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Epstein-Barr virus (EBV) is associated with hematologic and solid tumors. In this study, we utilized a hybridization capture-based next generation sequencing (NGS) platform that targets 400 genes associated with hematological malignancies to detect and quantify non-targeted viral-derived EBV reads that aligned to the EBV reference contig (NC_007605). We evaluated 5,234 samples from 3,636 unique patients with hematological neoplasms and found that 100 samples (1.9%) in 93 unique patients had ≥ 6 EBV reads (range, 6-32,325; mean, 827.5; median, 54). The majority (n=73, 73%) represented known EBV-associated conditions, and the most common was post-transplant lymphoproliferative disorders (n=21, 29%). Documented EBV viremia accounted for a moderate quantity of EBV reads in 4/27 samples corresponding to conditions not known to be EBV-associated, while suspected viremia or low-level activation was likely the etiology in the remaining 23 samples. A good correlation (Spearman r=0.8, 95% CI 0.74-0.85) was found between EBV reads by NGS and systematic semi-quantitative EBER ISH assessment in 162 available samples, particularly at higher level of EBV-involvement. An optimal threshold for significant morphologic EBV-involvement was found to be ≥10 reads by the receiver operating characteristic (ROC) analysis (AUC 0.990 and 95% CI 0.9974-1.000%). Thus, in addition to mutational analysis, hybrid-capture-based NGS panels can be used to detect and quantitate off-target EBV-derived viral DNA, which correlates well with morphology.

Hematological and hematopoietic cells malignancies of the genes and hematopoietic cells are associated with the genetic mutation, often at the chromosomal level. The standard cytogenetic study is widely accepted as one of the main diagnostics and prognostic determinants in patients. Therefore, the current descriptive and cross-sectional study sought to determine the cytogenetic analysis of frequent hematological malignancies in Pakistan. A total of 202 peripheral bone marrow or blood samples from patients with benign and malignant hematological malignancy were taken using a conventional G-banding technique. Among enrolled patients, the mean age was 21.5 years ± 23.4, and gender-wise distribution showed a marked predominance of the male 147 (73%) population compared to the female 55 (27%). Patients in the age group (2-10 years) had the highest frequency, 48 (24%), of hematological neoplasms, followed by age (11-20 years) with 40 (20%). Normal karyotypes (46, XX/46, XY) was found in 51% (n=103) patients. Furthermore, the frequency of complex karyotype was 30 (15%), while normal was seen in 171 (85%) patients. Pre-B Acute Lymphoblastic Leukemia (Pre-B ALL) was the most prevalent malignancy of 66 (33%), followed by Chronic Myelogenous Leukemia (CML) of 41 (20%) and Acute Lymphocytic Leukemia of 29 (14%). Translocation was the most prevalent 50 (25%), followed by hypotriploidy 14 (7%) and monosomy 8 (4%) on chromosome aberration analysis. In addition, t(9:22) translocation was found to be 20 (10%) in CML, with the majority in the age group (31-40 years). This study recommends that karyotyping should be tested frequently in hematological conditions because it may provide insight into the relative chromosomal changes associated with particular malignancies. Resumo As neoplasias hematológicas e de células hematopoiéticas dos genes e as células hematopoiéticas estão associadas à mutação genética, geralmente em nível cromossômico. O estudo citogenético padrão é amplamente aceito como um dos principais determinantes diagnósticos e prognósticos em pacientes. Portanto, o presente estudo descritivo e transversal buscou determinar a análise citogenética de neoplasias hematológicas frequentes no Paquistão. Um total de 202 amostras de medula óssea periférica ou sangue de pacientes com malignidade hematológica benigna e maligna foi coletado usando uma técnica convencional de banda G. Entre os pacientes inscritos, a média de idade foi de 21,5 anos ± 23,4, e a distribuição por gênero mostrou uma marcada predominância da população masculina de 147 (73%) em comparação com a feminina de 55 (27%). Pacientes na faixa etária (2-10 anos) tiveram a maior frequência, 48 (24%), de neoplasias hematológicas, seguida da idade (11-20 anos) com 40 (20%). Cariótipos normais (46, XX / 46, XY) foram encontrados em 51% (n = 103) dos pacientes. Além disso, a frequência de cariótipo complexo foi de 30 (15%), enquanto normal foi observada em 171 (85%) pacientes. Leucemia linfoblástica aguda pré-B (LLA Pré-B) foi a doença maligna mais prevalente de 66 (33%), seguida por leucemia mieloide crônica (LMC) de 41 (20%) e leucemia linfocítica aguda de 29 (14%). A translocação foi o 50 mais prevalente (25%), seguido por hipotriploidia 14 (7%) e monossomia 8 (4%) na análise de aberração cromossômica. Além disso, a translocação t (9:22) encontrada foi de 20 (10%) na LMC, com a maioria na faixa etária (31-40 anos). Este estudo recomenda que o cariótipo deve ser testado com frequência em condições hematológicas porque pode fornecer informações sobre as alterações cromossômicas relativas associadas a doenças malignas específicas.

