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DUAL TARGETING OF HODGKIN'S LYMPHOMA BY ANTI-CD30 CAR-T CELLS CO-TRANSDUCED WITH AN ANTI-PDL1 COSTIMULATORY RECEPTOR TO OVERCOME THE IMMUNOSUPPRESSIVE MICROENVIRONMENT To overcome this issue, we propose (Figure 1A) to engineer T cells to coexpress 2nd-generation anti-CD30 CAR (CD28-based) and anti-PDL1 costimulatory chimeric receptor (CCR, 4.1BB-based) devoid of signaling domain. Clinical trials of CD30 CAR-T cells in relapsed/refractory ( I r i / I r i ) cHL showed inferior results compared to CD19 CAR-T cells in non-Hodgkin lymphomas. [Extracted from the article]

In particular (Figure A): (i) JAK-STAT signaling genes STAT6, SOCS1, CSF2RB and JAK2 were mutated in 85% EBV- versus 47% EBV+ cases ( I p i = 0.0057); (ii) PI3K-AKT signaling genes GNA13 and ITPKB were mutated in 34% EBV- versus 7% EBV+ cases ( I p i = 0.047); and (iii) NF- B signaling genes TNFAIP3, NFKBIE and REL were mutated in 85% EBV- versus 47% EBV+ cases ( I p i = 0.0057). Tumor and normal cells were purified from frozen samples by microdissection ( I n i = 39; 9 EBV+, 30 EBV-) or flow cytometry ( I n i = 18; 7 EBV+, 11 EBV-). EBV- cHL had also more frequent mutations of the MHC-I genes B2M and HLA-A/B/C (56% vs. 20% in EBV+ cHL, I p i = 0.0032; Figure A), possibly to prevent presentation of tumor neo-antigens generated by the much higher mutation burden. [Extracted from the article]

In the whole population of 690 patients, the tMTV threshold to categorized low and high tumor burden was 224 and 194 ml with and without sMTV, respectively. During the segmentation procedure, it has been observed that frequently spleen MTV (sMTV) heavily influenced the tMTV value, particularly in case of diffuse spleen uptake included in tMTV calculation. [Extracted from the article]

B Aim: b To assess the prognostic value of the PET metabolic response using the Deauville Score at the end of induction (EoI) therapy. In the whole population, the 5 yrs PFS (95% CI) in DS1-2, DS 3 ad DS4-5 was 74% (69-78), 55% (44-65; HR1.90 (1.36-2.66) I p i < 0.001) and 37%(26-48; HR 4.01 (2.90-5.54) I p i < 0.001); DS3 patients had an intermediate 5 yrs PFS rates between those of DS1-2 and DS4-5 patients. B Conclusion: b In FOLL12 trial, EoI-PET according DS criteria was a reliable tool to stratify PFS and OS in advanced follicular lymphoma patients treated with immunochemotherapy; in addition, these data showed DS3 patients as a new category with an intermediate prognosis in terms of PFS. [Extracted from the article]

