A Cross-Sectional, Multicentric, Disease-Specific, Health-Related Quality of Life Study in Greek Transfusion Dependent Thalassemia Patients.

The assessment of health-related quality of life (HRQoL) in thalassemia offers a holistic approach to the disease and facilitates better communication between physicians and patients. This study aimed to evaluate the HRQoL of transfusion-dependent thalassemia (TDT) patients in Greece. This was a multicentric, cross-sectional study conducted in 2017 involving 283 adult TDT patients. All participants completed a set of two QoL questionnaires, the generic SF-36v2 and the disease-specific TranQol. Demographic and clinical characteristics were used to predefine patient subgroups. Significant factors identified in the univariate analysis were entered into a multivariate analysis to assess their effect on HRQoL. The SF-36 scores of TDT patients were consistently lower compared to the general population in Greece. The mean summary score of TranQol was relatively high (71 ± 14%), exceeding levels observed in national surveys in other countries. Employment emerged as the most significant independent factor associated with better HRQoL, whereas age had the most significant negative effect. This study represents the first comprehensive QoL assessment of a representative sample of the TDT population in Greece. The implementation of TranQol allowed for the quantification of HRQoL in Greece, establishing a baseline for future follow-up, and identifying more vulnerable patient subgroups.

Real-world complication burden and disease management paradigms in transfusion-related ß-thalassaemia in Greece: Results from ULYSSES, an epidemiological, multicentre, retrospective cross-sectional study.

Patients with transfusion-dependent beta (ß)-thalassaemia experience a broad range of complications. ULYSSES, an epidemiological, multicentre, retrospective cross-sectional study, aimed to assess the prevalence and severity of treatment and disease complications, capture disease management and identify predictors of complications in patients with transfusion-dependent ß-thalassaemia, treated in routine settings in Greece. Eligible patients were adults diagnosed with ß-thalassaemia ≥12 months before enrolment and having received ≥6 red blood cell (RBC) units (excluding elective surgery) with no transfusion-free period ≥35 days in the 24 weeks before enrolment. Primary data were collected at a single visit and through chart review. Between Oct 21, 2019, and Jun 15, 2020, 201 eligible patients [median (interquartile range, IQR) age 45.7 (40.2-50.5) years; 75.6% > 40 years old; 64.2% female] were enrolled, a mean (standard deviation) of 42.9 (7.8) years after diagnosis. Median (IQR) age at diagnosis and RBC transfusion initiation were 0.8 (0.4-2.8) and 1.3 (1.0-5.0) years, respectively. From diagnosis to enrolment, patients had developed a median of six (range: 1-55) complications; 19.6% were grade ≥3. The most represented complications were endocrine/metabolic/nutrition disorders (91.5%), surgical/medical procedures (67.7%) and blood/lymphatic system disorders (64.7%). Real-world data generated by ULYSSES underscore the substantial complication burden of transfusion-dependent ß-thalassaemia patients, routinely managed in Greece.

Concomitant Presence of Hb Agrinio and - -Med Deletion in a Greek Male Patient with Hemoglobinopathy H: More Severe Phenotype and Literature Review.

Hemoglobin (Hb) Agrinio is a rare non-deletional a-globin mutation observed almost exclusively in Greek, Spanish or other Mediterranean families. The clinical manifestations of a carrier of a single Hb Agrinio mutation (single heterozygosity) depend on the concomitant presence or absence of other mutations or variants in the beta, alpha or other modifying genes. We present a Greek patient harboring a Hb Agrinio variant plus the - -Med alpha deletional allele, having an infrequent severe form of alpha thalassemia, in contrast to the typical alpha thalassemic patient and requiring regular red blood cell (RBC) transfusions and chelation treatment. We also provide a concise literature review regarding alpha thalassemic hemoglobin variants and their molecular and clinical combinations. A phase 2, double-blind, randomized, placebo-controlled, multicenter clinical trial to determine the efficacy and safety of luspatercept (BMS-986346/ACE-536) for the treatment of anemia in adults with alpha thalassemia with the participation of our center is currently recruiting patients (NCT05664737).

Clinical significance of mutational variants in beta and alpha genes in patients with hemoglobinopathies from two large Greek centers: a complex interplay between genotype and phenotype.