Key Points Comparison of the mutation frequencies and numbers of 122 genes in 3096 cases enables identification of “mutation-driven” entities.Differences in mutation patterns in cases with or without CHIP-associated mutations across entities suggest differences in pathophysiology., Visual Abstract, Acquired somatic mutations are crucial for the development of most cancers. We performed a comprehensive comparative analysis of the mutational landscapes and their correlation with CHIP-related (clonal hematopoiesis of indeterminate potential) mutations and patient age of 122 genes in 3096 cases of 28 different hematological malignancies. Differences were observed regarding (1) the median number of mutations (highest, median n = 4; lowest, n = 0); (2) specificity of certain mutations (high frequencies in atypical chronic myeloid leukemia [aCML; ASXL1, 86%], follicular lymphoma [FL; KMT2D, 87%; CREBBP, 73%], hairy cell lymphoma [BRAF, 100%], lymphoplasmacytic lymphoma [MYD88, 98%; CXCR4, 51%], myeloproliferative neoplasm [MPN; AK2, 68%]); (3) distribution of mutations (broad distribution within/across the myeloid/lymphoid lineage for TET2, ASXL1, DNMT3A, TP53, BCOR, and ETV6); (4) correlation of mutations with patient’s age (correlated with older age across entities: TET2, DNMT3A, ASXL1, TP53, EZH2, BCOR, GATA2, and IDH2; younger age: KIT, POT1, RAD21, U2AF2, and WT1); (5) correlation of mutation number per patient with age. Moreover, we observed high frequencies of mutations in RUNX1, SRSF2, IDH2, NRAS, and EZH2 in cases comprising at least 1 DTA (DNMT3A, TET2, ASXL1) mutation, whereas in cases without DTA mutations, TP53, KRAS, WT1, and SF3B1 were more frequent across entities, suggesting differences in pathophysiology. These results give further insight into the complex genetic landscape and the role of DTA mutations in hematological neoplasms and define mutation-driven entities (myelodysplastic syndrome/MPN overlap; secondary acute myeloid) in comparison with entities defined by chromosomal fusions (chronic myeloid leukemia; myeloid/lymphoid neoplasm with eosinophilia).

Background Multiple myeloma (MM) is one of the most common hematological neoplasms and accounts for approximately 1% of human cancers. Objectives Description of current diagnostics and classification of MM and related plasma cell neoplasms from the pathology viewpoint. Materials and methods Current knowledge regarding pathology and genetics of MM is summarized and tissue-based diagnostics following international consensus classifications and the current S3 guideline are described. Results MM and related neoplasms are composed of malignant plasma cells that secrete a monoclonal immunoglobulin, which is an important parameter of disease activity. MM shows a multistage development. Almost all cases are preceded by a clinically inapparent precursor lesion, monoclonal gammopathy of undetermined significance (MGUS), which can progress to smoldering myeloma with a higher tumor burden, but absence of organ damage. Systemic MM needs to be discerned from the localized forms, solitary osseous and primary extramedullary plasmacytoma. MM is genetically very heterogeneous and can be broadly subdivided into two cytogenetic groups, cases with primary IGH translocations and cases with hyperdiploidy. Intratumoral genetic heterogeneity is frequently pronounced and correlates with the size of focal lesions in imaging. Conclusions Diagnosis of plasma cell neoplasms is done according to the criteria of the International Myeloma Working Group (IWMG) and requires interdisciplinary evaluation of clinical, serological, pathological and radiological features. In addition to clinical parameters, molecular markers, especially cytogenetic aberrations, are of great prognostic relevance.

