after initial treatments poses a major threat and is one of the leading causes of cancer-related mortality in pediatric patients. To address this problem, innovative therapeutic approaches for ALL need to be continuously developed and refined. Synthetic lethality, an interaction between genes in which alteration of only one allows survival, but simultaneous alteration of both leads to inviability, is emerging as a promising therapeutic approach against ALL and other cancers. In this regard, the review aims to examine the documented cases of synthetic lethality in ALL reported to date (2023) and to elucidate the molecular mechanisms underlying this phenomenon. Furthermore, this review explores possible targets that have so far gone unnoticed, justifying their importance in this context.

Hemato doi: 10.3390/hemato5010001

Authors: Antonino Carbone

Hemato (ISSN 2673-6357) is an open access, peer-reviewed journal that publishes original articles and reviews highlighting important advances in the fundamental areas of Hematology [...]

Hemato doi: 10.3390/hemato4040029

Authors: Lívia de Oliveira Sales Lais Lacerda Brasil de Oliveira Jean Breno Silveira da Silva Manoel Odorico de Moraes Filho Maria Elisabete Amaral de Moraes Raquel Carvalho Montenegro Caroline Aquino Moreira-Nunes

The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in China and is responsible for Coronavirus disease (COVID-19). Despite being well tolerated by most patients, a fraction of cases evolve into a potentially fatal condition requiring intensive care. In addition to respiratory complications, several studies have reported cases of patients who developed intense thrombosis, including acute myocardial infarction and ischemic stroke, as well as the presence of elevated coagulation markers. Evidence has shown that the virus can interact directly with platelets and modulate their thrombotic and inflammatory functions, with significant prognostic implications. It is important to highlight that the emerging literature shows that when hyperactive these cells can act as pro-viral infections both in transporting their particles and in increasing inflammation, leading to a hyperinflammatory state and consequent clinical worsening. In this review, we searched for studies available in public databases and discussed the interaction of platelet biomarkers in the pathogenesis of COVID-19. In this context, understanding the mechanism of SARS-CoV-2 and these cells in different clinical conditions could help us to understand the coagulation and inflammation profiles of critically ill patients with the disease, guiding faster clinical management and enabling the reuse and targeting of more efficient therapies.

Hemato doi: 10.3390/hemato4040028

Authors: Guillermo A. Herrera Jiamin Teng Chun Zeng Luis Del Pozo-Yauner Bing Liu Elba A. Turbat-Herrera

The process of light-chain-associated amyloid (AL-Am) fibril formation in unique organelles (fibril-forming organelles) with lysosomal features has been documented in vitro in renal mesangial cells incubated with amyloidogenic light chains using electron microscopy and lysosomal gradient centrifugation to visualize intricate interactions between monoclonal light chains and endosomes/lysosomes. It is important to determine whether this process also occurs in vivo in the human renal mesangium. The present study analyzes 13 renal biopsies from patients with renal AL-amyloidosis and utilizes ultrastructural labeling techniques to define the nature and function of these organelles. Organelles were labeled for lysosomal-associated membrane protein (LAMP) and CD-68 (a macrophage marker). Furthermore, lambda was also localized inside these structures in transformed mesangial cells with a macrophage phenotype. These 11 cases from renal biopsies with a diagnosis of AL-amyloidosis (5 kappa and 8 lambda light-chain-associated) were examined ultrastructurally. All of the cases exhibited numerous fibrils forming organelles in approximately 40–50% of the remaining mesangial cells. All of the cases revealed mesangial cells engaged in active amyloidogenesis. Fibril-forming organelles are organelles with morphological/immunohistochemical and biochemical characteristics of lysosomes but with a unique, peculiar morphology. Five cases of other glomerular disorders used as controls were also carefully scrutinized for fibril-forming organelles and failed to show any. In the AL-amyloid renal cases, there was an intricate interaction between the fibril-forming organelles and lambda-/kappa-containing amyloid fibrils, supporting the notion that the monoclonal light chains participated in their formation.

Hemato doi: 10.3390/hemato4040027

Authors: Karina P. Verma Rebecca Steuer Camille V. Edwards

Monoclonal gammopathy of undetermined significance (MGUS) is a pre-malignant plasma cell disorder with an etiology that is incompletely understood. Modifiable risk factors and genetic predispositions likely interact to increase MGUS risk in specific individuals and populations. Identifying geographic prevalence patterns and modifiable risk factors is critical for understanding the etiology of MGUS. The aim of this review was to outline original research on MGUS prevalence across geographic locations and modifiable risk factors. We conducted a systematic review of 39 eligible studies from PubMed®, Embase®, and Web of Science® written in English and published by February 2023. Our protocol was registered in accordance with PROSPERO guidelines. Studies were synthesized using Research Electronic Data Capture and appraised using the National Heart, Lung, and Blood Institute study quality assessment tools. The prevalence of MGUS ranged from 0.24% to 9% across geographic locations. Modifiable risk factors for MGUS include infections, autoimmune diseases, chronic inflammatory conditions, lifestyle factors, environmental exposures, and ionizing radiation. Therefore, the development of MGUS may be related to chronic antigenic stimulation and genetic aberrations that promote clonal proliferation of plasma cells. Prospective studies assessing gene–environment interactions are needed to further define risk factors for MGUS and inform screening and preventative strategies.

Hemato doi: 10.3390/hemato4040026

Authors: Chiara Marvisi Elena Galli Caterina Ricordi Rexhep Durmo Massimo Roncali Francesco Muratore Carlo Salvarani Annibale Versari

The role of 18F-fluorodeoxyglucose (FDG) positron emission tomography (18F-FDG PET) in the diagnosis of large vessel vasculitis (LVV) is well established. It permits us to assess the extent and the grade of vascular involvement and to rule out the other causes in clinical scenarios characterized by less specific symptoms. The advantages of 18F-FDG PET are far less clear in monitoring disease activity over time. Studies looking for the role of 18F-FDG PET as a potential biomarker had conflicting results and whether and when to repeat it during follow-up is based on clinical experience. A comprehensive assessment, including clinical, laboratory and morphological imaging is still required to monitor patients with large-vessel vasculitis over time. The aim of this review is to present more recent data about the utility of 18 F-FDG PET in the diagnosis and follow-up of LVV.

Hemato doi: 10.3390/hemato4040025

Authors: David Bared Dukenik Deborah Soong Wenhui Li Ellen Madarang Justin Watts Justin Taylor

We describe a case of a female patient with acute lymphoblastic leukemia treated with high-dose systemic methotrexate and intrathecal methotrexate for leukemic relapse of the central nervous system. She developed complete bilateral lower-limb paralysis that was not attributable to any other cause. She was treated with folic acid, vitamin B12, methionine, S-adenosylmethionine, leucovorin, and dextromethorphan. After a 3-month period of paraplegia, she began to slowly recover motor function. She can now ambulate with assistance and continues to improve. There is a paucity of literature on methotrexate-induced subacute combined degeneration, which is typically described as irreversible. In addition to reporting our unique case, we review the published literature and call for more awareness and research in this area.

Hemato doi: 10.3390/hemato4040024

Authors: Leigh A. Madden Rebecca V. Vince Victoria C. Edwards Vivienne M. Lee Desmond M. Connolly

The blood coagulation response to decompression stress in humans has yet to be fully investigated. Here we utilised calibrated automated thrombogram (CAT) on samples from healthy volunteers exposed to decompression stress to investigate real-time thrombin generation. To induce decompression stress, fifteen apparently healthy males (age 20–50 yr) were exposed to two consecutive ascents to 25,000 ft for 60 min (1st ascent) and then 90 min (2nd ascent) while breathing 100% oxygen. Citrated blood samples were taken prior to exposure (T0), following the 2nd ascent (T8) and at 24 h (T24). Thrombin generation curves were obtained using ThrombinoscopeTM. Parameters determined were lag time (LAG), time to peak (TTP), peak thrombin (PEAK), endogenous thrombin potential (ETP) and velocity index (VEL). Of the 15 subjects, 12 had validated coagulation profiles. TTP and ETP showed no significant differences. However, there was a significant increase in VEL from T0 to T8 (p = 0.025) and from T8 to T24 (p = 0.043). A non-significant trend of an overall increase in PEAK was also observed from T0 to T8 (p = 0.069) and from T8 to T24 (p = 0.098). PEAK and VEL were found to be correlated. Taken together, these two parameters suggest an overall shift towards a more procoagulant profile following hypobaric stress.

Hemato doi: 10.3390/hemato4040023

Authors: Ringo Manta Chiara Lauri Maurizio Taurino Alberto Signore

Diagnosis of vascular graft/endograft infection (VGEI) is a challenge for clinicians due to the heterogeneity of clinical presentation and the complexity of its management. Microbiological culture is the gold standard, but it often fails to isolate the causative microorganism. A non-invasive imaging approach is therefore needed to assess VGEI. CTA is currently the first-choice imaging modality. Nuclear medicine techniques are recommended in case of negative or doubtful CTA results with persisting clinical suspicion. This review aims to summarize data from original studies published in the last decades regarding the role of both white blood cell (WBC) scans and fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT), their respective diagnostic performances, and their integration into the diagnostic approach for patients with a suspicion of VGEI.

Hemato doi: 10.3390/hemato4030022

Authors: Giacomo Malipiero Piernicola Machin Anna Ermacora Chiara Pratesi Antonino Carbone Desre’ Ethel Fontana Kathreena Paul Vattamattathil Rita De Rosa Paolo Doretto

Kikuchi–Fujimoto disease (KFD) is a rare, benign lymphoproliferative disease of uncertain origin that can mimic other inflammatory or clonal lymphoproliferative disorders. Given the lack of available blood biomarkers, diagnosis is based on the biopsy of an affected lymph node. In recent years, evidence has been mounting that a dysregulated type I INF innate immune response plays a pivotal role in the pathogenesis of the disease and might be a future therapeutic target. Nonetheless, laboratory assays measuring the expression of interferon alpha (INFα) and INF-stimulated genes (ISGs) are cumbersome and not widely available, limiting their use in clinical and translational research and encouraging the use of more convenient surrogate markers. In this study, a rapid flow cytometry assay detected increased levels of expression of CD169 (Siglec-1), an INFα-induced surface protein involved in innate immunity regulation, on circulating monocytes from two patients with KFD. Our results are in line with previous experiences and set the stage for a more extended investigation into the use of this assay in exploring the pathophysiology of KFD.

Hemato doi: 10.3390/hemato4030021

Authors: Tina Bagratuni Alexandra Papadimou Kostantina Taouxi Meletios A. Dimopoulos Efstathios Kastritis

High frequencies of MYD88L265P mutation are observed in IgM monoclonal gammopathies, and specifically in Waldenström macroglobulinemia (WM), indicating this mutation as a potential disease biomarker. Given the fact that MYD88L265P mutation has been described as a key driver mutation, has increased our understanding of the biology behind MYD88 signaling and helped us to identify the functional components which could be targeted. On the other hand, the absence of the MYD88L265P mutation in patients with IgM monoclonal gammopathies has been associated with a higher risk of transformation to aggressive lymphomas, resistance to several therapies, and shorter overall survival. The present review focuses on the molecular mechanisms that shape the signaling pattern in MYD88WT cells, as well as on the clinical implications and therapeutic challenges of WM patients that harbor the MYD88WT genotype.

Hemato doi: 10.3390/hemato4030020

Authors: Mario Tiribelli Giuseppe Petruzzellis Giulia Battaglia Martina Pucillo Marta Lisa Battista Michela Cerno Antonella Geromin Gabriele Facchin Umberto Pizzano Daniela Damiani Renato Fanin Francesca Patriarca

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML), granting patients a life expectancy close to that of the normal population and, in a subset of patients, the possibility to discontinue therapy. Nonetheless, for a not negligible minority of patients, TKIs are not able to control CML. Allogeneic hematopoietic cell transplantation (HCT) has long been a pivotal therapy for CML. At present, allogeneic HCT is considered an option in CML patients diagnosed or progressing to blast phase (BP), for those in chronic phase (CP) resistant to multiple lines of TKI therapy or for those experiencing severe toxicity, mostly hematologic, under TKIs. Moving from real-world cases, we reviewed the results of allogeneic HCT in the setting of advanced-phase CML or failure of TKIs, with a focus on the progresses in transplant technology that has extended transplant options in elderly CML patients and in those lacking a sibling donor, and on the post-HCT strategies for prevention and treatment of disease relapse.

