Editor’s Choice Articles

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. Full article

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. Full article

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. Full article

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. Full article

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

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

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

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

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

In this paper, we explore the application of Chimeric Antigen Receptor (CAR) T cell therapy for the treatment of Acute Lymphocytic Leukaemia (ALL) by means of in silico experimentation, mathematical modelling through first-order Ordinary Differential Equations and nonlinear systems theory. By combining the latter with systems biology on cancer evolution we were able to establish a sufficient condition on the therapy dose to ensure complete response. The latter is illustrated across multiple numerical simulations when comparing three mathematically formulated administration protocols with one of a phase 1 dose-escalation trial on CAR-T cells for the treatment of ALL on children and young adults. Therefore, both our analytical and in silico results are consistent with real-life scenarios. Finally, our research indicates that tumour cells growth rate and the killing efficacy of the therapy are key factors in the designing of personalised strategies for cancer treatment. Full article

Systemic auto-inflammatory or autoimmune diseases (SIADs) develop in up to a quarter of patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML). With or without the occurrence of SIADs, the distribution of MDS subtypes and the international or CMML-specific prognostic scoring systems have been similar between MDS/CMML patients. Moreover, various SIADs have been described in association with MDS, ranging from limited clinical manifestations to systemic diseases affecting multiple organs. Defined clinical entities including systemic vasculitis, connective tissue diseases, inflammatory arthritis and neutrophilic diseases are frequently reported; however, unclassified or isolated organ impairment can also be seen. Although the presence of SIADs does not impact the overall survival nor disease progression to acute myeloid leukemia, they can help with avoiding steroid dependence and make associated adverse events of immunosuppressive drugs challenging. While therapies using steroids and immunosuppressive treatment remain the backbone of first-line treatment, increasing evidence suggests that MDS specific therapy (hypomethylating agents) and sparing steroids may be effective in treating such complications based on their immunomodulatory effect. The aim of this review was to analyze the epidemiological, pathophysiological, clinical and therapeutic factors of systemic inflammatory and immune disorders associated with MDS. Full article

Several studies have examined the prognostic performance of therapeutic groups (TG) and early responses to therapy on positron emission tomography/computed tomography (PET/CT) in children and adolescents with classical Hodgkin lymphoma (cHL); less research has been performed on molecular parameters at diagnosis. The aim of the present study was to devise a scoring system based on the TG criteria for predicting freedom from progression (FFP) in 133 patients: 63.2% males; 14 years median age (interquartile range (IQR) 11.9–15.1); with cHL (108 nodular sclerosis (NS) subtype) treated according to the AIEOP LH-2004 protocol; and median 5.55 (IQR 4.09–7.93) years of follow-up. CHL progressed or relapsed in 37 patients (27.8%), the median FFP was 0.89 years (IQR = 0.59–1.54), and 14 patients (10.5%) died. The FPR (final prognostic rank) model associates the biological HLA-G SNP 3027C/A (numerical point assigned (pt) = 1) and absolute neutrophil count (>8 × 10⁹/L, pt = 2) as variables with the TG (TG3, pt = 3). Results of FPR score analyses for FFP suggested that FPR model (Kaplan–Meier curves, log-rank test for trends) was better than the TG model. At diagnosis, high-risk patients classified at FPR rank 4 and 5 identified 18/22 patients who relapse during the follow-up. Full article

The development of molecular studies to define the somatic genetic alterations has revolutionized the diagnostic and therapeutic management of acute myeloid leukemia (AML). AML is a highly heterogenous disease that includes many molecular subtypes; each subtype is heterogeneous both for the presence of variable co-mutations and complex combinations of clones and subclones, changing during disease evolution and in response to treatment. The treatment of AML is changing from standardized schemes of induction and consolidation chemotherapy to tailored approaches according to molecular and genetic profiles and to targeted therapy. Several molecularly targeted therapies have been approved for the treatment of some AML patients, including mutation-specific targeted drugs such as FLT3, IDH1 and IDH2 inhibitors, mutation-independent targeted drugs such as the Bcl2 inhibitor venetoclax, the hedgehog inhibitor glasdegib and the CD33-targeted drug gemtuzumab ozogamicin. Furthermore, recent studies have shown the feasibility of a personalized medicine approach for the treatment of AML patients, where the therapy decisions are guided by the results of genomic studies. Full article