Pediatric HIV is a significant contributor to childhood morbidity and mortality. As HIV infects bone marrow CD34-positive progenitor cells, the hematological abnormalities are well-expected. The viral load is much higher in children predisposing them to opportunistic infections and hematopoietic malignancies. The present study aimed to determine the spectrum of hematological abnormalities that may yield clinically useful information in HIV-infected children. This was a retrospective study of 19 HIV-infected children who underwent bone marrow examination. Overall, 20 peripheral blood and bone marrow samples were analyzed for morphological changes in all hematopoietic lineages. Immunohistochemistry was performed on trephine biopsy sections for evaluation of B and T cells and cytomegalovirus inclusions. Anemia was the most common cytopenia (95%), followed by thrombocytopenia (45%) and leukopenia (40%). Myelodysplasia was noted in 70% of cases. Dysmegakaryopoiesis was predominant in 65% of cases, while dyserythropoiesis was noted in 25% of cases. Hemophagocytosis and reactive cellular changes were noted in 20% of cases each. Benign lymphoid aggregates and granulomatous inflammation were observed in 15% and 10% of cases, respectively. Significant myelofibrosis was found in 35% of cases. One case showed infiltration by Burkitt lymphoma. Parvoviral inclusions were identified in 1 case. An interstitial increase and aggregates of CD8 + T cells and reduced CD4 + T cells were noted. CD20 + B cells were normal to mildly increased in the bone marrow. Bone marrow examination provides clinically significant information in pediatric HIV revealing the underlying cause of hematopoietic abnormalities and allows the exclusion of major hematological neoplasms.

El Síndrome Mielodisplásico (SMD) es un grupo de neoplasias hematológicas cuyo diagnóstico se basa en la presencia de citopenia inexplicada, displasia de alguna de las líneas mieloides y anormalidades citogenéticas típicas. Los estudios moleculares han permitido avanzar en el estudio de la fisiopatología y se han incorporado también al abordaje diagnóstico, permitiendo la clasificación en subtipos específicos, así como la predicción de respuesta a terapias específicas y el pronóstico. A pesar de esto, el diagnóstico aún recae en una adecuada historia clínica, en el análisis morfológico, en la exclusión de otras entidades que cursan con displasia y en los estudios de citogenética. La citometría de flujo no hace parte de los criterios diagnósticos, pero puede ser de utilidad en casos dudosos. El pronóstico es variable en función del subtipo pero, en general, es pobre y además del IPSS-R, se han identificado otras variables que inciden en el pronóstico, sobre todo en los casos asociados a terapia.

This study aimed to compare the detection performance of [68 Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT in the patients with various oncological and non-oncological lesions. A total of 123 patients underwent contemporaneous [68 Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT were included in this prospective study. The maximum standard uptake value (SUVmax) was measured to compare oncological and non-oncological lesion uptake. The sensitivity, specificity, predictive values, and accuracy of [18F]FDG and [68 Ga]Ga-DOTA-FAPI-04 PET/CT for detecting primary, metastatic, and non-oncological lesions were calculated and compared to evaluate the detection efficacy. The study subjects consisted of 123 patients (69 men and 54 women; mean age 56.11 ± 11.94 years). Among the 102 patients with either newly diagnosed (82 patients) or previously treated solid tumor (20 patients), a total of 88 solid primary malignant tumors in 84/102 patients were detected. Two patients had two primary tumors each and 1 patient had three primary tumors. Among them, 58/102 and 43/102 patients had nodal (376 lesions) and distant metastases (406 lesions), respectively. Eight patients had hematological neoplasm. No malignant oncological diseases were detected in the remaining 13 patients. A total of 145 non-oncological lesions and benign tumors in 52/123 patients were detected incidentally. [68 Ga]Ga-DOTA-FAPI-04 PET/CT demonstrated a significantly higher uptake and detection rate for the primary (SUVmax 10.98 ± 5.83 vs. 8.36 ± 6.43, p

In recent years, genome-based classifications for hematological neoplasms have been proposed successively and proved to be more accurate than histologic classifications. However, some previous studies have reported the racial differences of genetic landscape in persons with hematological neoplasms including myelodysplastic syndromes (MDS), which may cause a genomic classification based on a particular ethnic group does not operate in other races. To determine whether race plays an important role in the genomic-based classification, we validated a newly proposed genomic classification of MDS (J Clin Oncol.2021; JCO2001659), which was based on a large European database, in Chinese patients from our center. Our results showed significant differences between Chinese and European patients including proportion of each group to overall cohort when applying this novel genomic classification. Our data indicate that a genomic classification of hematological neoplasms probably should be revised according to specific genetic features in different races.

