Immunological derangement in Hypocellular Myelodysplastic Syndromes

Hypocellular or hypoplastic myelodysplastic syndromes (HMDS) are a distinct subgroup accounting for 10–15% of all MDS patients, that are characterized by the presence of bone marrow (BM) hypocellularity, various degree of dysmyelopoiesis and sometimes abnormal karyotype. Laboratory and clinical evidence suggest that HMDS share several immune-mediated pathogenic mechanisms with acquired idiopathic aplastic anemia (AA). Different immune-mediated mechanisms have been documented in the damage of marrow hematopoietic progenitors occurring in HMDS; they include oligoclonal expansion of cytotoxic T lymphocytes (CTLs), polyclonal expansion of various subtypes of T helper lymphocytes, overexpression of FAS-L and of the TNF–related apoptosis-inducing ligand (TRAIL), underexpression of Flice-like inhibitory protein long isoform (FLIPL) in marrow cells as well as higher release of Th1 cytokines, such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). It has also been documented that some HMDS patients have higher frequency of polymorphisms linked both to high production of proinflammatory cytokines such as TNF-α and transforming growth factor-β and to the inhibition of T-cell mediated immune responses such as interleukin-10, further suggesting that immune-mediated mechanisms similar to those seen in AA patients may also operate in HMDS. Clinically, the strongest evidence for immune–mediated hematopoietic suppression in some HMDS is the response to immunosuppression including mainly cyclosporine, anti-thymocyte globulin and/or cyclosporine, or alemtuzumab. Here we review all these immune mechanisms as well as the influence of this deranged cellular and humoral immunologic mileau on the initiation and possible progression of MDS. All these observations are pivotal not only for a better understanding of MDS pathophysiology, but also for their immediate clinical implications, eventually leading to the identification of MDS patients who may benefit from immunosuppression

A Case Series of Blastic Plasmacytoid Dendritic Cell Neoplasia

Blastic plasmacytoid dendritic cell neoplasm (BPDCN), an extremely rare and aggressive tumor, derives from plasmacytoid dendritic cell precursors and is characterized by CD4 and CD56 positivity accompanied by the expression of isolated myeloid, B- or T-cell lineage markers. Despite the recent introduction of specific targeted therapies, prognosis is still poor with a median overall survival of one year, and allogeneic bone marrow transplantation remains the only curative treatment in eligible patients. In this series, we described two cases of adult BPDCN treated with high dose cytarabine and methotrexate and autologous hematopoietic stem cell transplantation, or fludarabine, cytarabine, and idarubicin achieving the first a complete lasting remission, while the second only a transient improvement in skin lesion

67 kDa laminin receptor (67LR) in normal and neoplastic hematopoietic cells: is its targeting a feasible approach?

The 67 kDa laminin receptor (67LR) is a non-integrin cell surface receptor for laminin (LM) that derives from a 37 kDa precursor (37LRP). 67LR expression is increased in neoplastic cells and correlates with an enhanced invasive and metastatic potentialin many human solid tumors, recommending this receptor as a new promising target for cancer therapy. This is supported by in vivo studies showing that 67LR downregulation reduces tumour cell proliferation and tumour formation by inducing apoptosis. 67LR association with the anti-apoptotic protein PED/PEA-15 activates a signal transduction pathway, leading to cell proliferation and resistance to apoptosis. However, the main function of 67LR is to enhance tumor cell adhesion to the LM of basement membranes and cell migration, two crucial events in the metastasis cascade.Thus, inhibition of 67LR binding to LM has been proved to be a feasible approach to block metastatic cancer cell spread. Despite accumulating evidences on 67LR overexpression in hematologic malignancies, 67LR role in these diseases has not been clearly defined. Here, we review 67LR expression and function in normal and malignant hematopoietic cells, 67LR role and prognostic impact in hematological malignancies and first attempts in targeting its activity

Mean reticolocyte hemoglobin content index plays a key role to identify children who are carriers of β –thalassemia