Background: A small subset of patients with acute myeloid leukemia (AML) have cuplike nuclei. Other investigators have demonstrated that these neoplasms have distinctive clinicopathologic and molecular features.Methods: The authors searched for patients who had AML with cuplike nuclei at their institution over a 10-year interval. A strict definition for cuplike nuclei was used: >or=10% blasts with nuclear invaginations in >or=25% of the nuclear area. The relevant data were reviewed, and the results were compared with a control group of patients who had AML without cuplike nuclei.Results: In total, 22 patients who had AML with cuplike nuclei were identified and were classified as AML without maturation (French-American-British classification M1) (AML M1). Compared with the control group (AML M1), patients who had AML with cuplike nuclei were associated significantly with fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) (86% vs 38%, respectively; P = .002); nucleophosmin 1 (NPM1) mutations (86% vs 19%; P < .0001); both mutations (77% vs 14%; P < .0001); normal karyotype (86% vs 40%; P = .003); bone marrow blast count (90% vs 84%; P = .016); myeloperoxidase positivity (95% vs 30% blasts; P = .001); higher D-dimer levels (>5000 ng/mL vs 569 ng/mL; P = .001); and the absence of CD7 (91% vs 52%; P = .007), CD34 (82% vs 5%; P < .0001), and human leukocyte antigen, D-related (59% vs 10%; P = .001). There were no differences in age, sex, or peripheral blood counts. The positive predictive value of recognizing AML with cuplike nuclei for FLT3-ITD, NPM1, and both mutations was 81%, 86%, and 77%, respectively.Conclusions: Cuplike nuclei in AML were highly associated with the presence of NPM1 and FLT3-ITD mutations and with several clinicopathologic and immunophenotypic features. Recognition of the distinctive morphologic features of AML with cuplike nuclei may be helpful in streamlining the workup of these neoplasms. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) is the commonest type of lymphoid tumour world-wide. This category was included both in the REAL and WHO Classification aiming to lump together all malignant lymphomas characterized by the large size of the neoplastic cells, B-cell derivation, aggressive clinical presentation, and the need for highly effective chemotherapy regimens. These tumours are detected as primary or secondary forms both at the nodal and extranodal levels, in immunocompetent hosts as well as in patients with different types of immunosuppression. They display a significant variability in terms of cell morphology and clinical findings, which justifies the identification of variants and subtypes. Among the latter, the primary mediastinal one does actually correspond to a distinct clinicopathological entity. Immunophenotypic, tissue microarray and molecular studies underline the extreme heterogeneity of DLBCLs and suggest a subclassification of the tumour, based on the identification of different pathogenic pathways, which might have much greater relevance than pure morphology for precise prognostic previsions and adoption of ad hoc therapies. The more recent acquisitions on the pathobiology of DLBCLs are reviewed in the light of the authors' experience, aiming to contribute to the existing debate on the topic. [ABSTRACT FROM AUTHOR]

Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases Neoplasms of histiocytes and dendritic cells are rare, and their phenotypic and biological definition is incomplete. Seeking to identify antigens detectable in paraffin-embedded sections that might allow a more complete, rational immunophenotypic classification of histiocytic/dendritic cell neoplasms, the International Lymphoma Study Group (ILSG) stained 61 tumours of suspected histiocytic/dendritic cell type with a panel of 15 antibodies including those reactive with histiocytes (CD68, lysozyme (LYS)), Langerhans cells (CD1a), follicular dendritic cells (FDC: CD21, CD35) and S100 protein. This analysis revealed that 57 cases (93%) fit into four major immunophenotypic groups (one histiocytic and three dendritic cell types) utilizing six markers: CD68, LYS, CD1a, S100, CD21, and CD35. The four (7%) unclassified cases were further classifiable into the above four groups using additional morphological and ultrastructural features. The four groups then included: (i) histiocytic sarcoma (n =18) with the following phenotype: CD68 (100%), LYS (94%), CD1a (0%), S100 (33%), CD21/35 (0%). The median age was 46 years. Presentation was predominantly extranodal (72%) with high mortality (58% dead of disease (DOD)). Three had systemic involvement consistent with `malignant histiocytosis'; (ii) Langerhans cell tumour (LCT) (n =26) which expressed: CD68 (96%), LYS (42%), CD1a (100%), S100 (100%), CD21/35 (0%). There were two morphological variants: cytologically typical (n =17) designated LCT; and cytologically malignant (n =9) designated Langerhans cell sarcoma (LCS). The LCS were often not easily recognized morphologically as LC-derived, but were diagnosed based on CD1a staining. LCT and LCS differed in median age (33 versus 41 years), male:female ratio (3.7:1 versus 1:2), and death rate (31% versus 50% DOD).... [ABSTRACT FROM AUTHOR]