Hematological neoplasias are the fourth cause of death in the world. All of them are responsible of bad quality of life, due to heavy therapies administration and a lot of side effects correlated to. It arises a new concept of "multitherapy", in which fatty acids availment is used to contrast and reduce toxic effects and ameliorate chemotherapeutic agents asset. In Vitro studies have confirmed that fatty acids, in particular ω-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are able to help canonical therapies to contrast cancer cell expansion and proliferation. In clinical trials it is also almost clear that fatty acids are useful to build new personalized therapies for a better condition of life. In this review we have summarized most recent studies on cancer cell lines and clinical trials on patients with fatty acids supplementation in diet therapies. We have found that fatty acids could be useful to contrast side effects during chemotherapeutic drugs therapies; they are also able to block cancer cell metabolic pathways for proliferation and contrast adverse effects, even when they are used in combination with traditional therapies or innovative, like monoclonal antibodies or CAR-T therapy. These aspects are crucial for better health condition of patients.

Background Myeloid sarcoma (MS) is a very rare condition, develops both in patients with other hematological neoplasms, and as isolated tumor. MS of the gynecologic tract is extremely rare. An available literature data about diagnosis and management of MS is summarized in the article. The role of chemotherapy, radiation therapy, surgery and bone marrow transplantation in the treatment is discussed. Polychemotherapy and allogeneic bone marrow transplantation were suggested to be the optimal treatment strategy of MS of the gynecological tract. The use of new targeted agents results in promising clinical data. Case presentation We are presenting a rare clinical case of a MS of the uterine cervix with concomitant bone marrow involvement and describe all the peculiarities of the clinical course, diagnosis, and treatment. The patient received chemotherapy followed by allogeneic bone marrow transplantation. The pre-transplant therapy allowed us to perform allogeneic bone marrow transplantation with the deepest response possible: complete PET-negative and MRD-negative remission of the disease. Conclusions MS remains a subject of discussion regarding its diagnostic and therapeutic aspects. The use of novel targeting agents can be perspective option for patient with extramedullary disease.

The tumors that induce autoimmune hemolytic anemia (AIHA) are usually hematological neoplasms such as malignant lymphoma and chronic lymphocytic leukemia. AIHA associated with germ cell tumors is very rare with literature limited to case reports with most of them reported with ovarian dermoid, which abated with the removal of the tumor. We report an unusual presentation of AIHA with malignant sacrococcygeal germ cell tumor in a 3-year-old child, which rapidly disappeared after the excision of a sacrococcygeal teratoma.

Lymphatic filariasis is a vector borne infection classified under the WHO category of Neglected Tropical Disease (NTD). It is a major public health concern globally. This study describes this vector-borne infection in a young pregnant lady, a known case of chronic myeloid leukemia (CML) on chemotherapy. Such an association is hitherto unreported.

Acute panmyelosis with myelofibrosis (APMF) is a subtype of acute myeloid leukemia (AML) classified among the category of “AML, not otherwise specified” in the WHO 2016 classification of hematopoietic tumors. It is a rare, fatal hematological neoplasm that is characterized by acute onset of cytopenias and bone marrow fibrosis in the absence of splenomegaly or fibrosis related morphological changes in the red blood cells. The difficulty of diagnosis and management explains why APMF is rarely reported in Africa. We report here the case of a 30-year-old man who presented with dizziness, palpitations and dyspnea. Diagnosis of APMF was retained on bone marrow histology and immunohistochemistry which showed bone marrow fibrosis and high cellularity with majority of myeloid blast cells. The patient was treated by low dose cytarabine monotherapy 30 mg/m2 per week. At 3 months of treatment, the patient was transfusion-independent, with normalization of hemoglobin and platelets counts. However, the death occurred after 8 months. This case highlights the diagnosis specificity and management of AMPF, knowing the number of potential differential diagnoses and difficulties of its therapeutic management.

Immunotherapies, such as monoclonal antibody therapy and checkpoint inhibitor therapy, have shown inspiring clinical effects for the treatment of cancer. Chimeric antigen receptor T (CAR-T) cells therapy was an efficacious therapeutic approach treating hematological malignancies and encouraging results have been achieved. Three kinds of CAR-T cell therapies, Kymriah (tisagenlecleucel), Yescarta (axicabtagene ciloleucel), were approved for clinical application in 2017 and Tecartus (brexucabtagene autoleucel) was approved in 2020. Despite some progress have been made in treating multiple hematologic tumors, threats still remain for the application of CAR-T cell therapy considering its toxicities and gaps in knowledge. To further comprehend present research status and trends, the review concentrates on CAR-T technologies, applications, adverse effects and safety measures about CAR-T cell therapy in hematological neoplasms. We believe that CAR-T cell therapy will exhibit superior safety and efficacy in the future and have potential to be a mainstream therapeutic choice for the elimination of hematologic tumor.

