Hemato, Volume 2, Issue 2 (June 2021) – 15 articles

Our aim was to investigate the usefulness of 18fluorine-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) in the diagnosis, treatment response evaluation, and follow-up of human herpesvirus-8 (HHV-8)-associated multicentric Castleman’s disease (MCD). Fifteen patients with histologically diagnosis of HHV-8-associated MCD were retrospectively included. For all patients, a ¹⁸F-FDG PET/CT scan was performed before any treatment for diagnosis and PET/CT scans after Rituximab (4 cycles) for the evaluation of treatment response; moreover, 22 PET/CT were performed during the follow-up to check disease status. To evaluate treatment response, we applied Deauville criteria. PET/CT findings were compared with other conventional imaging (CI) findings. At diagnosis, ¹⁸F-FDG PET/CT showed an increased FDG-uptake in all cases corresponding to lymph nodes and confirming the MCD. The average SUVmax of the FDG avid lesions were 8.75, average lesion-to-liver SUVmax ratio was 3.6, and average lesion-to-blood pool SUVmax ratio was 3.9. After first-line therapy, ¹⁸F-FDG PET/CT resulted negative (Deauville score < 4) in seven patients and positive in the remaining eight (Deauville score 4–5). A negative restaging PET/CT was associated with a lower risk of relapse. During follow-up, PET/CT detected the presence of relapse or progression in 5 (23%) cases with an accuracy higher than CI. ¹⁸F-FDG PET/CT seems to be an useful tool in studying HHV-8-associated MCD both at diagnosis and during follow-up. Full article

The clinical and biological significance of programmed death-1 (PD-1) expression by B-lymphoma cells is largely unknown. Here, using multicolor immunofluorescent staining (MC-IF), we investigated PD-1 and PD-L1 expression in PAX5⁺ (B-lymphoma), CD68⁺ (macrophage), or CD3⁺ (T-cell) cells in formalin-fixed, paraffin-embedded samples of 32 consecutive patients with de novo diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus chemotherapy. PD-1- and PD-L1-expressing PAX5⁺ cells were observed in 59% and 3% of the patients, respectively. PD-1-expressing CD3⁺ lymphocytes and PD-L1-expressing CD68⁺ macrophages were observed in 89% and 86% of the patients, respectively. PD-L1 expression on PAX5⁺ lymphoma cells or CD68⁺ macrophages and PD-1 expression on CD3⁺ lymphocytes were not correlated with prognosis. However, patients with PD-1 expression on lymphoma cells showed shorter progression-free survival than those lacking PD-1-expressing lymphoma cells (p = 0.033). Furthermore, genetically modified PD-1-knockout human B-lymphoma VAL cells showed reduced cell growth and migration, and decreased S6 kinase phosphorylation than VAL/mock cells. Our data suggest that PD-1 expression on DLBCL cells detected by MC-IF was associated with poor prognosis and cell-intrinsic PD-1 signaling was related with cell growth and migration in a subpopulation of B-cell lymphoma. These findings may allow the development of distinct DLBCL subtypes affecting prognosis. Full article

Parents’ attitudes and practices may support the children’s reactions to treatments for leukaemia and their general adjustment. This study has two aims: to explore parenting depending on the child’s age and to develop and test a model on how family processes influence the psycho-social development of children with leukaemia. Patients were 118 leukemic children and their parents recruited at the Haematology–Oncologic Clinic of the Department of Paediatrics, University of Padua. All parents were Caucasian with a mean age of 37.39 years (SD = 6.03). Children’s mean age was 5.89 years (SD = 4.21). After the signature of the informed consent, the parents were interviewed using the EFI-C from which we derived Parenting dimension and three parental perceptions on the child’s factors. One year later, the clinical psychologist interviewed again parents using the Vineland Adaptive Behavior Scales (VABS). The analyses revealed the presence of a significant difference in parenting by the child’s age: Infants required a higher and more intensive parenting. The child’s coping with medical procedures at the second week after the diagnosis, controlled for parenting effect, impacted upon the child’s adaptation one-year post diagnosis. Specific intervention programmes are proposed in order to help children more at risk just after the diagnosis of developmental delays. Full article

Extranodal involvement of non-Hodgkin lymphoma (NHL) has been reported in 20–40% of patients and has been typically observed in the skin, bones, gastrointestinal tract, liver and brain. Cardiac involvement has been reported in up to 20% of autopsy cases of patients with NHL and accounts for about 2% of all cardiac malignancies. Here, we report a peculiar case of a secondary cardiac diffuse large B-cell lymphoma (DLBCL), occurring with an abrupt hemodynamic instability, characterized by a sudden ventricular tachycardia and cardiogenic shock. The patient promptly started the first cycle of chemotherapy and was admitted to the cardiac intensive care unit (CICU) of our institution to prevent potential cardiovascular complications during treatment. We applied a fractionated treatment approach, progressively reaching standard doses, to decrease the risk of early death and ensure a successful management. Full article