THE physiological role of the pro-myelocytic leukaemia (PML) gene product is poorly defined. Among other functions, PML is involved in haem atopoietic differentiation and in control of cell growth and tumorigenesis. We investigated the regulation of human PML expression by interferons (IFNs) and IL-1 in various human haematopoietic lines (U937, THP1, HL60, NB4), in human diploid fibroblasts and in human peripheral blood leukocytes. Cytokineinduced modulation of PML expression was assessed by Northern blot analyses, flow cytometry studies and in s itu immunolabelling. Our data show that IFNs and IL-1 upregulate PML transcript and protein expression in a time and dose-dependent manner. In s itu immunolabelling revealed that upregulation of protein expression by IFN- alpha is a consequence of a marked increase in both the number and the intensity of the staining of so-called PML nuclear bodies. Our data suggest that stimulation of PML expression by interferons and IL-1 may account for upregulation of PMLproteins observed in inflammatory tissues and in proliferative states. [ABSTRACT FROM AUTHOR]

Various surface molecules are expressed by activated T cells. Among them, the CD30 antigen has been proposed as a reproducible marker that identifies a subset of differentiated and/or activated T lymphocytes that produce T helper (Th)-2-type cytokines, i.e. interleukin (IL)-4 and IL-5. However, because CD30 has mainly been detected on established T-cell clones, it is still unclear whether a priming allergen and/or cytokine can induce its membrane expression on naive T cells, perhaps in parallel with the up-regulation of other relevant activation markers, such as CD25, HLA-DR and L-selectin. It is also unknown whether proper allergen stimulation affects the cytokine secretion pattern by CD30+ T-cell clones derived from antigen-unprimed (naive) T lymphocytes. More information on these questions was sought by adopting a model that used cord blood as a source of virgin T cells and exposing them to native cypress allergen or cytokine (IL-2 or IL-4) stimulation, as well as to conventional polyclonal activators such as PHA or anti-CD3. Peripheral blood MC from four adult cypress-sensitive patients was also assayed and used as controls for all culture experiments. Freshly isolated cord and adult T cells did not express the CD30 antigen on their membrane. Many of the stimulating agents tested were able to up-regulate the expression of CD30. However, despite high expression of this molecule, cloned allergen-specific cord CD4+ T lymphocytes were unable to produce IFN-γ and/or IL-4. In contrast, they retained the capability to produce IL-2. Thus, expression of the CD30 antigen on virgin T cells does not correlate with a polarized model of T helper (Th)-1 or Tb-2 cytokine-producing cells, suggesting that these types of lymphokine-secreting lymphocytes are not a paradigmatic example of T-cell subpopulations that display stable phenotypical features. [ABSTRACT FROM AUTHOR]

A new monoclonal antibody, 4KB51, is described which labels the majority of B ceils in blood and in mantle and marginal zones but not germinal centre lymphocytes or plasma cells. Antibody 4KB51 also stains monocytes, neutrophils and the majority of T cells. It recognizes an intracellular antigen of 160,000 MW (unreduced) and 68,000 MW (reduced). Antibody 4KB51 labels the turnout cells in all cases of hairy cell leukaemia and in four of the 16 cases of centrocytic B-cell lymphoma studied. No labelling of the other lymphomas (114 cases) or lymphoid leukaemias (13 cases) tested was seen. Antibody 4KB51 may be of value in defining B-cell subsets and in the differential diagnosis of hairy cell leukaemia and centrocytic lymphomas. The pattern of reactivity of 4KB51 suggests that its target antigen may play a functional role, possibly involved in lymphocyte homing. [ABSTRACT FROM AUTHOR]

A monoclonal antibody KB90 recognizing a molecule containing two polypeptide subunits of 140 and 98 kd is described. Biochemical studies following high pH dissociation of the molecule showed KB90 to bind to an epitope on the 140 kd subunit. The molecule recognized by KB90 appears to correspond to the p150/95 molecule in the family of leucocyte differentiation antigens of which the LFA-I and Mac- I molecules are members. Analysis of the immunocytochemical reactivity of KB90 shows that it stains monocytes, tissue macrophages, granulocytes and a small population of lymphocytes. These reactions are clearly distinct from those of the LFA-1 and Mac-I molecules. [ABSTRACT FROM AUTHOR]