Blood cell morphological identification on the peripheral blood and bone marrow films remains a cornerstone for the diagnosis of hematological neoplasms to be integrated with immunophenotyping, molecular genetics, and histopathology. Although standardization is still far from being achieved, with high interobserver variability, in recent years, several classification approaches, from the 1976 FAB to the 2016 WHO classification, have provided hematologists with detailed morphological descriptions for a large number of diseases. Counting blasts and detecting dysplastic specimens are two cornerstones of morphological diagnosis. This review deals with identifying difficult cells, with particular reference of those with relevant diagnostic implications.

In the era of precision medicine, liquid biopsy is becoming increasingly important in oncology. It consists in the isolation and analysis of tumor-derived biomarkers, including extracellular vesicles (EVs), in body fluids. EVs are lipid bilayer-enclosed particles, heterogeneous in size and molecular composition, released from both normal and neoplastic cells. In tumor context, EVs are valuable carriers of cancer information; in fact, their amount, phenotype and molecular cargo, including proteins, lipids, metabolites and nucleic acids, mirror nature and origin of parental cells rendering EVs appealing candidates as novel biomarkers. Translation of these new potential diagnostic tools into clinical practice could deeply revolutionize the cancer field mainly for solid tumors but for hematological neoplasms, too.

Propósito de la revisión: el objetivo de la revisión es delinear la fisiopatología de los linfomas de estirpe B. Buscamos reportes en donde se incluye la descripción del origen de los Linfomas B para una mejor comprensión de esta patología, a la luz de los avances en las diferentes áreas. Recientes hallazgos: El Grupo Euroflow ha publicado una lista de paneles de Expresión de Antígenos de Superficie en Linfoma no Hodgkin, cuya lista se presenta en este artículo. Extracto: Las neoplasias hematológicas han tenido grandes avances en los últimos años en varios campos, evolucionando desde la identificación citológica, pasando por su caracterización inmunofenotípica por medio de la Citometría de Flujo e Inmunohistoquímica y llegando a la caracterización molecular, iniciando por Técnicas de Cariotipo Convencional, continuando por técnicas de Inmunohibridación in situ y actualmente con la identificación molecular por medio de la Secuenciación de Nueva Generación. Esta es la razón por la que los sistemas de estadificación han ido evolucionando también, siendo el que está al momento en vigencia el propuesto por la Organización Mundial de la Salud en el año 2016. Los linfomas constituyen un grupo heterogéneo de neoplasias hematológicas con un amplio espectro de presentación clínica, cuyo origen se encuentra en los precursores de linfoides y que afectan a los diversos órganos linfoides. De estos, los linfomas de la línea B son los más comunes, motivo de esta revisión.

Greater than 90% of cases of systemic mastocytosis (SM) harbor pathogenic KIT mutations, particularly KITD816V. Prognostically-significant pathogenic KIT mutations also occur in 30–40% of core binding factor-associated acute myeloid leukemia (CBF-AML), but are uncommonly associated with concurrent SM. By comparison, the occurrence of SM in other myeloid neoplasms bearing pathogenic KIT mutations, particularly those with a chronic course, is poorly understood. Review of clinical next-generation sequencing (NGS) performed at our institutions in patients with known or suspected hematologic malignancies over an 8-year period revealed 64 patients with both a pathogenic KIT mutation detected at one or more timepoints and available bone marrow biopsy materials. Patients with KITD816V-mutated myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), or overlap MDS/MPN (n = 22) accounted for approximately one-third of our cohort (34%). Comprehensive morphologic and immunophenotypic characterization revealed that nearly all cases (n = 20, 91%) exhibited concurrent SM. In contrast, of the 18 patients (28%) with AML and KITD816V, only eight (44%) showed evidence of SM at any point in their disease course (p = 0.0021); of these eight, the AML component was characterized as AML with myelodysplasia-related changes (AML-MRC) in all but one instance (n = 7, 87%). Twelve patients (19%) had pathogenic KIT mutations other than p.D816V, all in the setting of AML (CFB-AML, n = 7; AML, not otherwise specified, n = 2; AML-MRC, n = 1; acute promyelocytic leukemia, n = 1); only two of these patients (17%), both with CBF-AML, exhibited concurrent SM. The remaining 12 patients (19%) had SM without evidence of an associated hematological neoplasm (AHN). For nearly one-third of the 30 SM-AHN patients in our cohort (n = 9, 30%), the SM component of their disease was not initially clinicopathologically recognized. We propose that identification of the KITD816V mutation in patients diagnosed with MDS, MPN, MDS/MPN, or AML-MRC should trigger reflex testing for SM.