Hemato doi: 10.3390/hemato4030019

Authors: Jahanzaib Khwaja Simon J. Salter Shirley D’Sa

Cryoglobulinaemia is characterised by serum immunoglobulins that precipitate at temperatures below 37 °C and redissolve on warming. Monoclonal IgM immunoglobulin can be associated with type I and II cryoglobulinaemia with underlying Waldenström macroglobulinemia, monoclonal gammopathy of undetermined significance, or another non-Hodgkin lymphoma. In this research, we review the clinical characteristics of monoclonal IgM-associated cryoglobulinaemia and suggest a management approach for addressing them. Laboratory testing is critical as even a minimal amount of measurable cryoglobulin may result in symptoms. Accurate detection of cryoglobulins may be challenging, care must be taken with preanalytical variables, and repeated testing of monoclonal protein and cryoglobulins is indicated if clinical suspicion is high. Presentations range from asymptomatic to showing multisystem involvement, meaning that careful evaluation of the features and a thorough interrogation of organ systems and the underlying clone are critical. Immediate management is required for clinical red-flag features. Due to their rarity, data to inform treatment decisions are scant and collaborative research is imperative must be conducted to aid researchers in efforts to define optimal treatment strategies.

Hemato doi: 10.3390/hemato4030018

Authors: Maria Auxiliadora Parreiras Martins João Antonio de Queiroz Oliveira Daniel Dias Ribeiro Cibele Comini César Vandack Alencar Nobre Daniel Moore Freitas Palhares Manoel Otávio da Costa Rocha Antonio Luiz Pinho Ribeiro

Anticoagulation clinics (ACs) have a greater impact on anticoagulation control than usual medical care (UMC). There is little evidence of the performance of AC in patients on warfarin living in low and middle-income countries. We sought to investigate the efficacy and safety of an AC in patients treated at a Brazilian public hospital. This was a randomized clinical trial that tested the efficacy of a recently implemented AC, compared to UMC, in outpatients with heart disease. The primary and secondary endpoints were time in the therapeutic range (TTR) and warfarin-related complications, respectively. Overall, 280 patients were enrolled and randomly assigned to Group A: one year at an AC (A1: first half-year; A2: second half-year); and Group B: first half-year receiving UMC (B1) and second half-year being assisted at the AC (B2). The mean age was 56.8 ± 13.1 years, and most patients were female (54.6%). Above 68% of patients had limited reading capability. A1 demonstrated greater TTR (62.4 ± 20.8%) than B1 (55.1 ± 28.5%) (p = 0.014). Group B improved TTR from 55.1 ± 28.5% (B1) to 62.2 ± 23.1% (B2) (p = 0.008). Despite the underpowered analysis of safety, A1 exhibited a lower incidence rate (IR) per patient-year (p-y) of total bleeding than B1 (incidence rate ratio (IRR): 0.78; p = 0.041) and a reduction in intra-group comparisons (both groups: IRR 0.58; p < 0.001). AC care helped increase TTR in a low-income setting showing favorable performance in a distinct population of those evaluated by previous studies. Extending AC care to similar populations may improve the outcomes of warfarin use.

Hemato doi: 10.3390/hemato4030017

Authors: Alessandro Costa Raimondo Pittorru Giovanni Caocci Federico Migliore Francesco Tona Olga Mulas Giorgio La Nasa

Since their introduction, tyrosine kinase inhibitors (TKIs) have radically changed the treatment paradigm of Chronic Myeloid Leukemia (CML), leading to deep and lasting molecular responses and profoundly influencing survival. However, cancer-therapy-related Cardiovascular Toxicities (CTR-CVTs) associated with BCR::ABL1 TKIs are one of the main sources of concern: hypertension, arterial occlusive events, arrhythmias, dysmetabolic alteration, and glomerular filtration impairment are frequently reported in clinical trials and real-life experiences. Therefore, a close interaction between hematologists and cardiologists becomes crucial to implementing prevention protocols based on a comprehensive assessment of baseline cardiovascular risk, the management of any detectable and modifiable risk factors, and the elaboration of a monitoring plan for CTR-CVTs during treatment. Here, we provide the most comprehensive and recent evidence in the literature on the pathophysiological patterns underlying CTR-CVTs, providing useful evidence-based guidance on the prevention and management of CVD risk factors at baseline and during treatment with BCR::ABL1 TKIs.

Hemato doi: 10.3390/hemato4030016

Authors: Stefano Pileri Valentina Tabanelli Roberto Chiarle Angelica Calleri Federica Melle Giovanna Motta Maria Rosaria Sapienza Elena Sabattini Pier Luigi Zinzani Enrico Derenzini

The concept of gray-zone lymphoma (GZL) has been progressively refined since its introduction in the literature in 1998. For several years, it was applied to a rather broad spectrum of conditions, posing the problem of the differential diagnosis between any type of Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma, with special reference to primary mediastinal forms (PMBL). Officially recognised as a provisional entity in the 4th and revised 4th editions of the WHO Classification of Tumour of Haematopoietic and Lymphoid Tissues with the term “B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma”, it was limited to tumours showing either morphologic features reminiscent of classic HL (CHL) but carrying a complete B-cell phenotype or conversely provided with a PMBL morphology yet revealing CHL phenotypic characteristics. The definition of GZL has been further revised in the recently published International Lymphoma Classification and 5th edition of the WHO Classification of Haematolymphoid Tumours, which have limited it to mediastinal neoplasms (MGZL) based on emerging molecular evidence. The aim of this review is to critically discuss the issue of MGZL, as well as in light of the suboptimal response to current therapies.

Hemato doi: 10.3390/hemato4020015

Authors: Guy Pratt Hannah V. Giles Jennifer H. Pinney

Renal disorders are uncommonly associated with IgM MGUS and Waldenström macroglobulinaemia (WM). Data are limited to large case series that suggest that related renal involvement occurs in 5% of patients with WM. Although uncommon, there is a much greater variety of renal pathologies associated with WM and IgM MGUS than that seen in patients with multiple myeloma, where cast nephropathy predominates. In WM, uncommonly direct infiltration of the renal system by lymphoma or cast nephropathy with a high light-chain level can occur. AL amyloidosis can present with nephrotic syndrome as a feature with IgM MGUS or WM. Cryoglobulinaemia and light-chain deposition disease are other important potential causes of renal impairment with IgM MGUS and WM. There are other rarer monoclonal gammopathy of renal significance (MGRS) conditions characterised by typically isolated kidney disease that are causally related to a B-cell or plasma-cell clonal disorder usually in a precancerous MGUS state, although in some renal pathologies, the association is less clear. Central to the majority of these diagnoses is the need for an accurate renal histological diagnosis, and management requires close joint working of renal and haematology teams.

Hemato doi: 10.3390/hemato4020014

Authors: José Luis Piñana Manuel Guerreiro Carlos Solano

Hematopoietic stem cell transplantation (HSCT) results in profound immunosuppression for the first few months after the procedure, requiring patients to be revaccinated against childhood vaccine-preventable infectious diseases. Patients who undergo allo-HSCT are at high risk of bacterial, fungal, and viral infections, with infectious complications responsible for at least one third of deaths. Even before the COVID-19 pandemic, respiratory virus infections were known to be more severe in HSCT recipients. The pandemic has highlighted the vulnerability of HSCT recipients, who experience an increased risk of morbidity and mortality after COVID-19 compared with healthy populations due to their severe immunodeficiency status. However, the current pandemic has also provided an exceptional scenario to better understand the immune response to SARS-CoV-2 cases and mRNA vaccines in HSCT recipients, including those receiving CD19-directed chimeric antigen receptor T cell (CAR-T) therapy. Researchers have focused on the role of the immune system in protecting against severe SARS-CoV-2 in patients with hematologic malignancies, including HSCT recipients. Insights gained during the pandemic will likely soon be used to improve preventive strategies in this population against viral infections in the near future. This narrative review summarizes the current knowledge on SARS-CoV-2 immunity in HSCT and cell therapy recipients following SARS-CoV-2 cases or vaccination.

Hemato doi: 10.3390/hemato4020013

Authors: Jessica Gill Davide Stella Irene Dogliotti Chiara Dellacasa Luisa Giaccone Alessandro Busca

Cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplant (allo-HSCT) is mainly due to an increase of latent viremia in previously exposed patients. Furthermore, CMV reactivation in this setting has a significant impact on patient survival. Traditional approach to CMV reactivation post allo-HSCT was a pre-emptive treatment with antivirals in the case of increased viremia. However, since 2017, a new antiviral compound, letermovir, has been introduced in clinical practice and is deeply changing the common CMV approach. The toxicity profile of letermovir allowed its use in prophylaxes in patients at high risk of CMV reactivation. This review will focus on the present role of letermovir post allo-HSCT and discuss some possible future applications of the drug. Finally, our single center CMV management in view of the recent introduction of letermovir will be discussed.

Hemato doi: 10.3390/hemato4020012

Authors: Karan L. Chohan Prashant Kapoor

Waldenström macroglobulinemia (WM) is a rare, non-Hodgkin lymphoma that remains incurable. Rituximab, an anti-CD20 monoclonal antibody has been the cornerstone of treatment against WM, and its combination with an alkylator, bendamustine, achieves durable remission in treatment-naive patients with symptomatic WM. However, novel “druggable” targets that have been identified within the clonal lymphoplasmacytic cells in WM have resulted in a rapid development of targeted therapies in both the frontline and relapsed and refractory (R/R) settings. Several agents directed against the known targets have shown promising efficacy, with mostly manageable toxicities. The class of Bruton’s tyrosine kinase (BTK) inhibitors has transformed the therapeutic landscape for patients with WM, given their convenient oral dosing and strong efficacy, with high rates of attainment of very good partial response (VGPR). The tolerability of the next-generation BTK inhibitors appears to be superior to that of the first-in-class agent, ibrutinib. Targeted therapies from other classes have also demonstrated efficacy in both single-agent and combination regimens. Inhibitors of proteasome BCL-2, mTOR and PI-3 kinase have demonstrated efficacy in WM. Emerging therapies under investigation will continue to further shape the management paradigm, especially in the R/R setting. These include bispecific antibodies, radiotherapeutic agents and chimeric antigen receptor T-cell (CART) cell therapies. This review outlines the current literature and future direction of targeted therapies in WM.

Hemato doi: 10.3390/hemato4020011

Authors: Marco Pizzi Carmela Gurrieri Attilio Orazi

Myeloid leukemias are a broad group of hematological disorders, characterized by heterogeneous clinical and biological features. In recent years, unprecedented genetic discoveries and clinical–biological correlations have revolutionized the field of myeloid leukemias. The most relevant changes have specifically occurred in acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), chronic myeloid leukemia (CML) and myeloid neoplasms (MNs) with eosinophilia. The recently published International Consensus Classification (ICC) of myeloid neoplasms has addressed these changes, providing an updated framework and revised diagnostic criteria for such entities. This is also the aim of the 5th edition of the WHO classification of hematopoietic tumors, whose preliminary version was published in 2022. Parallel to this, new therapeutic options and novel molecular targets have changed the management of many myeloid entities, including AML and CML. This review aims to address the most relevant updates in the classification and diagnosis of AML, CMML, CML and MNs with eosinophilia. The state of the art of treatment and future therapeutic options for such disorders are also discussed.

Hemato doi: 10.3390/hemato4010010

Authors: Rohan Halder Dipti Talaulikar Reema Singh Nidhi Menon Bhaarat Folbs Pallavi Mehta Jyotsna Kapoor Vishvdeep Khushoo Megha Verma Nitin Bansal Narendra Agrawal Rayaz Ahmed Dinesh Bhurani

Previous studies have shown the vulnerability of hematological patients with the Coronavirus disease of 2019 (COVID-19). We aimed to compare the outcomes and risk factors for poor survival in patients with hematological conditions hospitalized with COVID-19 infection. Single centre, retrospective, cohort study included all patients with a hematological condition admitted to Rajiv Gandhi Cancer Institute & Research Centre, New Delhi, India between 1 April 2020 and 31 May 2021. Of a total of 154 patients, 81 were in the pre-delta group and 73 were in the delta group out of which 21 (25.97%) in the pre-delta group and 24 (33.88%) patients in the delta group died. Haematological characteristics—age > 60 years, progressive hematological cancer, more than two lines of anti-cancer therapy, and active chemo-immunotherapy or targeted therapy were associated with higher mortality in the delta group. COVID-19 characteristics associated with higher mortality during the delta wave were severity of COVID infection, higher oxygen requirements, and COVID plasma therapy There were no deaths in individuals (n = 15) within the delta group who received COVID-19 vaccination. This study adds to the evidence that patients with hematological diseases are a particularly vulnerable group and the delta variant of the virus is associated with higher mortality. We could identify patient characteristics and features related to COVID-19 infection and underlying hematological conditions that were associated with poor outcomes in the delta sub-group. Vaccination was found to be an effective strategy for overcoming mortality and morbidity in these patients.