The present paper describes a new monoclonal antibody (K 1361) raised against hairy cell leukaemia cells. Antibody K861 recognizes a molecule of approximately 40,000 molecular weight on human B cells. It reacts with B lymphocytes in the peripheral blood, in primary lymphoid follicles, in the mantle zone of secondary follicles, in interfollicular areas and in splenic marginal zone areas. However, germinal centre lymphoid cells do not express the antigen recognized by antibody KB6I. The antibody shows limited reactivity outside the lymphoid system, i.e. polymorphs, tissue macrophages endothelial cells in the hepatic sinusoids. Antibody K861 discriminates between different types of B- cell malignancies, reacting with the neoplastic cells in hairy cell leukaemia, chronic lymphocytic leukaemia (of B-cell type), prolymphocytic leukaemia and centrocytic lymphoma, but not with acute lymphoblastic leukaemia, germinal centre-derived lymphomas (other than centrocytic), Burkitt's lymphoma and lymphoblastic lymphoma. Antibody KB61 may be of value in the study of B-cell subpopulations and in the differential diagnosis of B-cell neoplasms. [ABSTRACT FROM AUTHOR]

Since the publication in 2017 of the revised 4th Edition of the World Health Organization (WHO) classification of haematolymphoid tumours, here referred to as WHO-HAEM4, significant clinicopathological, immunophenotypic and molecular advances have been made in the field of lymphomas, contributing to refining the diagnostic criteria of several diseases, upgrading entities previously defined as provisional and identifying new entities. This process has resulted in two recent classification proposals of lymphoid neoplasms: the International Consensus Classification (ICC) and the 5th edition of the WHO classification (WHO-HAEM5). In this paper, we review and compare the two classifications in terms of diagnostic criteria and entity definition, focusing on T-cell lymphomas and histiocytic/dendritic cell tumours. Moreover, we update the genetic data of the various pathological entities. The main goal is to provide a tool to facilitate the work of the pathologists, haematologists and researchers involved in the diagnosis and treatment of these haematological malignancies., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

The nucleophosmin (NPM1) gene encodes for a multifunctional chaperone protein that is localized in the nucleolus but continuously shuttles between the nucleus and cytoplasm. NPM1 mutations occur in about one-third of AML, are AML-specific, usually involve exon 12 and are frequently associated with FLT3-ITD, DNMT3A, TET2, and IDH1/2 mutations. Because of its unique molecular and clinico-pathological features, NPM1-mutated AML is regarded as a distinct leukemia entity in both the International Consensus Classification (ICC) and the 5th edition of the World Health Organization (WHO) classification of myeloid neoplasms. All NPM1 mutations generate leukemic mutants that are aberrantly exported in the cytoplasm of the leukemic cells and are relevant to the pathogenesis of the disease. Here, we focus on recently identified functions of the NPM1 mutant at chromatin level and its relevance in driving HOX/MEIS gene expression. We also discuss yet controversial issues of the ICC/WHO classifications, including the biological and clinical significance of therapy-related NPM1-mutated AML and the relevance of blasts percentage in defining NPM1-mutated AML. Finally, we address the impact of new targeted therapies in NPM1-mutated AML with focus on CAR T cells directed against NPM1/HLA neoepitopes, as well as XPO1 and menin inhibitors., (© 2023 The Author. American Journal of Hematology published by Wiley Periodicals LLC.)