Mutations in the additional sex combs like 1 (ASXL1) gene are frequently involved in clonal hematopoiesis and are connected with an increased risk of hematologic cancer. These aberrations are frequently detected in a number of different hematological neoplasms including acute myeloid leukemia (AML). Patients harboring ASXL1 mutations tend to have a poor prognosis and poor response to therapy. Here, we report the coexistence of four different mutations in ASXL1 gene in a patient with AML. Such accumulation of mutations, in this gene, has not been described yet. Our findings suggest that accumulations of mutations in ASXL1 gene may play an important role in the development and/or progression of AML.

Systemic mastocytosis (SM) is a rare clonal disorder with multi-organ involvements and shortened life expectancy. To date, no curative treatment for SM exists. Cladribine (2-CdA) is a purine analogue showing activity against neoplastic mast cells and its use was found to be effective in some patients with SM. Nine patients (six males and three females) with advanced SM at median age of 63 years (range 33–67) who received at least one course of 2-CdA were included in a retrospective analysis. Study patients were classified as having aggressive SM (ASM; n = 7) and SM with an associated hematological neoplasm (SM-AHN; n = 2). The “C” findings were as follows: (1) absolute neutrophil count (ANC) 9/l (n = 1) and/or hemoglobin level n = 4) and/or platelet count 9/l (n = 4); (2) hepatomegaly with ascites (n = 4); (3) skeletal involvement (n = 2); (4) palpable splenomegaly with hypersplenism (n = 3) and (5) malabsorption with weight loss (n = 5). Treatment consisted of 2-CdA at dose 0.14 mg/kg/day intravenously over a 2-h infusion for 5 consecutive days. Median dose per cycle was 45 mg (range 35–60). Median number of cycles was 6 (range 1–7). Overall response rate (ORR) was 66% (6/9 pts) including three partial responses and three clinical improvements. ORR was 100% and 66% for SM-AHN and ASM, respectively. Median duration of response was 1.98 years (range 0.2–11.2). At the last contact, five patients died, four have little disease activity, but remain treatment- free. 2-CdA seems to be beneficial in some patients with SM, however the response is incomplete.

Infants diagnosed with acute myeloid leukemia (AML) frequently harbor cytogenetically cryptic fusions involving KMT2A, NUP98, or GLIS2. Those with AML driven specifically by CBFA2T3::GLIS2 fusions have a dismal prognosis and are currently risk-stratified to receive hematopoietic stem cell transplantation (HSCT) in first remission. Here we report an infant with AML who was refractory to multiple lines of chemotherapy but lacked an identifiable fusion despite cytogenetic, fluorescence in situ hybridization (FISH) and targeted next generation sequencing (NGS) testing. Research-grade RNA-seq from a relapse sample revealed in-frame CBFA2T3::GLIS3 and GLIS3::CBFA2T3 fusions. A patient-derived xenograft (PDX) generated from this patient has a short latency period and represents a strategy to test novel agents that may be effective in this aggressive subtype of AML. This report describes the first case of AML with a CBFA2T3::GLIS3 fusion and highlights the need for unbiased NGS testing including RNA-seq at diagnosis, as patients with CBFA2T3::GLIS3 fusions should be considered for HSCT in first remission.

Hodgkin’s lymphoma (HL) is a hematological neoplasm generally related to a favorable prognosis, since approximately 80% of patients will be cured with actual regimen treatment. However, 10 to 30% o...

B-cell acute lymphoblastic leukemia (B-ALL) is often driven by chromosome translocations that result in recurrent and well-studied gene fusions. Currently, fluorescent in situ hybridization probes are used to detect candidate translocations in bone marrow samples from B-ALL patients. Recently Hi-C, a sequencing-based technique originally designed to reconstruct the three-dimensional architecture of the nuclear genome, was shown to effectively recognize structural variants. Here, we demonstrate that Hi-C can be used as a genome-wide assay to detect translocations and other structural variants of potential clinical interest. Structural variants were identified in both bone marrow and peripheral blood samples, including an ETV6–RUNX1 translocation present in one pediatric B-ALL patient. Our report provides proof of principle that Hi-C could be an effective strategy to globally detect driver structural variants in B-ALL peripheral blood specimens, reducing the need for invasive bone marrow biopsies and candidate-based clinical tests.