Hemato doi: 10.3390/hemato4010009

Authors: Sajee Alummoottil Mia van Rooy Janette Bester Craig Grobbelaar Alisa Phulukdaree

Background: Non-communicable diseases are often associated with chronic inflammation, placing patients suffering from these conditions at a higher risk of thrombosis and other complications. The pathophysiology of asthma and/or atopic asthma is also linked to chronic inflammation, which consequently may alter blood parameters including erythrocyte structure and function. Methodology: The objective of this study was to evaluate differences in erythrocytes between patients with atopic asthma (n = 30) and healthy individuals (n = 30) by evaluating routine haematological parameters; structures and axial ratios of erythrocytes using light microscopy; erythrocyte membrane elasticity using atomic force microscopy; and erythrocyte ultrastructure using scanning electron microscopy. Results: The haematological findings of healthy participants and patients suffering from asthma were within normal clinical ranges together with significantly higher levels of circulating monocytes (p = 0.0066), erythrocytes (p = 0.0004), haemoglobin (p = 0.0057), and haematocrit (p = 0.0049) in asthma patients. The analysis of eosin-stained erythrocytes by light microscopy showed more echinocytes, acanthocytes, and ovalocytes compared to controls and a significant difference in axial ratios (p < 0.0001). Atomic force microscopy findings showed reduced erythrocyte membrane elasticity in asthmatic erythrocytes (p = 0.001). Ultrastructural differences in erythrocytes were visible in the asthma group compared to controls. Conclusion: Altered erythrocyte ultrastructural morphology and a significant change in the haematological profile are evident in atopic asthma and may influence common complications associated with asthma. The impact of these changes on the physiological mechanisms of coagulation and the pathophysiology of asthma needs to be further elucidated.

Hemato doi: 10.3390/hemato4010008

Authors: Carla Berengua Rodrigo Martino

Pneumonia is among the most serious manifestations of HCMV infection, with high morbidity and mortality. Probable pneumonia is defined as the detection of HCMV in bronchoalveolar lavage (BAL) by viral isolation or DNA quantification (qPCR) combined with symptoms and/or signs of respiratory infection. However, currently, there is no reproducible and well-defined viral load (VL) from BAL that can reliably differentiate patients with pneumonia from the much more common detection of viral DNA in seropositive patients without true HCMV pneumonia. Several studies have been published with the aim of establishing an optimal VL for differentiating pneumonia from viral lung shedding. The aim of this review is to collect and analyze the methodology and the conclusions obtained in studies whose objectives included the correlation between HCMV VL in BAL and/or the plasma and the occurrence of HCMV pneumonia. For this purpose, a total of 14 articles have been included. There are some conclusions on which they all agree. PCR techniques were more sensitive and had a higher NPV than culture techniques but were less specific and had a low PPV. The mean HCMV loads in both BAL and the plasma were significantly higher in patients with pneumonitis than in those without. The HCMV load in patients with pneumonitis was higher in BAL than in the plasma, making qPCR in BAL a better predictor of HCMV pneumonitis than in the plasma. Nevertheless, this review highlights the difficulty of establishing a universal VL value, both in BAL and in the blood, to differentiate patients with HCMV pneumonia from those without. To complete the information available in these studies, prospective multicentre studies would be required. Methodologically, a large number of patients with HCMV pneumonitis would have to be included, and a subclassification of the type of immunosuppression of each patient should be made in order to obtain an optimal VL threshold in different host groups.

Hemato doi: 10.3390/hemato4010007

Authors: Adriatik Berisha Angelo Placci Pier Paolo Piccaluga

In the past twenty years, tyrosine kinase inhibitors (TKIs) have substantially changed the therapeutic landscape and the clinical outcome of several cancers, including Philadelphia-chromosome positive chronic myeloid leukemia and acute lymphoblastic leukemia, chronic eosinophilic syndromes, gastrointestinal stromal tumors, and others. Despite the obvious advantages offered in terms of efficacy and the overall safety profile, this new class of agents presents novel side effects, sometimes different from those induced by conventional chemotherapy. Among others, the potential cardiac toxicity, characterized by possible arrhythmias and the highest rates of cardiac ischemic disease and heart failure, were predominantly investigated. In this article, the authors review the most significant evidence in this regard, highlighting the overall benefit of TKI usage and the need for careful monitoring, especially in elderly patients.

Hemato doi: 10.3390/hemato4010006

Authors: Tarik Hadid Ayad Al-Katib Jose Binongo Gina M. Berteotti Salman Fazal James M. Rossetti John Lister

Purpose: Oral mucositis (OM) is a common, debilitating complication of conditioning regimens for hematopoietic stem cell transplantation (HSCT). Supersaturated calcium phosphate rinse (SCPR) and palifermin have shown efficacy in preventing severe OM. However, whether their efficacy differs is unknown. We aimed to compare the efficacy of SCPR and palifermin in HSCT patients receiving myeloablative conditioning. Methods: A comprehensive review of our institutional database was performed to identify patients who received myeloablative-conditioning therapy over 5 years. All HSCT patients who received radiotherapy-based myeloablative conditioning and received either palifermin or SCPR within the study period were included. Most patients received Fludarabine, Busulfan, and total body irradiation (FBT). Patients were divided into two groups based on the OM prophylactic agent received. The primary outcome is prevalence of severe OM (WHO Grade 3 and 4). The secondary outcomes are a prevalence of all-grade OM and WHO Grade 4 OM. These outcomes were compared between the two groups. Results: We identified 26 patients who received SCPR and 122 patients who received palifermin for OM prophylaxis. The prevalence of World Health Organization (WHO) Grade 3 or 4 OM was significantly lower in the palifermin group (57% vs. 100%, p = 0.01). In addition, the palifermin group had lower WHO Grade 4 OM (22% vs. 62%, p = 0.0006). The overall prevalence of OM was not significantly different between the two groups (86% for palifermin group vs. 100% for SCPR arm, p = 0.15). Subgroup analyses demonstrated improved outcomes with palifermin, regardless of age, sex, disease status, donor type, and primary diagnosis. Conclusion: When compared to SCPR, the use of palifermin is associated reduced severity of OM in HSCT patients receiving radiotherapy-based myeloablative conditioning.

Hemato doi: 10.3390/hemato4010005

Authors: Hemato Editorial Office Hemato Editorial Office

High-quality academic publishing is built on rigorous peer review [...]

Hemato doi: 10.3390/hemato4010004

Authors: Pier Paolo Piccaluga Stefania Paolini Giuseppe Visani

The prognosis of adult acute lymphoblastic leukemia (ALL) is variable but more often dismal. Indeed, its clinical management is challenging, current therapies inducing complete remission in 65–90% of cases, but only 30–40% of patients being cured. The major determinant of treatment failure is relapse; consequently, measurement of residual leukemic blast (minimal residual disease, MRD) has become a powerful independent prognostic indicator in adults. Numerous evidences have also supported the clinical relevance of MRD assessment for risk class assignment and treatment selection. MRD can be virtually evaluated in all ALL patients using different technologies, such as polymerase chain reaction amplification of fusion transcripts and clonal rearrangements of antigen receptor genes, flow cytometric study of leukemic immunophenotypes and, the most recent, high throughput sequencing (HTS). In this review, the authors focused on the latest developments on MRD monitoring with emphasis on the use of HTS, as well as on the clinical impact of MRD monitoring.

Hemato doi: 10.3390/hemato4010003

Authors: Amy Chadburn Annunziata Gloghini Antonino Carbone

New insights from genomic studies have had an impact on the definition and the diagnosis of several lymphoid tumors including follicular B-cell lymphomas, aggressive diffuse large B-cell lymphomas, and lymphoproliferations associated with acquired and posttransplant immunodeficiencies. Follicular lymphoma (FL) includes tumors whose behavior varies widely from indolent/early lesions to aggressive/transformed lymphomas. Although some large B-cell lymphomas can be subclassified as specific entities, the majority lack the characteristics necessary for subclassification and, thus, are termed diffuse large B-cell lymphoma, NOS. There have been, however, some changes in the classification of specific subtypes of large B-cell lymphoma as well as the addition of new entities, a few of which are highlighted in this article. The immunodeficiency-related lymphoproliferative disorders are currently divided into four major categories based on the clinical setting in which they arose: primary immune deficiency, post-transplant, HIV infection, and iatrogenic immunosuppression. In the two upcoming classifications systems for hematolymphoid neoplasms, International Consensus Classification (ICC) and WHO-HAEM-5, there is a divergence in the approach to categorize these lesions. Furthermore, whereas the WHO-HAEM-5 confirms the ability to classify a spectrum of EBV+ lesions as EBV+ DLBCL, NOS, the ICC has separated out lesions that are composed of a heterogenous cellular infiltrate into a new separate category, “EBV-positive polymorphic B cell lymphoproliferative disorder, NOS”. Both WHO-HAEM-5 and ICC recognize a number of KSHV/HHV8-associated lymphoid lesions and acknowledge that there is significant overlap among the different lesions. In the future, translation of these innovations in general practice requires further validation.

Hemato doi: 10.3390/hemato4010002

Authors: Chengcheng Fu Xiaohong Wang Xian Cao Lingjie Xu Wang Liu Jingnan Pi Bin Wang Wenming Chen

Immunoglobulin light chain (AL) amyloidosis is the most common type of systemic amyloidosis in China and is associated with increased morbidity and a poor prognosis. However, the clinical characteristics of Chinese patients with AL amyloidosis have not been systematically investigated. This scoping review aimed to summarize the available literature regarding the clinical characteristics of patients with AL amyloidosis and identify potential knowledge gaps. We searched three electronic databases from inception to 7 February 2021. PICOS (Patient, Intervention, Comparison, Outcome and Study) design structure was used to formulate the data extraction. All statistical calculations and analyses were performed with R (version 3.6.0). Sixty-seven articles with 5022 patients were included. Results suggest Chinese patients were younger (57 years) at the time of diagnosis when compared with other patient populations and were predominantly male (61.2%). The time interval from the onset of symptoms to diagnosis was between 6 and 12 months. It was found that 41.1% of Chinese patients with AL amyloidosis were diagnosed with an advanced stage III disease when diagnosed, and 20.2% had a concurrent disease. The most involved organs were the kidneys (84.3%) and the heart (62.5%). In conclusion, our study shows some similarities and differences with other studies on the clinical characteristics of Chinese patients with AL amyloidosis, including the age at diagnosis, Mayo stage, and organ involvement. However, a nationwide epidemiological investigation is still needed to provide a comprehensive overview of this patient population in China.

Hemato doi: 10.3390/hemato4010001

Authors: Simona Bernardi Michele Malagola Mirko Farina Nicola Polverelli Federica Re Domenico Russo

The effective and sensitive monitoring of Minimal Residual Disease or Measurable Residual Disease (MRD) is a very important aspect in the management of patients affected by hematologic malignancies. The recent availability of new technologies has opened to the improvement of MRD monitoring. It is particularly relevant in patients affected by Chronic Myeloid Leukemia (CML). MRD monitoring is key in the management of CML patients thanks to the efficacy of TKIs therapy. Moreover, the policies of TKIs discontinuation aimed at treatment free remission are strongly based on the good selection of patients eligible for stopping TKIs therapy. The recently described application of digital PCR in CML patients monitoring seems to improve the accuracy and precision in the identification of optimal responders. The present review reports an overview on the application of digital PCR in the monitoring of MRD in CML and its impact on TKIs discontinuation trials and, consequently, on TFR success.