Reticulocyte (r) and red blood cell (RBC) indices provide reliable parameters for screening and monitoring iron deficiency anemia (IDA) patients and β-thalassemia trait (BTT) carriers. The aim of this study is to identify a simple method for use to distinguish β-thalassemia trait carriers from IDA and to evaluate the correlation between BTT genetic mutation and MCV values and new discrimination index for the detection of β-thalassemia trait (DI-BTT). We analyzed CHr, MCHCr, MCVr, RBC, mean cellular hemoglobin concentration (MCHC) and mean cellular volume (MCV) indices among a pediatric population of IDA patients (n=90), βthalassemia trait carriers (n=72) and normal controls (NC) (n=131). Furthermore, to distinguish IDA patients from β-thalassemia trait carriers we evaluated clinical utility of new DI for the detection BTTcarriers, using the following polynomial: (RBC × MCHC × 50/MCV)/CHr. We found that CHr, MCVr and DI-BTT mean values were significantly different between βthalassemia trait carriers and IDA patients. CHr, MCVr and DI-BTT plotting curves showed exclusive distribution in β-thalassemia trait carriers. Moreover, DI-BTT was very accurate in differentiating β-thalassemia trait carriers from IDA patients. All BTT patients showed a heterozygous mutation of the β-globin gene including CD39, IVS1.110, IVS1.6 and IVS2.745, IVS2.1 and IVS1.1. The highest MCV values were displayed by those carrying the IVS1.6 mutation. Conclusions: The simultaneous measurement and plotting of CHr and MCVr indices, as well as the DI-BTT allow to distinguish β-thalassemia carriers from IDA patients

OPSI threat in hematological patients

Overwhelming post-splenectomy infection (OPSI) is a rare medical emergency, mainly caused by encapsulated bacteria, shortly progressing from a mild flu-like syndrome to a fulminant, potentially fatal, sepsis. The risk of OPSI is higher in children and in patients with underlying benign or malignant hematological disorders. We retrospectively assessed OPSI magnitude in a high risk cohort of 162 adult splenectomized patients with malignant (19%) and non malignant (81%) hematological diseases, over a 25-year period: 59 of them splenectomized after immunization against encapsulated bacteria, and 103, splenectomized in the previous 12-year study, receiving only life-long oral penicillin prophylaxis. The influence of splenectomy on the immune system, as well as the incidence, diagnosis, risk factors, preventive measures and management of OPSI are also outlined. OPSI occurred in 7 patients (4%) with a median age of 37 years at time interval from splenectomy ranging from 10 days to 12 years. All OPSIs occurred in non immunized patients, except one fatal Staphylococcus aureus-mediated OPSI in a patient adequately immunized before splenectomy. Our analysis further provides evidence that OPSI is a lifelong risk and that current immune prophylaxis significantly decreases OPSI development. Improvement in patients’ education about long-term risk of OPSI and increased physician awareness to face a potentially lethal medical emergency, according to the current surviving sepsis guidelines, represent mandatory strategies for preventing and managing OPSI appropriately

Case report: PIK3CA somatic mutation leading to Klippel Trenaunay Syndrome and multiple tumors

We report a case of Klippel Trenaunay Syndrome that was monitored both clinically and molecularly over a period of 9 years. A somatic mosaic mutation of PIK3CA (p(E545G)) was identified using both cfDNA NGS liquid biopsy and tissue biopsy. At the age of 56, due to intervening clonal mutations in PIK3CA background, she developed a squamous cell carcinoma in the right affected leg which was treated surgically. Nine years later, lung bilateral adenocarcinoma arose on PIK3CA mutated tissues supported by different clonal mutations. One year later, the patient died from metastases led by a new FGFR3 clone unresponsive to standard-of-care, immunotherapy-based. Our results highlight the presence of a molecular hallmark underlying neoplastic transformation that occurs upon an angiodysplastic process and support the view that PIK3CA mutated tissues must be treated as precancerous lesions. Importantly, they remark the effectiveness of combining cfDNA NGS liquid and tissue biopsies to monitor disease evolution as well as to identify aggressive clones targetable by tailored therapy, which is more efficient than conventional protocols

In vitro apoptotic effects of farnesyltransferase blockade in acute myeloid leukemia cells