Abnormal chromatin clumping (ACC) in cells of myeloid lineage is a distinct morphological entity. It has been described mainly in polymorphs in haematological neoplasms involving myelodysplasia or myeloproliferation. We here describe a rare case of ACC in myeloblasts in an elderly man that mimicked chronic lymphocytic leukaemia. Flow cytometry played a crucial role in characterizing the myeloid lineage of the blasts, thus avoiding a misdiagnosis. To the best of our knowledge, this is the third time such a case has been reported in the literature.

Bone marrow (BM) is a highly complex tissue that provides important regulatory signals to orchestrate hematopoiesis. Resident and transient cells occupy and interact with some well characterized niches to produce molecular and cellular mechanisms that interfere with differentiation, migration, survival, and proliferation in this microenvironment. The acute myeloid leukemia (AML), the most common and severe hematological neoplasm in adults, arises and develop in the BM. The osteoblastic, vascular, and reticular niches provide surface co-receptors, soluble factors, cytokines, and chemokines that mediate important functions on hematopoietic cells and leukemic blasts. There are some evidences of how AML modify the architecture and function of these three BM niches, but it has been still unclear how essential those modifications are to maintain AML development. Basic studies and clinical trials have been suggesting that disturbing specific cells and molecules into the BM niches might be able to impair leukemia competencies. Either through niche-specific molecule inhibition alone or in combination with more traditional drugs, the bone marrow microenvironment is currently considered the potential target for new strategies to treat AML patients. This review describes the cellular and molecular constitution of the BM niches under healthy and AML conditions, presenting this anatomical compartment by a new perspective: as a prospective target for current and next generation therapies.

Systemic mastocytosis (SM) is a rare neoplasm resulting from extracutaneous infiltration of clonal mast cells (MC). The clinical features of SM are very heterogenous and treatment should be highly individualized. Up to 40% of all SM cases can be associated with another hematological neoplasm, most frequently myeloproliferative neoplasms. Here, we present a patient with indolent SM who subsequently developed a myeloid neoplasm with PDGFRA rearrangement with complete response to low-dose imatinib. The 63-year-old patient presented with eosinophilia and elevated serum tryptase level. Bone marrow analysis revealed aberrant MCs in aggregates co-expressing CD2/CD25 and KIT D816V mutation (0.01%), and the FIP1L1-PDGFRA fusion gene was not identified. In the absence of ‘B’ and ‘C’ findings, we diagnosed an indolent form of SM. For 2 years after the diagnosis, the absolute eosinophil count progressively increased. Bone marrow evaluation showed myeloid hyperplasia and the FIP1L1-PDGFRA fusion gene was detected. Thus, the diagnosis of myeloid neoplasm with PDGFRA rearrangement was established. The patient was treated with imatinib 100 mg daily and rapidly obtained a complete molecular remission. The clinical, biological, and therapeutic aspects of SM might be challenging, especially when another associated hematological disease is diagnosed. Little is known about the underlying molecular and immunological mechanisms that can promote one entity prevailing over the other one. Currently, the preferred concept of SM pathogenesis is a multimutated neoplasm in which KIT mutations represent a “phenotype modifier” toward SM. Our patient showed an evolution from KIT mutated indolent SM to a myeloid neoplasm with PDGFRA rearrangement; when the eosinophilic component expanded, a regression of the MC counterpart was observed. In conclusion, extensive clinical monitoring associated with molecular testing is essential to better define these rare diseases and consequently their prognosis and treatment.