Hemato doi: 10.3390/hemato3040052

Authors: Valeria Filipponi Stefania Trasarti Francesca Maccioni Maddalena Zippi Ludovica Busato Francesca Arienzo Mario Biglietto Paolina Saullo Carla Giordano Roberto Caronna

The finding of lymphadenopathy is usually the consequence of a benign infection, although a neoplastic origin must always be excluded. Through a careful anamnesis, physical examination, and serological tests several differential diagnoses are frequently possible. Nevertheless, sometimes an excisional biopsy of superficial lymph nodes is required, which is the best means to reach a definitive diagnosis. More concerns arise when lymphadenopathy is only abdominal/retroperitoneal: percutaneous biopsy is often inconclusive and the excisional node biopsy becomes a surgical procedure, certainly indicated in case of malignancy but avoidable in case of inflammatory diseases. We present the case of a 30-year-old man with a deep iliac lymphadenopathy who was evaluated at the Hematological Unit of Sapienza University of Rome. The enlargement of an iliac lymph node is quite unusual for an infectious disease. Although symptoms such as pain, fever, and chills suggested it was the case, cat-scratch disease was not hypothesized. Radiological investigations did not exclude a malignant disease and a laparoscopic excisional biopsy was scheduled, but the slight improvement of his spontaneous symptoms suggested a careful follow-up. Given the lack of disappearance of lymphadenopathy, the lack of diagnosis, and an ipsilateral superficial (inguinal) lymph node with similar ultrasonographic and radiological features, the patient underwent biopsy, which disclosed a diagnosis of cat-scratch disease, avoiding more invasive surgical procedures.

Hemato doi: 10.3390/hemato3040051

Authors: Evangeline Y. Wong Shirley D’Sa Monique C. Minnema Jorge J. Castillo Dipti Talaulikar

Bing–Neel syndrome (BNS) is a rare neurological complication of Waldenström macroglobulinaemia. We highlight key issues in clinical presentation, diagnosis, and treatment while focusing on new and emerging therapies available for patients diagnosed with BNS. It is anticipated that further development of Bruton Tyrosine Kinase (BTK) inhibitors and less toxic chemoimmunotherapies will improve treatment delivery and response.

Hemato doi: 10.3390/hemato3040050

Authors: Federico Zingarelli Letizia Zannoni Antonio Curti

TP53 mutated/deleted acute myeloid leukemia (AML) stands out as one of the poorest prognosis forms of acute leukemia with a median overall survival not reaching one year in most cases, even in selected cases when allogenic stem-cell transplantation is performed. This aggressive behavior relies on intrinsic chemoresistance of blast cells and on high rates of relapse. New insights into the biology of the disease have shown strong linkage between TP53 mutant AML, altered metabolic features and immunoregulation uncovering new scenarios and leading to possibilities beyond current treatment approaches. Furthermore, new targeted therapies acting on misfolded/dysfunctional p53 protein are under current investigation with the aim to improve outcomes. In this review, we sought to offer an insight into TP53 mutant AML current biology and treatment approaches, with a special focus on leukemia-associated immune and metabolic changes.

Hemato doi: 10.3390/hemato3040049

Authors: Shayna Sarosiek Andrew R. Branagan Steven P. Treon Jorge J. Castillo

Waldenström macroglobulinemia (WM) is a rare lymphoplasmacytic disorder characterized by an IgM paraprotein. The clinical presentation of WM varies and can include common manifestations such as anemia and hyperviscosity, in addition to less common features such as cryoglobulinemia, IgM-related neuropathy, and immunoglobulin light chain (AL) amyloidosis. Amyloidosis is a protein-folding disorder in which vital organ damage occurs due to the accumulation of misfolded protein aggregates. The most common type of amyloidosis in patients with an IgM paraprotein is AL amyloidosis, although other types of amyloidosis may occur. IgM-related amyloidosis has distinct clinical features when compared with other subtypes of AL amyloidosis. This review highlights the diagnostic criteria of IgM-related AL amyloidosis, as well as the clinical characteristics and treatment options for this disorder.

Hemato doi: 10.3390/hemato3040048

Authors: Fiorina Giona Simona Bianchi

Chronic myeloid leukemia (CML) in childhood represents only 3% of newly diagnosed pediatric leukemia. The diagnostic hallmark of CML is the Philadelphia (Ph) chromosome, which derives from the fusion of the ABL1-oncogene located on chromosome 9 to the breakpoint cluster region (BCR) gene on chromosome 22, resulting in a constitutively dysregulated ABL1 tyrosine kinase, either as 210 kDa or 190 kDa. Depending on the localization of the breakpoint site within the major BCR region, the majority of CML patients exhibit transcripts with either the b3a2 or b2a2 junction, or both. Several questions are still open with regard to childhood CML, especially concerning the biologic and clinical features of the disease, and the treatment of choice for pediatric patients with CML. Moreover, over the last few years, several tyrosine kinase inhibitors (TKIs) have been available for children and adolescents with CML, and current clinical practice investigates what the effective and optimal doses of TKIs are in these two categories of patients. The use of TKIs in pediatric patients with CML has also opened up questions on the following items: (1) the long-term effects of these drugs on children; (2) the management of pediatric CML forms resistant or intolerant to TKIs; (3) the monitoring of disease outcomes during treatment; (4) and the right timing to discontinue therapy. Despite the efficacy of TKIs also in the pediatric population, the potential late adverse effects, and the drug resistance, leave open the possibility of allogeneic hematopoietic stem cell transplantation as a treatment option in pediatric CML. Published data and personal experiences regarding these issues will be analyzed and discussed.

Hemato doi: 10.3390/hemato3040047

Authors: Karima Amaador Marie José Kersten Hein P. J. Visser Laurens Nieuwenhuizen Roelandt F. J. Schop Martine E. D. Chamuleau Gerjo A. Velders Monique C. Minnema Josephine Mathilde Iris Vos

Waldenström macroglobulinemia (WM) is a rare B-cell Non-Hodgkin Lymphoma. There are only few prospective randomized clinical trials to guide treatment recommendations and there is no international consensus on a preferred first line treatment approach. In the recently revised Dutch guideline for WM, we describe recommendations for practice based as much as possible on the known data. Here, we summarize the considerations for first-line treatment based on these Dutch guidelines. Available evidence is summarized, including efficacy and toxicity data. Combinations of Rituximab with chemotherapy, proteasome inhibition or BTK-inhibition are all valid first line treatment options. The Dutch WM working group considers Dexamethasone/Rituximab/Cylofosfamide (DRC) a suitable first-line treatment for many WM patients, given the efficacy, the relatively mild toxicity profile and the extensive experience with this regimen. However, the long-term toxicities of DRC are unclear and need further clarification. Other regimens such as R-bendamustine, R-Bortezomib-dexamethason are also effective options, however with specific toxicities. BTK-inhibitors are not a preferred option in first line for most patients in the Dutch WM guidelines because of the need for longterm treatment and toxicities. Based on patient preferences research, future clinical trials should focus on effective fixed-duration regimens with non-cytotoxic therapies that have a favorable toxicity profile. Further development of (combinations with) BCL-2 inhibititors, novel proteasome inhibitors and BTK-inhibition could be interesting. In addition T-cell-directed treatments including bispecific antibodies as a monotherapy or combined with other novel agents deserve further study in WM.

Hemato doi: 10.3390/hemato3040046

Authors: Marina Deodato Anna Maria Frustaci Giulia Zamprogna Giulia Cotilli Roberto Cairoli Alessandra Tedeschi

Waldenström Macroglobulinemia (WM) is a rare indolent lymphoma with heterogeneous clinical presentation. As there are no randomised trials suggesting the best treatment option in treatment-naive patients, guidelines suggest either rituximab-combining regimens or BTK-inhibitors (BTKi) as feasible alternatives. Several factors play in the decision-making process: patients’ age and fitness, disease characteristics and genotype. Chemoimmunotherapy (CIT) represents a fixed-duration, less expensive and effective option, able to achieve prolonged time-to-next treatment even in patients with unfavourable genotypes. Immunosuppression and treatment-related second cancers may represent serious concerns. Proteasome-inhibitor-based regimens are effective with rapid disease control, although bortezomib-related neuropathy discourages the choice of these agents and treatment schedules may not be easily manageable in the elderly. BTKi have demonstrated high rates of response and prolonged survival together with the convenience of an oral administration and limited cytopenias. However, outcomes are impacted by genotype and some concerns remain, in particular the continuous drug exposure that may result in extra-haematological complications and drug resistance. Although next-generation BTKi have improved treatment tolerance, the question whether BTKi should be offered as frontline therapy to every patient is still debated. Giving fixed-duration schedule, prolonged time-to-next treatment and outcomes independent of genotype, CIT is still our preferred choice in WM. However, BTKi remain a valuable option in frail patients unsuitable for CIT.

Hemato doi: 10.3390/hemato3040045

Authors: Johannes P. M. van de Mortel Shirley D’Sa Alexander F. J. E. Vrancken Nicolette C. Notermans Josephine M. I. Vos Monique C. Minnema

With increasing age, the chances of developing either MGUS or polyneuropathy increase as well. In some cases, there is a causative relationship between the IgM M-protein and polyneuropathy. In approximately half of these cases, IgM targets the myelin-associated glycoprotein (MAG). This results in chronic polyneuropathy with slowly progressive, predominantly sensory neurological deficits and distally demyelinating features in nerve conduction studies. Despite the disease being chronic and developing slowly, it can cause considerable impairment. We reviewed English medical publications between 1980 and May 2022 on IgM gammopathy-associated polyneuropathy, with special attention to studies addressing the pathophysiology or treatment of anti-MAG polyneuropathy. Treatment options have been limited to a temporizing effect of intravenous immunoglobulins in some patients and a more sustained effect of rituximab but in only 30 to 55 percent of patients. An increase in our knowledge concerning genetic mutations, particularly the MYD88L265P mutation, led to the development of novel targeted treatment options such as BTK inhibitors. Similarly, due to the increasing knowledge of the pathophysiology of anti-MAG polyneuropathy, new treatment options are emerging. Since anti-MAG polyneuropathy is a rare disease with diverse symptomatology, large trials with good outcome measures are a challenge.

Hemato doi: 10.3390/hemato3040044

Authors: Eric Durot Cécile Tomowiak Elise Toussaint Pierre Morel Dipti Talaulikar Prashant Kapoor Jorge J. Castillo Alain Delmer

Histological transformation (HT) to an aggressive lymphoma results from a rare evolution of Waldenström macroglobulinemia (WM). A higher incidence of transformation events has been reported in MYD88 wild-type WM patients. HT in WM can be histologically heterogeneous, although the diffuse large B-cell lymphoma of activated B-cell subtype is the predominant pathologic entity. The pathophysiology of HT is largely unknown. The clinical suspicion of HT is based on physical deterioration and the rapid enlargement of the lymph nodes in WM patients. Most transformed WM patients present with elevated serum lactate dehydrogenase (LDH) and extranodal disease. A histologic confirmation regarding the transformation to a higher-grade lymphoma is mandatory for the diagnosis of HT, and the choice of the biopsy site may be dictated by the findings of the 18fluorodeoxyglucose-positron emission tomography/computed tomography. The prognosis of HT in WM is unfavorable, with a significantly inferior outcome compared to WM patients without HT. A validated prognostic score based on 3 adverse risk factors (elevated LDH, platelet count < 100 × 109/L and any previous treatment for WM) stratifies patients into 3 risk groups. The most common initial treatment used is a chemo-immunotherapy (CIT), such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). The response duration is short and central nervous system relapses are frequent. Whether autologous stem cell transplantation could benefit fit patients responding to CIT remains to be studied.

Hemato doi: 10.3390/hemato3040043

Authors: Gioia Di Stefano Francesca Magnoli Massimo Granai Federico Vittone Raffaella Santi Domenico Ferrara Emanuela Boveri Ada M. Florena Falko Fend Elena Sabattini Marco Paulli Maurilio Ponzoni Stefano Lazzi Stefano A. Pileri Lorenzo Leoncini the Italian Group of Hematopathology the Italian Group of Hematopathology

Lymphoproliferative neoplasms of uncertain biological significance are increasingly encountered due to widespread usage of immunophenotypic and molecular techniques. Considering that clearer biological criteria and patient management have been established for B-cell lymphoproliferative diseases of undetermined significance occurring in the peripheral blood, many issues are still obscure for early lesions detected in lymphoid tissues. Regardless that some categories of lymphoproliferative neoplasms of uncertain biological significance have been recognized by the 4th edition of the WHO, other anecdotal early lymphoproliferative lesions still remain fully undefined. Some early lesions frequently originate from the germinal center, including atypical germinal centers BCL2-negative, an early pattern of large B-cell lymphoma with IRF4 rearrangement, and “in situ” high-grade B lymphomas. Moreover, other early lymphoproliferative lesions arise outside the germinal center and include those developing within the setting of monocytoid B-cell hyperplasia, but they also can be directly or indirectly associated with chronic inflammations. This review aims to summarize the concepts discussed during the IV Workshop organized by the Italian Group of Hematopathology, focus on the state-of-the-art on B-cell lymphoproliferative neoplasms of uncertain biological significance, and offer operative insights to pathologists and clinicians in routine diagnostics.