Hemoglobinopathies affect patients in the wider Mediterranean area consisting of 4 distinct subgroups: beta thalassemia major (TM), beta thalassemia intermedia (TI), sickle cell disease (SCD) and hemoglobin H disease (alpha thalassemia). The clinical spectrum varies from mild to severe. Complex interactions between genes and environmental factors form the clinical manifestations. There is an unmet need to clarify these multifactorial mechanisms. This is the first Greek study describing mutational alleles (HBB and HBA1/HBA2 gene variants) in 217 patients with hemoglobinopathies of two large centers in Greece (Larissa and Athens) and associating particular genotypes or gene variants with clinical manifestations (transfusion frequency, complications). Thus, the complex interplay between corresponding genotypes and phenotypes was investigated. Our results are in accordance with previous national studies with limited variations, due to regional prevalence of specific gene variants, as expected. It is also a description of the prevalence of hemoglobinopathies in the Greek population. The type and prevalence of beta and alpha globin gene variants differ significantly among countries. We also confirm the well-known observation of many studies that in our beta thalassemic or SCD patients, co-inheritance of variants in the alpha globin genes, leading to absence or reduction of alpha globin synthesis were associated with milder clinical course, whereas the inheritance of additional alpha genes (triplication) led to a more severe clinical phenotype. In cases in whom the genotype and phenotype did not correlate, factors like the function or modification of possible regulatory genes or additional nutritional-environmental effects should be investigated. KEY MESSAGES: • This is the first Greek study, fully molecularly defining the beta and alpha mutational alleles in 217 patients with hemoglobinopathies of two large centers in Greece and correlating particular genotypes or gene variants with clinical manifestations (transfusion frequency, complications). • In the beta thalassemic or SCD patients of our cohort, co-inheritance of variants in the alpha globin genes, leading to absence or reduction of alpha globin synthesis were associated with milder clinical course (confirmation of a well-known previous observation). • The inheritance of additional alpha genes (triplication) led to a more severe clinical phenotype (confirmation of a well known previous observation). • The function or modification of possible regulatory genes should be investigated in cases in whom the genotype and phenotype did not correlate.

Exploring the current molecular landscape and management of multiple myeloma patients with the t(11;14) translocation.

Multiple myeloma (MM) is a genetically complex disease. The key myeloma-initiating genetic events are hyperdiploidy and translocations involving the immunoglobulin heavy chain (IgH) enhancer on chromosome 14, which leads to the activation of oncogenes (e.g., CCND1, CCND3, MAF, and MMSET). The t(11;14) translocation is the most common in MM (15%-20%) and results in cyclin D1 (CCND1) upregulation, which leads to kinase activation and tumor cell proliferation. Notably, t(11;14) occurs at a higher rate in patients with plasma cell leukemia (40%) and light chain amyloidosis (50%). Patients with myeloma who harbor the t(11;14) translocation have high levels of the anti-apoptotic protein B-cell lymphoma 2 (BCL2). Multiple studies demonstrated that the presence of t(11;14) was predictive of BCL2 dependency, suggesting that BCL2 could be a target in this subtype of myeloma. Venetoclax, an oral BCL2 inhibitor, has shown remarkable activity in treating relapsed/refractory MM patients with t(11;14) and BCL2 overexpression, either as monotherapy or in combination with other anti-myeloma agents. In this review, we describe the molecular defects associated with the t(11;14), bring into question the standard cytogenetic risk of myeloma patients harboring t(11;14), summarize current efficacy and safety data of targeted venetoclax-based therapies, and discuss the future of individualized or precision medicine for this unique myeloma subgroup, which will guide optimal treatment.

Hemophagocytic lymphohistiocytosis diagnosed by bone marrow trephine biopsy in living post-COVID-19 patients: case report and mini-review.

Hemophagocytic lymphohistiocytosis (HLH) constitutes a life-threatening inflammatory syndrome. Postmortem histological findings of bone marrow (BM) from COVID-19 patients showed histiocytosis and hemophagocytosis and supported the hypothesis that secondary HLH (sHLH) may be triggered by SARS-CoV-2 infection. However, there are a limited number of sHLH cases in which trephine has been performed in living post-COVID-19 patients. Here we present a recent case and a mini-review of sHLH diagnosed by trephine biopsy in living patients after COVID-19. An 81-year-old man with a past medical history of hypertension, diabetes, ischemic stroke, was referred to the hospital to evaluate leukocytosis, pyuria, and elevation of inflammatory markers four weeks after recovering from COVID-19. Computed tomography of the abdomen did not reveal focal signs of infection or hepatosplenomegaly. The patient received intravenous meropenem and two packed red blood cell units. Leukocytes and C-reactive protein were gradually decreased. A BM biopsy was performed and the patient was discharged on cefixime. BM smear revealed severe anemia, lymphopenia, and dysplastic morphologic findings of erythroblasts, neutrophils, and megakaryocytes. Trephine biopsy revealed hypercellular marrow dyserythropoiesis, plasmacytosis, lymphocytosis, histiocytosis, hemophagocytosis, and the absence of granulomas or carcinoma. Immunohistochemistry documented a mixed population of T lymphocytes (CD3+) and B lymphocytes (CD20+). Strong positivity for CD68 confirmed histiocytosis. CD138 κ, λ staining proved polyclonal plasmacytosis. Perl's staining showed excess hemosiderin deposits. Based on our findings, we document sHLH in trephine BM biopsy of a living post-COVID-19 patient and persistent leukocytosis, underscoring the diagnostic value of trephine biopsy in preventing life-threatening conditions such as COVID-19.