Farnesyltransferase inhibitors (FTIs) are a class of oral anti-cancer drugs currently tested in phase I-II clinical trials for treatment of hematological malignancies. The in vitro effects of various FTIs (alpha-hydroxyfarnesylphosphonic acid, manumycin-A and SCH66336) were tested on CD34+ KG1a cell line and in primary acute myeloid leukemia (AML) cells from 64 patients. By cell viability and clonogeneic methylcellulose assays, FTIs showed a significant inhibitory activity in CD34+ KG1a and primary bone marrow (BM) leukemic cells from 56% of AML patients. FTIs also induced activation of caspase-3 and Fas-independent apoptosis, confirmed by the finding that inhibition of caspase-8 was not associated with the rescue of FTItreated cells. We concluded that other cellular events induced by FTIs may trigger activation of caspase-3 and subsequent apoptosis, but the expression of proapoptotic molecules, as Bcl-2 and Bcl-XL, and antiapoptotic, as Bcl-X(s), were not modified by FTIs. By contrast, expression of inducible nitric oxide synthase (iNOS) was increased in FTI-treated AML cells. Our results suggest a very complex mechanism of action of FTIs that require more studies for a better clinical use of the drugs alone or in combination in the treatment of hematological malignancies

Effective Neutralizing Antibody Response Against SARS-CoV-2 Virus and Its Omicron BA.1 Variant in Fully Vaccinated Hematological Patients

SARS-CoV-2 and its variants cause CoronaVIrus Disease 19 (COVID-19), a pandemic disease. Hematological malignancies increase susceptibility to severe COVID-19 due to immunosuppression. Anti-SARS-CoV-2 neutralizing antibodies protect against severe COVID-19. This retrospective real-life study aimed to evaluate seropositivity and neutralizing antibody rates against SARS-CoV-2 and its Omicron BA.1 variant in hematological patients. A total of 106 patients with different hematologic malignancies, who have mostly received three or more vaccine doses (73%), were included in this study. Serum was collected between May and June 2022. The primary endpoint was anti-SARS-CoV-2 antibody response against ancestral (wild type; wt) and Omicron BA.1 virus, defined as a neutralizing antibody titer ≥ 1:10. Adequate neutralizing antibody response was observed in 75 (71%) and 87 (82%) of patients for wt and Omicron BA.1 variants, respectively.However, patients with B-cell lymphoproliferative disorders and/or those treated with anti-CD20 monoclonal antibodies in the prior 12 months showed a lower seropositivity rate compared to other patients against both Omicron BA.1 variant (73% vs 91%; P = 0.02) and wt virus (64% vs 78%; P = 0.16). Our real-life experience confirmed that full vaccination against SARS-CoV-2 induces adequate neutralizing antibody protection for both the wt virus and Omicron BA.1 variants, even in hematological frail patients. However, protective measures should be maintained in hematological patients, especially those with B-cell lymphoproliferative diseases treated with anti-CD20 monoclonal antibodies, because these subjects could have a reduced neutralizing antibody production

Accelerated bone mass senescence after hematopoietic stem cell transplantation

Osteoporosis and avascular necrosis (AVN) are long-lasting and debilitating complications of hematopoietic stem cell transplantation (HSCT). We describe the magnitude of bone loss, AVN and impairment in osteogenic cell compartment following autologous (auto) and allogeneic (allo) HSCT, through the retrospective bone damage revaluation of 100 (50 auto- and 50 allo-HSCT) longterm survivors up to 15 years after transplant. Current treatment options for the management of these complications are also outlined. We found that auto- and allo-HSCT recipients show accelerated bone mineral loss and microarchitectural deterioration during the first years after transplant. Bone mass density (BMD) at the lumbar spine, but not at the femur neck, may improve in some patients after HSCT, suggesting more prolonged bone damage in cortical bone. Phalangeal BMD values remained low for even more years, suggesting persistent bone micro-architectural alterations after transplant. The incidence of AVN was higher in allo-HSCT recipients compared to autoHSCT recipients. Steroid treatment length, but not its cumulative dose was associated with a higher incidence of bone loss. Allo-HSCT recipients affected by chronic graft versus host disease seem to be at greater risk of continuous bone loss and AVN development. Reduced BMD and higher incidence of AVN was partly related to a reduced regenerating capacity of the normal marrow osteogenic cell compartment. Our results suggest that all patients after autoHSCT and allo-HSCT should be evaluated for their bone status and treated with anti-resorptive therapy as soonas abnormalities are detected