Hemato, Volume 3, Issue 1 (March 2022) – 20 articles

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article