Hemato doi: 10.3390/hemato3040042

Authors: Miguel Alcoceba María García-Álvarez Jessica Okosun Simone Ferrero Marco Ladetto Jude Fitzgibbon Ramón García-Sanz

Histological transformation (HT) to a more aggressive disease–mostly diffuse large B-cell lymphoma–is considered one of the most dismal events in the clinical course of follicular lymphoma (FL). Current knowledge has not found a single biological event specific for HT, although different studies have highlighted common genetic alterations, such as TP53 and CDKN2A/B loss, and MYC translocations, among others. Together, they increase genomic complexity and mutational burden at HT. A better knowledge of HT pathogenesis would presumably help to find diagnostic biomarkers allowing the identification of patients at high-risk of transformation, as well as the discrimination from patients with FL recurrence, and those who remain in remission. This would also help to identify new drug targets and the design of clinical trials for the treatment of transformation. In the present review we provide a comprehensive overview of the genetic events frequently identified in transformed FL contributing to the switch towards aggressive behaviour, and we will discuss current open questions in the field of HT.

Hemato doi: 10.3390/hemato3040041

Authors: Cristina López Pablo Mozas Armando López-Guillermo Sílvia Beà

Follicular lymphoma (FL), a generally indolent disease that derives from germinal center (GC) B cells, represents around 20–25% of all new lymphomas diagnosed in Western countries. The characteristic t(14;18)(q32;q21) translocation that places the BCL2 oncogene under control of the immunoglobulin heavy-chain enhancer occurs in pro- or pre-B cells. However, additional secondary alterations are required for the development of overt FL, which mainly affects genes involved in epigenetic and transcriptional regulation, signaling and B cell differentiation, the BCR/NF-κB pathway, and proliferation/apoptosis. On the other hand, new insights into the FL pathogenesis suggest that FL lacking the BCL2 translocation might be a distinct biological entity with genomic features different from the classical FL. Although FL is considered an indolent disease, around 10–20% of cases eventually transform to an aggressive lymphoma, usually a diffuse large B cell lymphoma, generally by a divergent evolution process from a common altered precursor cell acquiring genomic alterations involved in the cell cycle and DNA damage responses. Importantly, FL tumor cells require interaction with the microenvironment, which sustains cell survival and proliferation. Although the use of rituximab has improved the outlook of most FL patients, further genomic studies are needed to identify those of high risk who can benefit from innovative therapies. This review provides an updated synopsis of FL, including the molecular and cellular pathogenesis, key events of transformation, and targeted treatments.

Hemato doi: 10.3390/hemato3040040

Authors: Sigbjørn Berentsen Shirley D’Sa Ulla Randen Agnieszka Małecka Josephine M. I. Vos

The last 2 decades have seen great progress in understanding the pathogenesis of cold agglutinin disease (CAD) and development of effective therapies. Cold agglutinins can cause hemolytic anemia as well as peripheral circulatory symptoms such as acrocyanosis. We distinguish CAD, a well-defined clinicopathologic entity, from secondary cold agglutinin syndrome. This review addresses the histopathologic, immune phenotypic, and molecular features that allow CAD to be classified as a distinct clonal lymphoproliferative disorder of the bone marrow, recently recognized in the WHO classification. We discuss recent data on the possible overlap or distinction between CAD and Waldenström’s macroglobulinemia. Two major steps in the pathogenesis of CAD are identified: clonal B-cell lymphoproliferation (leading to monoclonal IgM production) and complement-mediated hemolysis. Each of these steps constitutes a target for treatment. Established as well as novel and experimental therapies are reviewed.

Hemato doi: 10.3390/hemato3030039

Authors: Chen Wang Yiyun Shi

Extramedullary hematopoiesis is rarely seen in patients with myelodysplastic syndromes, and its clinical characterizations are not well-defined. Here, we systematically reviewed the published literature to summarize the clinical manifestations, treatments, and long-term outcomes of biopsy-proven extramedullary hematopoiesis in patients with myelodysplastic syndromes. We included 41 patients, and ring sideroblasts were the most common myelodysplastic subtype (30.6%). Extramedullary hematopoiesis was typically symptomatic on presentation due to local compression, frequently involving the liver or spleen (36.6%), or the paravertebral region (24.4%). Notably, ring sideroblasts were predominantly seen in patients with non-hepatosplenic involvement (38.5 vs. 6.7%, p = 0.034). Interventions, when required, usually included surgery (36.8%) or radiation (13.2%), which led to symptomatic improvement in 55.5% of patients. The median overall survival of the current cohort was 7 months. The current study confirms the rarity of extramedullary hematopoiesis as a complication of myelodysplastic syndromes; however, its outcomes in response to systemic modern therapies require further investigation.

Hemato doi: 10.3390/hemato3030038

Authors: Ugo Testa Germana Castelli Elvira Pelosi

Acute myeloid leukemia (AML) is a highly heterogeneous hematologic malignancy characterized by the clonal proliferation of hematopoietic stem and progenitor cells (HSPCs) and blockade of differentiation and proliferation of immature myeloid cells that accumulate in bone marrow at the expense of normal hematopoiesis. AMLs originate from the expansion of HSPCs progressively acquiring somatic mutations. The development of high-throughput sequencing techniques has helped to discover the genetic heterogeneity and complexity of AMLs, revise diagnostic and prognostic criteria, and to identify new therapeutic targets. These studies have allowed the identification of several recurrent driver mutations and the definition of a rational molecular classification of these tumors. In parallel, the development of techniques for the determination of single-cell mutational profiling has considerably contributed to understanding the clonal heterogeneity and evolution of AMLs. The acquisition of these genetic data coupled with the identification of molecular therapeutic targets has determined a considerable expansion of the therapeutic armamentarium, with the development of several new drugs highly active against specific AML subtypes. These developments have increased the interest and the need for sensitive techniques for the identification of minimal residual disease, the population of leukemia cells that survives despite morphological remission and causes disease relapse.

Hemato doi: 10.3390/hemato3030037

Authors: Emanuela Vaccher Annunziata Gloghini Chiara C. Volpi Antonino Carbone

Lymphomas in people living with HIV (PLWH) are associated with Epstein Barr virus (EBV) and Kaposi-sarcoma-associated herpesvirus (KSHV). They include primary effusion lymphoma, large B-cell lymphoma arising in multicentric Castleman disease, plasmablastic lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, and Hodgkin lymphoma (HL). Inclusion of these lymphomas in the WHO classification of tumors of hematopoietic and lymphoid tissues and the increasing recognition of these disorders have resulted in established clinical management that has led to improved outcomes. In this review, we report on the current management in lymphomas occurring in PLWH with an emphasis on KSHV-associated disorders and EBV-related HL. We also report on the simultaneous occurrence of KSHV- and EBV-associated disorders and highlight preventive measures that have been planned for tumor prevention in PLWH. In conclusion, it is recommended that treatment choice for PLWH affected by lymphoma, and receiving effective combined antiretroviral therapy (cART), should not be influenced by HIV status. Moreover, there is an urgent need (1) to reduce the current large disparities in health care between HIV-infected and HIV-uninfected populations, (2) to disseminate effective treatment, and (3) to implement preventive strategies for PLWH.

Hemato doi: 10.3390/hemato3030036

Authors: Roza Chaireti Hareth Nahi

Multiple myeloma (MM) is a hematological malignancy characterized by a high risk for thrombotic episodes, mainly venous thromboembolism (VTE). This risk is accentuated by cancer treatments such as immunomodulatory drugs (IMiDs). Cancer-associated thrombosis is one of the leading causes of mortality and morbidity, and the prevention of thrombosis is, therefore, of paramount significance. To this day, it is unclear which type of thromboprophylaxis is the most effective. This is partly due to the multifactorial etiology behind thrombosis since the compound of patient-, disease- and treatment-associated factors characterizing each patient with MM is unique. Additionally, the established risk scores are not reliable in patients with MM. The scope of this review is to summarize the factors contributing to increased thrombosis risk in MM, as well as the risk scores and thromboprophylaxis regimes available.

Hemato doi: 10.3390/hemato3030035

Authors: Mark Roschewski Dan L. Longo

Mantle cell lymphoma (MCL) is an aggressive yet incurable B-cell lymphoma that was only first recognized as a distinct subtype in 1992, with early reports suggesting a poor median survival. Elaine Jaffe is a renowned hematopathologist and scientist from the National Cancer Institute who was instrumental in many of the early descriptions of MCL that distinguished it from other B-cell lymphomas. Further, she has led multiple international collaborations that have harmonized the lymphoma classification systems that are currently in use today. The early morphologic descriptions of MCL along with the contributions of immunologic and genetic techniques have confirmed MCL as a distinct entity with unique biology and clinical behavior. Importantly, these scientific discoveries laid the foundation for unprecedented therapeutic breakthroughs that have led to significant improvements in overall survival.

Hemato doi: 10.3390/hemato3030034

Authors: Wing C. Chan Javeed Iqbal

Technological and informatics advances as well as the availability of well-annotated and reliable genomic data have ushered in the era of genomics research. We describe in this brief review how the genomics approach has impacted lymphoma research in the understanding of the pathogenesis and biology of lymphoma, in lymphoma diagnosis and in targeted therapy. Some exciting directions that could be explored in the future are also discussed.

Hemato doi: 10.3390/hemato3030033

Authors: Loredana Benedetto Irene Marino Francesca Ronco Grazia Iaria Luisa Foletti Massimo Ingrassia

Caring for a child with an acute/life threatening disease exposes parents to multiple stressors and challenges, resulting in a physical and psychological burden. Parents experience many health-related issues and worries that often remain underestimated. The aims of the study were: (a) to explore the associations between needs/disease-related issues and burden in parents of children with leukemia or Hodgkin’s disease; (b) to estimate predictors of parents’ burden using a stepwise linear regression analysis. Children (N = 33) followed an active therapy protocol (48.5%), or they were off therapy (51.5%). Forty-four parents completed surveys on caregiver burden levels and needs to cope with the child’s illness. Parental factors impacting burden (personal resources, loss of control, depression) and child’s quality of life (QoL) were also assessed. Among the needs, information about the illness/resources were the most urgently expressed by parents, followed by reassurance against fears for the child’s development and future well-being. Parents reported severe (27.3%) and moderate (22.7%) burden, with a higher percentage of caregivers with severe burden in the off-therapy phase (18.2%) than in the active-therapy phase (9.1%). The child’s decreased physical QoL and parent’s loss of control predicted higher levels of burden. The implications for supportive interventions aimed at responding to parental needs and preventing caregiver burden are discussed.

Hemato doi: 10.3390/hemato3030032

Authors: Elaine S. Jaffe Antonino Carbone

The definitions of follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are evolving in the era of personalized medicine. Early stages of the evolution of FL have been recognized. Two histological manifestations of early lesions are in situ follicular neoplasia and duodenal type FL. Additionally, FL frequently undergoes histological transformation, the most common form being DLBCL. High-grade B-cell lymphoma with double hit, with translocations involving BCL2 and MYC are important clinically. Rarer forms of transformation include classic Hodgkin lymphoma (CHL) and histiocytic sarcoma. In addition to conventional FL associated with the BCL2 translocation, alternative forms of BCL2-negative FL have been observed. These are heterogenous clinically and genetically. A distinctive group of B-cell lymphomas of follicle cell derivation arise in young patients and include pediatric type FL, testicular FL and a large B-cell lymphoma with IRF4 rearrangement. Historically DLBCL was separated into only two histological variants, centroblastic and immunoblastic. In 2017 the WHO classification recommended (1) the segregation of activated B cell and germinal center B cell derived DLBCL, (2) the identification of high-grade B-cell lymphoma with double hit, and (3) the recognition of an aggressive lymphoma that may resemble Burkitt lymphoma, currently designated in the International Consensus Classification as Large B-cell lymphoma with 11q aberration. Today we appreciate greater genomic complexity among aggressive B-cell lymphomas. Recent studies with NGS and mutational profiling have identified clinically significant genetic subgroups. It is hoped that these data ultimately will lead to targeted therapy based on the genetic profile.