We report a case of a young patient suffering from very-high risk B-acute lymphoblastic leukemia (ALL) refractory to first-line therapy with early central nervous system relapse, sequentially treated with inotuzumab. At this timepoint, the patient showed persistent transfusion-refractory thrombocytopenia (platelets < 5000/uL), fever and cytomegalovirus infection. A bone marrow revaluation showed complete remission of ALL, but hemophagocytic elements and activated macrophages were present. At physical examination, the spleen was palpable. Blood chemistry showed hyperferritinemia (1419 ng/mL, normal range 24–336), NK cells suppression (11 cells/microL, minimum value 90) and IL-6 increase (119.1 pg/dL, normal values < 1.8). Triglycerides and fibrinogen were normal. A diagnosis of hemophagocytic lymphohistiocytosis (HLH) was made according to HLH-2004 criteria. The patient was treated with the IL-1 inhibitor anakinra at escalating dosage. After an initial improvement in altered HLH parameters, a clinical worsening occurred with progressing thrombocytopenia and anemia and a remarkable increase in ferritin (4066 ng/mL). The patient then underwent rituximab-based salvage treatment but died due to HLH and B-ALL progression. HLH could be a rare complication in ALL patients. Despite increasing biological knowledge, prognosis remains poor, and more efforts are needed in order to improve survival in these patients. 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

Despite recent advances in diagnosis and therapy, arterial and venous thrombosis remain a major cause of morbidity and mortality in Philadelphia-negative myeloproliferative neoplasms (MPNs). Preventing and treating arterial and venous thrombosis represent one of the major goals in MPNs. The prothrombotic phenotype of MPNs is the result of a complex interplay between several components. Neutrophils, platelets, red blood cells (RBCs) and endothelial cells assume an activated phenotype in MPNs and undergo morphologic and metabolic changes that render these cells prothrombotic. These changes are in part the result of alterations induced by MPN initiating, driving mutations as well as the effect of extrinsic factors that stem from cell interactions as well as the inflammatory environment and rheological properties that characterize MPNs. In this review, we address current management issues in MPNs and provide an update on recent understanding of the pathogenesis of thrombosis in MPNs. We also address how lessons learned from other thrombo-inflammatory conditions can further inform and improve management of thrombosis in MPNs. Based on the above data and recent discoveries and developments, we discuss potential novel targets and therapeutic approaches to tackle the challenge of thrombosis in MPNs. Full article

Diffuse large B-cell lymphomas (DLBCL)s, the most common type of Non-Hodgkin’s Lymphoma, constitute a heterogeneous group of disorders including different disease sites, strikingly diverse molecular features and a profound variability in the clinical behavior. Molecular studies and clinical trials have partially revealed the underlying causes for this variability and have made possible the recognition of some molecular variants susceptible of specific therapeutic approaches. The main histogenetic groups include the germinal center, activated B cells, thymic B cells and terminally differentiated B cells, a basic scheme where the large majority of DLBCL cases can be ascribed. The nodal/extranodal origin, specific mutational changes and microenvironment peculiarities provide additional layers of complexity. Here, we summarize the status of the knowledge and make some specific proposals for addressing the future development of targeted therapy for DLBC cases. 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

Myeloproliferative neoplasms are a common cause of splanchnic vein thrombosis, which causes significant morbidity and mortality. Indefinite anticoagulation is the mainstay of therapy, and vitamin K antagonists (VKAs) are routinely used since hematologists have the most experience with this drug class. The role of direct oral anticoagulants (DOACs) is promising, but still undergoing evaluation. Cytoreduction with hydroxyurea or pegylated interferon is often used when cytosis is present, but their roles are yet to be defined when the complete blood count is normal. Janus kinase (JAK) inhibition may have a complementary role in reducing splenomegaly and portal hypertension. Full article

Chronic myeloid leukemia (CML) is a myeloproliferative disorder that is caused by the formation of a fusion onco-protein, BCR-ABL. Since BCR-ABL plays a role in the progression of CML, the most common treatments of CML are tyrosine kinase inhibitors (TKIs) that specifically target BCR-ABL. However, resistance to TKIs is a major problem in CML treatment. A promising target in overcoming drug resistance in other cancers is the thioredoxin (TRX) system, an antioxidant system that maintains cellular redox homeostasis. The TRX system is upregulated in many cancers and this is associated with a poor prognosis. Analysis of a patient database showed that the expression of the TRX system was upregulated in CML patients compared to healthy donors. Our experiments revealed a significant link between the TRX and BCR-ABL systems since inhibition of BCR-ABL with chemical inhibitors and siRNA resulted in a decrease in the activity and expression of the TRX system in CML cells. This is notable as it shows that the TRX system may be a viable target in the treatment of CML. Full article