Mastocytosis is a rare hematological neoplasm characterized by the proliferation of abnormal clonal mast cells (MCs) in different cutaneous and extracutaneous organs. Its diagnosis is based on well-defined major and minor criteria, including the pathognomonic dense infiltrate of MCs detected in bone marrow (BM), elevated serum tryptase level, abnormal MCs CD25 expression, and the identification of KIT D816V mutation. The World Health Organization (WHO) classification subdivides mastocytosis into a cutaneous form (CM) and five systemic variants (SM), namely indolent/smoldering (ISM/SSM) and advanced SM (AdvSM) including aggressive SM (ASM), SM associated to hematological neoplasms (SM-AHN), and mast cell leukemia (MCL). More than 80% of patients with SM carry a somatic point mutation of KIT at codon 816, which may be targeted by kinase inhibitors. The presence of additional somatic mutations detected by next generation sequencing analysis may impact prognosis and drive treatment strategy, which ranges from symptomatic drugs in indolent forms to kinase-inhibitors active on KIT. Allogeneic stem cell transplant (SCT) may be considered in selected SM cases. Here, we review the clinical, diagnostic, and therapeutic issues of SM, with special emphasis on the translational implications of SM genetics for a precision medicine approach in clinical practice.

Evidence regarding the effectiveness of COVID-19 vaccine in patients with impaired immunity is limited. Initial observations suggest a lower humoral response in these patients. We evaluated the relative effectiveness of the mRNA BNT162b2 vaccine in patients with hematological neoplasms compared with matched controls. Data on patients with hematological neoplasms after 2 vaccine doses were extracted and matched 1:1 with vaccinated controls. Subpopulation analyses focused on patients receiving therapy for hematological neoplasm, patients without treatment who were only followed, and recipients of specific treatments. The analysis focused on COVID-19 outcomes from days 7 through 43 after the second vaccine dose in these areas: documented COVID-19 infection by polymerase chain reaction; symptomatic infection; hospitalizations; severe COVID-19 disease; and COVID-19–related death. In a population of 4.7 million insured people, 32 516 patients with hematological neoplasms were identified, of whom 5017 were receiving therapy for an active disease. Vaccinated patients with hematological neoplasms, compared with vaccinated matched controls, had an increased risk of documented infections (relative risk [RR] 1.60, 95% CI 1.12-2.37); symptomatic COVID-19 (RR 1.72, 95% CI 1.05-2.85); COVID-19–related hospitalizations (RR 3.13, 95% CI 1.68-7.08); severe COVID-19 (RR 2.27, 95% CI 1.18-5.19); and COVID-19–related death (RR 1.66, 95% CI 0.72-4.47). Limiting the analysis to patients on hematological treatments showed a higher increased risk. This analysis shows that vaccinated patients with hematological neoplasms, in particular patients receiving treatment, suffer from COVID-19 outcomes more than vaccinated individuals with intact immune system. Ways to enhance COVID-19 immunity in this patient population, such as additional doses, should be explored.

Systemic mastocytosis is a rare hematologic disorder characterized by the clonal proliferation of mast cells in extra-cutaneous organs. This disease can be further subdivided into five different phenotypes: indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN) and mast cell leukemia (MCL). The tyrosine kinase inhibitor (and also potent KIT D816V inhibitor) avapritinib, initially approved for the treatment of gastrointestinal stromal tumors (GISTs) bearing a PDGFRA exon 18 mutation, also showed great promise in patients with systemic mastocytosis, a disease known to be driven by a mutation in KIT (D816V). We present an overview of this rare disorder, including a review of the current understanding of the genetic mechanisms which lead to the disease state, the action of the tyrosine kinase inhibitors, as well as the latest clinical trial data which led to the current recommendations for the use of avapritinib.

SARS-COV2 pandemic has caused profound challenges in health care systems worldwide. Patients affected by hematological neoplasms appear to be particularly at risk of developing COVID-19 complications, with unfavorable outcomes. Here, we present the case of a 57-years-old woman diagnosed with severe COVID-19 pneumonia and concurrent acute myeloid leukemia (AML). At the time of diagnosis, it was decided to postpone leukemia therapy to enable adequate COVID-19 pneumonia treatment. When her conditions related to pneumonia improved, the combination of Azacitidine-Venetoclax was used as first-line treatment, instead of conventional intensive chemotherapy. At the end of the first two cycles, the patient showed complete remission, and a post-remission consolidation with allogeneic hematopoietic stem cell transplantation has been planned. This case suggests that Azacytidine-Venetoclax induction may represent a valid and safe alternative to intensive chemotherapy in the challenging setting of patients with a concomitant diagnosis of AML and severe COVID-19 infection.

Megakaryocytes in circulation are rarely found in blood smear; however, several studies have reported megakaryocytes as present in the peripheral blood of patients with hematological neoplasms. Herein we report a number of cases of megakaryocytes in peripheral blood smears of patients with non-hematological diseases observed in our clinical practice.