Hemato doi: 10.3390/hemato3030031

Authors: Theresia Akhlaghi Ross Firestone Malin Hultcrantz

The prognosis and clinical outcomes for patients with multiple myeloma have improved significantly over the past two decades. A substantial number of patients now achieve complete remission after induction therapy, and more sensitive methods are needed to assess response. Minimal or measurable residual disease (MRD) has been incorporated in many clinical trials as well as in clinical practice. The importance of MRD assessment and correlation between MRD negativity and prolonged progression-free and overall survival has been confirmed in numerous clinical trials and several meta-analyses. Recent studies have even suggested that MRD negativity can partly overcome the impact of the negative prognostic factors such as high-risk cytogenetics or adverse revised international scoring system (R-ISS) stage. MRD can be measured in the bone marrow via imaging and via emerging blood-based techniques. The most common methods are multicolor flow cytometry and next-generation sequencing of bone marrow samples. Using these methods in optimal settings, MRD negativity with a sensitivity level of 10−6 can be detected. In this review, we discuss the benefits and limitations of these techniques as well as the clinical implications.

Hemato doi: 10.3390/hemato3030030

Authors: Sam M. Mbulaiteye Susan S. Devesa

Burkitt lymphoma (BL) is a rare non-Hodgkin lymphoma first described in 1958 by Denis Burkitt in African children. BL occurs as three types, endemic, which occurs in Africa and is causally attributed to Epstein-Barr virus and P. falciparum infections; sporadic, which occurs in temperate areas, but the cause is obscure; and immunodeficiency-type, which is associated with immunosuppression. All BL cases carry IG∷MYC chromosomal translocations, which are necessary but insufficient to cause BL. We report a comprehensive study of the geographic, sex, and age-specific patterns of BL among 15,122 cases from Cancer Incidence in Five Continents Volume XI for 2008–2012 and the African Cancer Registry Network for 2018. Age-standardized BL rates were high (>4 cases per million people) in Uganda in Africa, and Switzerland and Estonia in Europe. Rates were intermediate (2–3.9) in the remaining countries in Europe, North America, and Oceania, and low (<2) in Asia. Rates in India were 1/20th those in Uganda. BL rates varied within and between regions, without showing a threshold to define BL as endemic or sporadic. BL rates were twice as high among males as females and showed a bimodal age pattern with pediatric and elderly peaks in all regions. Multi-regional transdisciplinary research is needed to elucidate the epidemiological patterns of BL.

Hemato doi: 10.3390/hemato3030029

Authors: Jian Wu Min Zhang Allison Faircloth

The Peroxisome proliferator-activated receptors (PPARs) play vital roles in regulating cellular differentiation, proliferation, and caspase-mediated cell death pathways. They are regarded as promising targets for anti-tumor drug development, particularly for multiple myeloma (MM) and different hematological malignancies. Several early section clinical trials are conducted to measure the clinical practicableness of PPAR agonists, notably PPARα and PPARγ agonists, against various cancers. A spread of studies has investigated PPARs expression in metabolic regulation. Furthermore, it has been suggested that careful designing of partial agonists for PPARs may show improvement with side effects and increase the therapeutic value. This review summarizes the organic chemistry and metabolic actions of PPARs, and the therapeutic potential of their agonists underneath clinical development. It investigates therapeutic agents for hematologic malignancies.

Hemato doi: 10.3390/hemato3030028

Authors: Elyse Redder Qiuhong Zhao Naresh Bumma Rami Kahwash Ajay Vallakati Courtney Campbell Samir Parikh Salem Almaani Miriam Freimer Yvonne Efebera Nidhi Sharma

Amyloidosis is a rare, systemic disease that can result in significant functional impairment. Specific guidelines for the rehabilitation assessment of amyloidosis patients have yet to be established. The purpose of this study was to identify functional deficits and assess differences based on disease type, organ involvement, age, and gender of patients with amyloidosis. Materials and Methods: The multidisciplinary Comprehensive Amyloidosis Clinic (CAC) at Ohio State University (OSU) has developed structured assessment guidelines for amyloidosis patients. A retrospective, single-institution review of patients assessed in CAC between December 2017 and April 2020 was performed. Outcome measure data from the Timed Up and Go (TUG), 30 s sit-to-stand, and physical function portion of the SF 36 were gathered by chart review. Comparisons were made between CAC patient scores and normative data. Kruskal–Wallis tests were used to compare scores across the disease types (light chain, transthyretin wild-type, and hereditary variant transthyretin) and the Mann–Whitney U test was used for pairwise comparisons within disease types and cardiac involvement. Linear regression models were used to assess associations between patient characteristics (including age, gender, disease type, and cardiac involvement) and performance scores. Results: Data from sixty-four patients was evaluated. On the 30-s sit-to-stand test, patients with light chain amyloidosis performed 3.32 fewer repetitions than patients with transthyretin wild-type, p = 0.03. Patients with cardiac involvement had 2.55 fewer repetitions than patients without cardiac involvement, p = 0.03. Older patients were found to have slower TUG performance, and a 10-year increase in age was associated with an 11% increase in TUG scores. Conclusions: Findings indicate patients with light chain amyloidosis and patients with cardiac involvement, when compared to other amyloidosis patients, present with more physical impairments.

Hemato doi: 10.3390/hemato3030027

Authors: Joana Caetano Filipa Barahona Paulo Lúcio Cristina João

The introduction of new and more effective therapeutic options for Multiple Myeloma (MM) has significantly deepened and prolonged patients’ remission. As currently used treatment protocols induce high rates of complete responses, Measurable Residual Disease (MRD) assessment has become essential to enhance the evaluation of treatment efficacy. Detection of MRD has improved with the development of highly sensitive and standardized techniques such as Next Generation Flow or Next Generation Sequencing, complemented by functional imaging techniques. These advances offer a valuable opportunity to further optimize criteria of response to treatment. Currently, extensive data demonstrate that MRD status is a valuable prognostic factor of survival. Since MRD represents a real measurement of disease burden, its incorporation in clinical trials to guide treatment decisions will certainly translate into clinical benefits. Sustained MRD negativity can be used to consider optimal candidates for treatment discontinuation, whereas MRD positive high-risk patients may have access to novel immunotherapeutic strategies such as bispecific drugs or CAR T cell therapy. In this review, we describe the available techniques to detect MRD, address the current data regarding MRD as a surrogate endpoint within clinical trials, examine how MRD can be introduced into the clinical management of MM patients, and discuss the future of MRD monitoring.

Hemato doi: 10.3390/hemato3020026

Authors: Tatsuki Shibuta Honoka Shimizu Yukichi Takada Asuka Fuku Satoshi Tomiyasu Tsukuru Umemura

Extracellular vesicles (EVs) are nano-sized particles released from cells and transferring molecules (proteins, lipids and nucleic acids such as mRNA, tRNA and miRNA) to recipient cells. Surface antigens and components are important for the functions as cell-to-cell communication of EVs. Thus, EVs are useful biomarkers for various diseases including leukemias and other types of malignancies. We evaluated whether miRNAs in EVs released from chronic myelogenous leukemia (CML) cells could be used for diagnosis. Microarray analysis of miRNAs in EVs obtained from the culture supernatants of two CML cell lines showed that miR-494 and miR-373-5p were significantly decreased by tyrosine kinase inhibitor for BCR-ABL1. Validation analysis with Taqman-based qRT-PCR of whole serum obtained patients with CML in the chronic phase (n = 5) did not show a significant difference in miR-494 levels compared to the CML accelerated phase and blast crisis patients (n = 5). However, the levels of miR-494 were 2.9-fold higher in the accelerated phase or blast crisis than in the chronic phase (p < 0.05). These results indicate that it is important to measure miR-494 using only EVs rather than whole serum. Our data suggest that EV-miR-494 is a useful biomarker of CML progression and evaluation of response to tyrosine kinase inhibitors.

Hemato doi: 10.3390/hemato3020025

Authors: Roberta Fenoglio Gianluca Rabajoli Antonella Barreca Emanuele De Simone Savino Sciascia Dario Roccatello

Background: AL amyloidosis is a systemic disorder characterized by extracellular deposition of characteristic fibrils that results in progressive multi-organ failure and premature death. Recently daratumumab has been demonstrating higher hematological and organ response rates when compared to the standard of care. We hereby report our long-term experience on the effects of daratumumab given alone on the deposition of amyloid as evaluated in repeat renal biopsy. Results: Six patients were enrolled. All patients had proteinuria that was associated with renal function impairment in four. After therapy with daratumumab, four patients achieved complete hematological response and two had partial hematological response at the end of treatment. With regard to renal response, four out of six patients achieved an organ response; one patient had fluctuating proteinuria levels and did not meet the needed criteria at the end of the treatment and the last patient, who was already in dialysis at the time of therapy initiation, remained on dialysis despite complete hematological and cardiac responses. A significant decrease in 24-h proteinuria from 7.9 g/24 h to 1.1 (p < 0.005) with stabilization or improvement of sCr (from 1.5 mg/dL to 1.2 mg/dL; p = 0.34) were observed. All patients underwent a repeat biopsy after 24 administrations of daratumumab. In five patients, the repeat biopsy showed unchanged features; while in one it showed an improvement. Conclusions: Our data, based on real life experience, show that daratumumab monotherapy can be an effective therapeutic option. It is capable not only of achieving a substantial rate of renal improvement in pre-treated and naïve patients, but also of limiting renal deposition

Hemato doi: 10.3390/hemato3020024

Authors: Cameron K. Tebbi

Sickle cell disease and its variants constitute the most common inherited blood disorders affecting millions of individuals worldwide. Significant information regarding the nature of the genetic mutations and modifier genes that result in increased or decreased severity of the disease are available. In recent years, detailed data regarding molecular genetics, pathophysiology, mechanisms for the development of symptoms and side effects of sickle cell disease have been published. The relationship of physiological changes, cellular interactions, coexisting coagulation disorders, effects of association with other genetic disorders and a number of intervening factors have been explored. New techniques for pre-conception, prenatal, in utero, and neonatal screening are available. Means for prediction of the severity of the disease, clinical course of the disorder, and prevention of some of its major complications have been developed. The effects of psychosocial and environmental factors have been explored. Various therapeutic strategies including bone marrow and stem cell transplantation are currently employed in the treatment of patients with sickle cell disease. Recent progress in understanding the molecular pathways controlling mammalian erythropoiesis and globin switching, as well as advances in genome engineering, particularly the gene-editing techniques, have opened a venue for genetic-based treatment of the disease. Currently, sickle cell disease is often associated with a high rate of complications and mortality. The development of new pharmacological agents, methods for gene therapy, and alterations and modification of the coexisting genetic factors and modifiers for treatment of the disease are encouraging.

Hemato doi: 10.3390/hemato3020023

Authors: Marco Lucioni Sara Fraticelli Giuseppe Neri Monica Feltri Giuseppina Ferrario Roberta Riboni Marco Paulli

Primary cutaneous B-cell lymphomas (PCBCLs) account for 25% of all primary cutaneous lymphomas. Three major types are currently recognized by the WHO classification: primary cutaneous marginal zone B-cell lymphoma (PCMZL), primary cutaneous follicle centre lymphoma (PCFCL) (both considered indolent lymphomas) and primary cutaneous diffuse large B-cell lymphoma, leg-type (PCDLBCL-LT), which is, instead, a very aggressive disease. Nowadays, the PCBCL’s category also includes some rare entities such as intravascular B-cell lymphoma (IVBL) and the EBV+ mucocutaneous ulcer (EBVMCU). Furthermore, controversies still exist concerning the category of primary cutaneous diffuse large B-cell lymphoma (PCDLBCL), because some cases may present with clinical and histological features between PCFCL and PCDLBCL-LT. Therefore, some authors proposed introducing another category called PCDLBCL, not otherwise specified (NOS). Regardless, PCBCLs exhibit distinct features and differ in prognosis and treatment from their nodal/systemic counterparts. Therefore, clinicopathologic analysis is a key diagnostic element in the work-up of these lymphomas.

Hemato doi: 10.3390/hemato3020022

Authors: Giada Bianchi Maria Moscvin Raymond L. Comenzo

AL amyloidosis is an incurable plasma cell dyscrasia with limited therapeutic options. The pathogenetic mechanism in AL amyloidosis is the deposition of insoluble fibrillary aggregates of misfolded immunoglobulin (Ig) free light chains (FLC) and chaperone proteins in target organs. Therefore, AL amyloidosis is the prototypic, protein-toxicity hematologic disorder. Based on laboratory evidence of increased, constitutive proteotoxic stress, PCs are intrinsically vulnerable to agents that target proteins whose function is to guarantee that nascent polypeptides either reach a functional conformation or are disposed of (proteostasis network). The clinical efficacy of proteasome inhibitors (PIs), such as bortezomib, in the treatment of plasma cell (PC) disorders has provided proof of concept that disrupting protein homeostasis is an effective and generally safe therapeutic approach. Therefore, the intrinsic biology of PC offers us the opportunity to rationally develop therapies that target this distinct proteostasis vulnerability of PC dyscrasias. In this manuscript, we will review the laboratory rationale for the effectiveness of FDA-approved and investigational agents targeting protein homeostasis in AL amyloidosis and related PC disorders.