Myelodysplastic syndromes (MDS) encompass a variety of myeloid neoplasms characterized by ineffective hematopoiesis. The interaction of abnormal clonal hematopoiesis and changes in the bone marrow microenvironment propagate abnormal clones. Advances in next generation sequencing has identified over 100 somatic mutations, but despite deepened understanding of the genetics of MDS, therapeutic discoveries have remained limited. To date, only five drugs have been approved for MDS: Azacitidine, Decitabine, Lenalidomide, Luspatercept, and oral Decitabine with Cedazuridine. Current strategies for low-risk MDS continue to focus on symptomatic management and correction of cytopenias, while treatment for high-risk MDS focuses on delaying progression of disease and improving survival. In this review we discuss some of the challenges in developing pre-clinical models of MDS in which to test therapeutics, the advances that have been made, and promising novel therapeutics in the pipeline. Full article

Donor lymphocyte infusion (DLI) has the potential to significantly deepen the response after allogeneic stem cell transplantation (ASCT) in multiple myeloma (MM). Subsequently, DLI offers the opportunity for long-term progression-free and, most importantly, overall survival for patients with MM. DLI application is a complex procedure, whereby many factors need to be considered (e.g., patient-oriented factors prior to application, disease-specific factors, as well as possible combinations with further therapies during and after DLI). There are two settings in which DLI can be given, they are as follows: as a salvage option in progressive disease or in the prophylactic setting for MM patients with resolved disease to further deepen the response. While the first studies used DLI in the salvage setting, results for prophylactic DLI appear to be associated with better and prolonged outcomes. Furthermore, DLI (both prophylactic and salvage) given earlier after ASCT (3–6 months) appear to be associated with better outcomes. The incorporation of novel agents showed similar responses and survival after DLI. However, updated and larger evaluations are urgently needed to determine the specific role of multiple variables in such a complex treatment environment of ASCT in an ever-evolving field of MM. This review underlines the rationale for DLI after ASCT, results in the salvage and prophylactic settings, patterns of disease progression after DLI, as well as avenues to further enhance the graft-versus-myeloma effect exerted by DLI. Full article

Tumor-associated macrophages (TAMs) of the immune microenvironment play an important role in the Diffuse Large B-cell Lymphoma (DLBCL) pathogenesis. This research aimed to characterize the expression of macrophage colony-stimulating factor 1 receptor (CSF1R) at the gene and protein level in correlation with survival. First, the immunohistochemical expression of CSF1R was analyzed in a series of 198 cases from Tokai University Hospital and two patterns of histological expression were found, a TAMs, and a diffuse B-lymphocytes pattern. The clinicopathological correlations showed that the CSF1R + TAMs pattern associated with a poor progression-free survival of the patients, disease progression, higher MYC proto-oncogene expression, lower MDM2 expression, BCL2 translocation, and a MYD88 L265P mutation. Conversely, a diffuse CSF1R + B-cells pattern was associated with a favorable progression-free survival. Second, the histological expression of CSF1R was also correlated with 10 CSF1R-related markers including CSF1, STAT3, NFKB1, Ki67, MYC, PD-L1, TNFAIP8, IKAROS, CD163, and CD68. CSF1R moderately correlated with STAT3, TNFAIP8, CD68, and CD163 in the cases with the CSF1R + TAMs pattern. In addition, machine learning modeling predicted the CSF1R immunohistochemical expression with high accuracy using regression, generalized linear, an artificial intelligence neural network (multilayer perceptron), and support vector machine (SVM) analyses. Finally, a multilayer perceptron analysis predicted the genes associated with the CSF1R gene expression using the GEO GSE10846 DLBCL series of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP), with correlation to the whole set of 20,683 genes as well as with an immuno-oncology cancer panel of 1790 genes. In addition, CSF1R positively correlated with SIRPA and inversely with CD47. In conclusion, the CSF1R histological pattern correlated with the progression-free survival of the patients of the Tokai series, and predictive analytics is a feasible strategy in DLBCL. Full article

Myeloma tumor cells are particularly dependent on their microenvironment and sensitive to cellular antitumor immune response, including natural killer (NK) cells. These later are essential innate lymphocytes implicated in the control of viral infections and cancers. Their cytotoxic activity is regulated by a balance between activating and inhibitory signals resulting from the complex interaction of surface receptors and their respective ligands. Myeloma disease evolution is associated with a progressive alteration of NK cell number, phenotype and cytotoxic functions. We review here the different therapeutic approaches that could restore or enhance NK cell functions in multiple myeloma. First, conventional treatments (immunomodulatory drugs-IMids and proteasome inhibitors) can enhance NK killing of tumor cells by modulating the expression of NK receptors and their corresponding ligands on NK and myeloma cells, respectively. Because of their ability to kill by antibody-dependent cell cytotoxicity, NK cells are important effectors involved in the efficacy of anti-myeloma monoclonal antibodies targeting the tumor antigens CD38, CS1 or BCMA. These complementary mechanisms support the more recent therapeutic combination of IMids or proteasome inhibitors to monoclonal antibodies. We finally discuss the ongoing development of new NK cell-based immunotherapies, such as ex vivo expanded killer cell immunoglobulin-like receptors (KIR)-mismatched NK cells, chimeric antigen receptors (CAR)-NK cells, check point and KIR inhibitors. Full article