Little is known of the course of COVID-19 and the antibody response to infection or vaccination in patients with hairy-cell leukaemia (HCL). Among a total of 58 HCL cases we studied in these regards, 37 unvaccinated patients, mostly enjoying a relatively long period free from anti-leukaemic treatment, developed COVID-19 between March 2020 and December 2021 with a usually favourable outcome (fatality rate: 5/37, 14%); however, active leukaemia, older age and more comorbidities were associated with a worse course. Postinfection (n = 11 cases) and postvaccination (n = 28) seroconversion consistently developed, except after recent anti-CD20 or venetoclax therapy, correlating with perivaccine B-cell count. Vaccination appeared to protect from severe COVID-19 in 11 patients with breakthrough infection., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Chimeric antigen receptor (CAR) T cells targeting CD19 represent a promising salvage immunotherapy for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), offering ~40% of long-term responses. In everyday clinical practice, haematologists involved in CAR T cell treatment of patients with R/R DLBCL have to deal with diagnostically complex cases and difficult therapeutic choices. The availability of novel immunotherapeutic agents for R/R DLBCL and recent advances in understanding CAR T-cell failure mechanisms demand a rational approach to identify the best choice for bridging therapy and managing post-CAR T-cell therapy relapses. Moreover, positron emission tomography/computerised tomography may result in false-positive interpretation, highlighting the importance of post-treatment biopsy. In this review, we discuss all above issues, presenting four instructive cases, with the aim to provide criteria and new perspectives for CAR T-cell treatment of DLBCL., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Several editions of the World Health Organization (WHO) classifications of lympho-hemopoietic neoplasms in 2001, 2008, and 2016 served as the international standard for diagnosis. Since the 4th WHO edition, here referred as WHO-HAEM4, significant clinico-pathological, immunophenotypic, and molecular advances have been made in the field of myeloid neoplasms, which have contributed to refine diagnostic criteria, to upgrade entities previously defined as provisional and to identify new entities. This process has resulted in two recent classification proposals of myeloid neoplasms: the International Consensus Classification (ICC) and the 5th edition of the WHO classification (WHO-HAEM5). In this paper, we review and compare the two classifications in terms of diagnostic criteria and entity definition, with a focus on adult myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML). The goal is to provide a tool to facilitate the work of pathologists, hematologists and researchers involved in the diagnosis and treatment of these hematological malignancies., (© 2023 Wiley Periodicals LLC.)

COVID-19, the disease caused by SARS-CoV-2, is still afflicting thousands of people across the globe. Few studies on COVID-19 in chronic lymphocytic leukemia (CLL) are available. Here, we analyzed data from the CLL cohort of the Italian Hematology Alliance on COVID-19 (NCT04352556), which included 256 CLL patients enrolled between 25 February 2020 and 1 February 2021. Median age was 70 years (range 38-94) with male preponderance (60.1%). Approximately half of patients (n = 127) had received at least one line of therapy for CLL, including 108 (83.7%) who were on active treatment at the time of COVID-19 or received their last therapy within 12 months. Most patients (230/256, 89.9%) were symptomatic at COVID-19 diagnosis and the majority required hospitalization (n = 176). Overall, after a median follow-up of 42 days (IQR 24-96), case fatality rate was 30.1%, and it was 37.5% and 24.4% in the first (25 February 2020-22 June 2020) and second wave (23 June 2020-1 February 2021), respectively (p = 0.03). At multivariate analysis, male sex (HR 1.82, 95% CI 1.03-3.24, p = 0.04), age over than 70 years (HR 2.23, 95% CI 1.23-4.05, p = 0.01), any treatment for CLL given in the last 12 months (HR 1.72, 95% CI 1.04-2.84, p = 0.04) and COVID-19 severity (severe: HR 5.66, 95% CI 2.62-12.33, p < 0.0001; critical: HR 15.99, 95% CI 6.93-36.90, p < 0.0001) were independently associated with poor survival. In summary, we report a dismal COVID-related outcome in a significant fraction of CLL patients, that can be nicely predicted by clinical parameters., (© 2022 John Wiley & Sons Ltd.)