Hemato doi: 10.3390/hemato3020021

Authors: Faith E. Davies Brian A. Walker

Although treatment of multiple myeloma has changed dramatically over time, there is still a subpopulation of patients who do not respond to treatments and are labeled as high risk. A combination of serum and genomic markers can be used to identify and stratify these patients according to associations with outcome. The most common method of identifying the genomic markers of high-risk multiple myeloma is using fluorescence in situ hybridization using probes to identify IgH translocations or copy number changes including the t(4;14), t(14;16), t(14;20), gain 1q, and del(17p). However, as research studies utilize newer technologies, such as whole genome sequencing, more high-risk factors are being identified including mutations of TP53, DIS3, BRAF, and complex structural events. Integration of comprehensive genomic studies into clinical trials will aid in defining the genomic high-risk landscape of multiple myeloma, which in turn can be transferred to individual patient diagnostics and treatment management.

Hemato doi: 10.3390/hemato3010020

Authors: Karthik A. Ganapathi Kristin H. Karner Madhu P. Menon

Follicular helper T-cell (TFH) lymphomas comprise a unique group of T-cell lymphomas that represent neoplastic proliferations of follicular helper T-cells and share genetic, immunophenotypic, morphologic, and clinical features. Angioimmunoblastic T-cell lymphoma (AITL) is the prototypical TFH lymphoma; in addition, the 2017 revised World Health Organization (WHO) 4th edition recognizes two other unique subtypes: follicular T-cell lymphoma (FTCL) and nodal peripheral T-cell lymphoma with the T follicular helper phenotype (PTCL-TFH). This review discusses the morphologic spectrum, immunophenotype, diagnostic mimics/pitfalls, and unique genetic attributes of this category of T-cell lymphomas.

Hemato doi: 10.3390/hemato3010019

Authors: Luis Del Pozo-Yauner Elba A. Turbat-Herrera Julio I. Pérez-Carreón Guillermo A. Herrera

Studies carried out in the last three decades have significantly advanced our knowledge about the structural factors that drive the amyloid aggregation of the immunoglobulin light chains. Solid-state nuclear magnetic resonance and cryo-electron microscopy studies have resulted in huge progress in our knowledge about the AL fibril structure. Now, it is known that the assembly of the light chain into AL fibrils implies an extensive conformational rearrangement that converts the beta-sandwich fold of the protein into a near flat structure. On the other hand, there has also been significant progress made in understanding the role that some cell types play as facilitators of AL formation. Such a role has been studied in glomerular amyloidosis, where mesangial cells play an important role in the mechanism of AL deposition, as well as for the pathogenic mechanisms that result in glomerular/renal damage. This review addresses what we currently know about why and how certain light chains are prone to forming amyloid. It also summarizes the most recent publications on the structure of AL fibrils and analyzes the structural bases of this type of aggregate, including the origin of its structural diversity. Finally, the most relevant findings on the role of mesangial cells in the amyloid deposition of light chains in the glomerular space are summarized.

Hemato doi: 10.3390/hemato3010018

Authors: Craig R. Soderquist Govind Bhagat

Indolent T- and NK-cell lymphoproliferative disorders of the gastrointestinal tract are uncommon clonal neoplasms that have a protracted clinical course and limited response to therapy. In recent years, advances in the immunophenotypic, genetic, and clinical characterization of these disorders have led to increased awareness and a better understanding of disease pathogenesis. However, many questions remain unanswered, including those concerning the cell(s) of origin, inciting immune or environmental factors, and the molecular pathways underlying disease progression and transformation. In this review, we discuss recent findings regarding the immunophenotypic and genomic spectrum of these lymphoproliferative disorders and highlight unresolved issues.

Hemato doi: 10.3390/hemato3010017

Authors: Grigoris T. Gerotziafas Patrick Van Dreden Douglas D. Fraser Guillaume Voiriot Maitray A. Patel Mark Daley Alexandre Elabbadi Aurélie Rousseau Yannis Prassas Matthieu Turpin Marina Marchetti Loula Papageorgiou Evangelos Terpos Meletios A. Dimopoulos Anna Falanga Jawed Fareed Muriel Fartoukh Ismail Elalamy

In some patients, SARS-CoV-2 infection induces cytokine storm, hypercoagulability and endothelial cell activation leading to worsening of COVID-19, intubation and death. Prompt identification of patients at risk of intubation is an urgent need. Objectives. To derive a prognostic score for the risk of intubation or death in patients with COVID-19 admitted in intensive care unit (ICU), by assessing biomarkers of hypercoagulability, endothelial cell activation and inflammation and a large panel of clinical analytes. Design, Setting and Participants. A prospective, observational study enrolled 118 patients with COVID-19 admitted in the ICU. On the first day of ICU admission, all patients were assessed for biomarkers (protein C, protein S, antithrombin, D-Dimer, fibrin monomers, FVIIa, FV, FXII, FXII, FVIII, FvW antigen, fibrinogen, procoagulant phospholipid dependent clotting time, TFPI, thrombomodulin, P-selectin, heparinase, microparticles exposing TF, IL-6, complement C3a, C5a, thrombin generation, PT, aPTT, hemogram, platelet count) and clinical predictors. Main Outcomes and Measures. The clinical outcomes were intubation and mortality during hospitalization in ICU. Results: The intubation and mortality rates were 70% and 18%, respectively. The COMPASS-COVID-19-ICU score composed of P-Selectin, D-Dimer, free TFPI, TF activity, IL-6 and FXII, age and duration of hospitalization predicted the risk of intubation or death with high sensitivity and specificity (0.90 and 0.92, respectively). Conclusions and Relevance. COVID-19 is related to severe endothelial cell activation and hypercoagulability orchestrated in the context of inflammation. The COMPASS-COVID-19-ICU risk assessment model is accurate for the evaluation of the risk of mechanical ventilation and death in patients with critical COVID-19. The COMPASS-COVID-19-ICU score is feasible in tertiary hospitals and could be placed in the diagnostic procedure of personalized medical management and prompt therapeutic intervention.

Hemato doi: 10.3390/hemato3010016

Authors: Grigorios T. Gerotziafas Despina Fotiou Theodoros N. Sergentanis Loula Papageorgiou Jawed Fareed Anna Falanga Michèle Sabbah Laurent Garderet Evangelos Terpos Ismail Elalamy Patrick Van Dreden Meletios A. Dimopoulos

Biomarkers of hypercoagulability are potential candidates for the evaluation of risk for primary treatment resistance in patients with newly diagnosed multiple myeloma (NDMM). This study aimed to identify the most clinically relevant biomarkers for the evaluation of treatment-resistance risk. NDMM patients (n = 144) were enrolled prior to treatment initiation. Response to treatment was assessed at 3 months. STA-Procoag-PPL®, factor VIIa factor V, antithrombin, fibrin monomers, soluble thrombomodulin (TM), free TFPI, D-Dimer, P-selectin, heparanase, and thrombin generation (Calibrated Automated Thrombogram® and PPP-Reagent®) were measured. In total, 23% (n = 33) of the patients showed a poor response/resistance to treatment (defined as stable disease, minor response, progressive disease). Poor response/treatment resistance was associated with longer Procoag-PPL® clotting time, higher Peak of thrombin, and higher D-Dimer levels. These biomarkers were included in a prognostic model derived via multivariate analysis. The model had 84% sensitivity and 59% specificity to identify patients at high risk of treatment resistance. The AUC of the ROC analysis for the model was 0.75. In conclusion, Procoag-PPL®, D-Dimer, and Peak of thrombin generation are clinically relevant for the identification of NDMM patients at risk for poor response to antimyeloma treatment. A prospective multicenter study is necessary for the validation of this new approach.

Hemato doi: 10.3390/hemato3010015

Authors: Sean Harrop Costas Kleanthes Yannakou Carrie Van Der Weyden Henry Miles Prince

The characterisation of the lymphoma epigenome has provided insight into mechanisms involved in lymphomagenesis. Multiple lymphoma subtypes demonstrate recurrent mutations in key epigenetic regulators that have been utilised to define clinicogenetic groups that can predict clinical behaviour in these heterogenous entities. The high frequency of mutations in epigenetic regulators provides rationale to incorporate these in the classification of some subtypes of lymphoma. In addition, their recurrent nature provides a rationale to target such mutations, or the relevant pathway, for treatment. In this review, we summarised the available literature on epigenetic dysregulation in lymphoma and how it has been utilised in diagnosis and classification.

Hemato doi: 10.3390/hemato3010014

Authors: Fina Climent Joan Cid Anna Sureda

Cold agglutinin disease (CAD) is a distinct clinicopathologic entity characterized by clonal B-cell lymphoproliferative disorder in the bone marrow. B-cell gene mutations affect NF-ΚB as well as chromatin modification and remodeling pathways. Clonal immunoglobulins produced by B cells bind to red cells (RBCs) at cold temperatures causing RBC aggregation, complement cascade activation and cold-autoantibody autoimmune hemolytic anemia (cAIHA). The clinical picture shows cold-induced symptoms and cAIHA. Therapeutic options include “wait and watch”, rituximab-based regimens, and complement-directed therapies. Steroids must not be used for treating CAD. New targeted therapies are possibly identified after recent molecular studies.

Hemato doi: 10.3390/hemato3010013

Authors: Valeria Santini

Purpose of review: Management and Optimization of therapy for lower-risk myelodysplastic syndromes will be reviewed here. Recent findings: Lower-risk MDS typically present with clinical manifestations of anemia, which is the most frequently encountered cytopenia in this setting. While therapy with erythropoietic stimulating agents (ESAs) is used in the vast majority of cases, if correctly selected, some patients do not respond, or become irresponsive to ESAs. Novel agents with very different modes of action show promising clinical results in anemic LR-MDS refractory/relapsed after ESAs. Luspatercept, a TGFbeta family ligand trap, induces nearly 50% of transfusion independence in LR MDS. Another investigational agent showing efficacy and possibly disease modifying activity is the telomerase inhibitor imetelstat. Modulation of dose and schedule of hypomethylating agents, both injectable and oral, is currently being explored, and preliminary results are positive. There is still no standard therapeutic approach for thrombocytopenic and neutropenic LR MDS, although they do represent a smaller proportion of cases. Immunosuppressive treatments, as well as TPO mimetics, could represent a good option in selected MDS cases. Summary: At present, the availability of novel active agents allows the planning of sequential therapy, especially for anemic LR MDS. Better diagnosis and prognostic stratification may allow a more precise and personalized treatment.

Hemato doi: 10.3390/hemato3010012

Authors: Foteini Theodorakakou Despina Fotiou Meletios A. Dimopoulos Efstathios Kastritis

The treatment of AL amyloidosis has evolved, and outcomes have improved, but primarily for patients with low or intermediate-risk disease. Recent advances have been limited to improvements in anti-clonal therapies, which, alone, cannot change the poor prognosis of patients with high-risk disease. Thus, new strategies are needed that combine different approaches to the treatment of the disease. Targeted therapies against plasma/B-cell clones that avoid chemotherapy or potentially cardiotoxic drugs may improve the depth of hematologic responses and reduce complications. Amyloid fibril and light-chain oligomer targeting may reduce direct toxicity and enhance tissue clearance. Future combinations should be tailored to clone characteristics and specific amyloid properties, but early identification of those at high risk to develop AL amyloidosis will also be integrated into management algorithms.

Hemato doi: 10.3390/hemato3010011

Authors: Stefan Nagel

Homeobox genes encode transcription factors which control basic processes in development and differentiation. Concerning the sequence conservation in their homeobox, these genes are arranged into particular groups sharing evolutionary ancestry and resembling in function. We have recently described the physiological expression patterns of two homeobox gene groups, NKL and TALE, in early hematopoiesis and subsequent lymphopoiesis. The hematopoietic activities of eleven NKL and nine TALE homeobox genes have been termed as NKL- and TALE-codes, respectively. Due to the developmental impact of homeobox genes, these expression data indicate a key role for their activity in normal hematopoietic differentiation processes, including B-cell development. On the other hand, aberrant expression of NKL- and TALE-code members or ectopic activation of non-code members have been frequently reported in lymphoid malignancies, demonstrating their oncogenic potential in the hematopoietic compartment. Here, we provide an overview of the established NKL- and TALE-codes in normal lymphopoiesis and of deregulated homeobox genes in Hodgkin lymphoma, demonstrating the capability of gene codes to identify homeo-oncogenes in lymphoid malignancies.

Hemato doi: 10.3390/hemato3010010

Authors: Grigorios T. Gerotziafas Patrick Van Dreden Theodoros N. Sergentanis Marianna Politou Aurélie Rousseau Matthieu Grusse Michèle Sabbah Ismail Elalamy Vasiliki Pappa Tina Skourti Tina Bagratuni Ioannis Ntanasis-Stathopoulos Eleni Korompoki Stavroula Labropoulou Meletios A. Dimopoulos Evangelos Terpos

Background. Hypercoagulable state and endothelial cell activation are common alterations in patients with COVID-19. Nevertheless, the hypothesis of persistent hypercoagulability and endothelial cell activation following recovery from COVID-19 remains an unresolved issue. Objectives. To investigate the persistence of endothelial cell activation and hypercoagulability after recovery from COVID-19. Patients/Methods. COVID-19 survivors (n = 208) and 30 healthy individuals were enrolled in this study. The following biomarkers were measured: procoagulant phospholipid-dependent clotting time (PPL-ct), D-Dimer, fibrin monomers (FM), free Tissue factor pathway inhibitor (free-TFP)I, heparinase, and soluble thrombomodulin (sTM). Antibodies against SARS-CoV-2 (IgG and IgA) were also measured. Results. The median interval between symptom onset and screening for SARS-CoV-2 antibodies was 62 days (IQR = 22 days). Survivors showed significantly higher levels of D-Dimers, FM, TFPI, and heparanase as compared to that of the control group. Survivors had significantly shorter PPL-ct. Elevated D-dimer was associated with older age. Elevated FM was associated with female gender. Elevated heparanase was independently associated with male gender. Decreased Procoag-PPL clotting time was associated with female gender. One out of four of COVID-19 survivors showed increase at least one biomarker of endothelial cell activation or hypercoagulability. Conclusions. Two months after onset of COVID-19, a significant activation of endothelial cells and in vivo thrombin generation persists in at least one out of four survivors of COVID-19. The clinical relevance of these biomarkers in the diagnosis and follow-up of patients with long COVID-19 merits to be evaluated in a prospective clinical study.

Hemato doi: 10.3390/hemato3010009

Authors: Hemato Editorial Office Hemato Editorial Office

Rigorous peer-reviews are the basis of high-quality academic publishing [...]

Hemato doi: 10.3390/hemato3010008

Authors: Paolo Milani M. Teresa Cibeira

Light chain amyloidosis is a complex disease where a small B-cell clone produces a monoclonal immunoglobulin light chain that causes deposits and specific organ dysfunction. The available treatment strategies aim to reduce or eliminate amyloidogenic light chain production in order to avoid amyloid deposition and allow the repair of organ damage. An international effort allowed the definition of validated hematologic and organ response criteria based on biomarkers. Recently, new methods for the assessment of minimal residual disease were also proposed but still need international validation. Lastly, a joint effort is also required to accurately define relapse/progression criteria in order to apply timely therapeutic interventions. In this review, we describe the validated response criteria and report on the future direction for the definition of progression criteria in this disease.

Hemato doi: 10.3390/hemato3010007

Authors: Anna Daniel Fome Raphael Z. Sangeda Emmanuel Balandya Josephine Mgaya Deogratius Soka Furahini Tluway Upendo Masamu Siana Nkya Julie Makani Bruno P. Mmbando

Hematological and biochemical reference values in sickle cell disease (SCD) are crucial for patient management and the evaluation of interventions. This study was conducted at Muhimbili National Hospital (MNH) in Dar es Salaam, Tanzania, to establish laboratory reference ranges among children and adults with SCD at steady state. Patients were grouped into five age groups and according to their sex. Aggregate functions were used to handle repeated measurements within the individual level in each age group. A nonparametric approach was used to smooth the curves, and a parametric approach was used to determine SCD normal ranges. Comparison between males and females and against the general population was documented. Data from 4422 patients collected from 2004–2015 were analyzed. The majority of the patients (35.41%) were children aged between 5–11 years. There were no significant differences (p ≥ 0.05) in mean corpuscular hemoglobin concentration (MCHC), lymphocytes, basophils, and direct bilirubin observed between males and females. Significant differences (p < 0.05) were observed in all selected parameters across age groups except with neutrophils and MCHC in adults, as well as platelets and alkaline phosphatase in infants when the SCD estimates were compared to the general population. The laboratory reference ranges in SCD at steady state were different from those of the general population and varied with sex and age. The established reference ranges for SCD at steady state will be helpful in the management and monitoring of the progress of SCD.

Hemato doi: 10.3390/hemato3010006

Authors: Emilie Arnault Carneiro Filipa Barahona Carolina Pestana Cristina João

Multiple myeloma (MM) is the second deadliest hematological cancer. Despite the enormous innovation on MM treatment in the last decades, still 48% of patients die within 5 years after diagnosis. MM diagnosis and therapeutic strategy mainly rely on direct bone marrow (BM) assessment. Given the MM heterogeneity, BM biopsies do not accurately reflect the whole disease status, hampering accurate disease prognosis. Moreover, biopsies are painful and invasive procedures, highlighting the need for non-invasive and more accurate source of biomarkers. Liquid biopsies are promising sources of biomarkers that may overcome these limitations. Peripheral blood carries circulating myeloma components that are being extensively explored since the last few years as an alternative to BM aspirates. These include circulating tumor cells (CTC), cell-free DNA (cfDNA), and extracellular vesicles containing miRNA and proteins. The current review summarizes scientific evidence establishing BM as a gold standard for the diagnosis, prognosis, and evaluation of minimal residual disease. We discuss the last advances regarding cfDNA and CTC biomarkers from peripheral blood in patients with MM as well as the statistical validations. This paper addresses the technological hurdles associated with liquid biopsies and examines the missing steps for their inclusion into the clinical practice.

Hemato doi: 10.3390/hemato3010005

Authors: Francesca Lavatelli

The deposition of amyloid light chains (LCs) in target sites translates into tissue damage and organ dysfunction. Clinical and experimental advances have cast new light on the pathophysiology of damage in AL amyloidosis. The currently accepted view is that, besides the alterations caused by fibrillar deposits in the extracellular space, direct proteotoxicity exerted by prefibrillar LC species is an important pathogenic factor. As our knowledge on the pathological species and altered cellular pathways grows, novel potential therapeutic strategies to prevent or reduce damage can be rationally explored. Complementing chemotherapy with approaches aimed at disrupting the deposited fibrils and stabilizing prefibrillar amyloidogenic LC may allow halting or even reverting damage in target sites. This review recapitulates the current knowledge and the most recent acquisitions regarding the mechanisms of organ damage in AL amyloidosis, with special emphasis on the heart, and will provide a critical discussion on possible novel treatment targets.

Hemato doi: 10.3390/hemato3010004

Authors: Hamza Hassan Vaishali Sanchorawala

The survivorship needs of patients with light-chain (AL) amyloidosis are complex, as is the diagnosis and treatment itself. Early diagnosis is critical in improving patient outcomes; however, given the nonspecific nature of the symptoms, most patients with AL amyloidosis require evaluation by multiple specialists, resulting in significant delays in diagnosis of up to 3 years. An early and accurate diagnosis can help reduce the psychological toll of the patient’s journey to diagnosis. Given the high symptom burden and complex process of diagnosis, it is not surprising that patients with AL amyloidosis report worse health-related quality of life than the general population. Organ dysfunction associated with AL amyloidosis also may make the treatment directed towards plasma cell clone difficult to tolerate, leading to morbidity and mortality. Furthermore, supportive care requires an integrated, multidimensional and patient-centered approach to improve survival and feelings of well-being, as organ responses lag behind hematologic responses. The impact of AL amyloidosis is often devastating for the patient and may last beyond the effects of treatment. Future research is needed to study and assess the needs of survivors of AL amyloidosis utilizing valid, reliable and standardized measures.

Hemato doi: 10.3390/hemato3010003

Authors: Anjum B. Khan David Bowen

Myelodysplastic syndromes affect an older age group with a median age at onset in the eighth decade of life. As such, there is a relationship between the pathogenesis of MDS and age-related processes affecting haematopoietic stem/progenitor cells and/or the bone marrow microenvironment. MDS with an onset in younger people may be associated with recognised hereditary myeloid malignancy syndromes, and ‘forme fruste’ presentations of inherited syndromes in later life are now increasingly recognised such as germline mutations in DDX41. The considerable clinical and research interest in hereditary disorders is reflected in the relative emphasis within our manuscript. Prior chemo/radiotherapy is a clear cause of MDS but the predisposition factors for therapy-related MDS remain unclear. Clonal haematopoiesis is common in older people and may evolve to MDS, although once again, the biological factors driving this evolution are largely unknown. Finally, environmental exposure to genotoxic agents is likely to play only a minor role in the contemporary occupational/recreational setting.

Hemato doi: 10.3390/hemato3010002

Authors: Moshe E. Gatt Marjorie Pick

Primary systemic light chain amyloidosis (AL) is a rare monoclonal plasma cell disorder. Much research has been performed to determine the factors that underly amyloidogenicity. However, there is increasing evidence that the primary clone, and also patient-related factors, influence the mechanism and rate of the process. The lessons learnt from patient care definitely imply that this is not solely due to the deposition of material in the tissues that cause organ injury but amyloid light chain precursors are likely to mediate cellular toxicity. The disease rarity, combined with the lack of in vitro tools, and that multi-organ failure has a wide clinical spectrum, result in investigative challenges and treatment limitations (due to AL patient frailty). All these characteristics make the disease difficult to diagnose and indicate the need to further study its origins and treatments. This review will focus on the various aspects of the amyloidogenic plasma cell clone, as learnt from the patient care and clinics, and its implications on basic as well as clinical trials of AL research. Details regarding the etiology of the plasma cell clone, understanding the diagnosis of AL, and improvement of patient care with specific consideration of the future perspectives of individualized patient therapy will be described.

Hemato doi: 10.3390/hemato3010001

Authors: Nicolaus Kröger Laurent Garderet

Immunotherapy has become a major pillar in the treatment of multiple myeloma [...]

Hemato doi: 10.3390/hemato2040053

Authors: Uzma Faruqi Karen A. Breen

Philadelphia chromosome negative myeloproliferative neoplasms (MPN) are clonal haematopoietic stem cell disorders. Of the MPNs, polycythaemia vera (PV) and essential thrombocythaemia (ET) confer a high thrombotic risk which may be the presenting feature of the disease. Thrombotic complications consist of both arterial and venous events and the presence of the JAK2 V617F mutation is associated with higher risk. Patients presenting with an unprovoked thrombus, particularly at an unusual site, e.g., splanchnic circulation, should be screened for the presence of this mutation. Historically, warfarin has been the only option for oral anticoagulation; however, there is now increasing evidence and practise to use direct oral anticoagulants (DOACs) in cancer. The seminal randomised control trials have demonstrated non-inferiority compared to low molecular weight heparin (LMWH) with a preferable bleeding profile. DOACs are now the first line treatment for atrial fibrillation and venous thromboembolic disease, as recommended by NICE, and therefore there is increasing familiarity with these agents. Furthermore, there are now targeted antidotes available. This paper reviews evidence for efficacy and safety of DOACs in MPN. Whilst no randomised control trials have been performed, several retrospective studies and reviews of registry data have reproducibly demonstrated that, alongside cytoreduction, DOACs represent an effective modality of anticoagulation for treatment of venous thromboembolism in MPN. Furthermore, dosing regimens provide the option for longer term secondary prophylaxis. Use of DOACs in arterial thrombosis is an area for future development and there is already some evidence for utility in peripheral vascular disease.

Hemato doi: 10.3390/hemato2040052

Authors: Katie L. Thoren

In recent years, mass spectrometry has been increasingly used for the detection of monoclonal proteins in serum. Mass spectrometry is more analytically sensitive than serum protein electrophoresis and immunofixation, can help distinguish therapeutic monoclonal antibodies from M-proteins, and can detect the presence of post-translational modifications. Mass spectrometry also shows promise as a less-invasive, peripheral-blood-based test for detecting minimal residual disease in multiple myeloma. Studies comparing the clinical utility of mass spectrometry to current blood- and bone-marrow-based techniques have been conducted. Although still primarily limited to research settings, clinical laboratories are starting to adopt this technique for patient care. This review will discuss the current status of mass spectrometry testing for multiple myeloma, the benefits and challenges of this technique, and how it may be incorporated into clinical practice in the future.