Primary gastric non-Hodgkin lymphomas: Recent advances regarding disease pathogenesis and treatment.

Primary gastric lymphomas (PGLs) are distinct lymphoproliferative neoplasms described as heterogeneous entities clinically and molecularly. Their main histological types are diffuse large B-cell lymphoma (DLBCL) or mucosa-associated lymphoma tissue. PGL has been one of the main fields of clinical research of our group in recent years. Although gastric DLBCLs are frequent, sufficient data to guide optimal care are scarce. Until today, a multidisciplinary approach has been applied, including chemotherapy, surgery, radiotherapy or a combination of these treatments. In this minireview article, we provide an overview of the clinical manifestations, diagnosis and staging of these diseases, along with their molecular pathogenesis and the most important related clinical published series. We then discuss the scientific gaps, perils and pitfalls that exist regarding the aforementioned studies, in parallel with the unmet need for future research and comment on the proper methodology for such retrospective studies. Aiming to fill this gap, we retrospectively evaluated the trends in clinical presentation, management and outcome among 165 patients with DLBCL PGL who were seen in our institutions in 1980-2014. The study cohort was divided into two subgroups, comparing the main 2 therapeutic options [cyclophosphamide doxorubicin vincristine prednisone (CHOP) vs rituximab-CHOP (R-CHOP)]. A better outcome with immunochemotherapy (R-CHOP) was observed. In the next 2 mo, we will present the update of our study with the same basic conclusion.

Total Annual Economic Burden of Patients with Sickle Cell Disease in Steady State in Greece.

Sickle cell disease includes a group of congenital hemolytic anemias, all characterized by the predominance of Hb S (HBB: c.20A>T). The population movement due to economic migration or escape from conflict zones will further affect the health systems of countries by either increasing the number of patients or forcing countries to create care units for sickle cell disease patients. This will probably also increase the incidence of the disease in areas where their incidence and prevalence were previously low. In the present study, an attempt has been made to estimate the total annual cost of the treatment of sickle cell disease in Greece. This was the first attempt to calculate the total annual cost of treating sickle cell disease patients in a steady state. The annual cost of sickle cell disease was estimated to be €21,152,340.00 (US$25,219,300.41), without calculating the cost of hospitalization for severe complications. Since 2013, in Greece, a pharmaceutical expenditure limit (decreasing with the years) has been budgeted at €1,945,000,000.00 (US$2,318,965,150.00), annually. It is therefore calculated that approximately 1.0% of the budget allocated to pharmaceutical spending is used to treat patients with sickle cell disease.

Hemophagocytic Lymphohistiocytosis as a Manifestation of Underlying Visceral Leishmaniasis.

Hemophagocytic lymphohistiocytosis (HLH), or hemophagocytic syndrome (HS) is a severe syndrome involving an extreme participation of the immune system, resulting in a cascade of cytokines, hyperinflammation and extensive hemophagocytosis in the bone marrow (BM) and affecting the peripheral blood (PB) lineages. Fever, splenomegaly, hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia are often encountered in this disease. The syndrome can be seen in all ages and it is either primary due to genetic defects or secondary because of malignancies, immune deficiencies, rheumatic diseases, and infections. Bacteria, viruses, protozoa, and fungi are often implicated. Visceral leishmaniasis (VL) is among the infectious causes of HLH. We describe a patient with a successful treatment of HLH after the initiation of liposomal amphotericin B, due to VL, even though there was a delay in diagnosing the leishmaniasis. The exact precipitating pathophysiological events triggering HLH remain unknown and provide their clear impact for future research. An instructive, critical review of the literature related to the presented case is provided. Distinguishing secondary HS from primary HS is essential for the application of suitable treatment. Improper use of corticosteroids could cover up an underlying possible malignancy or infection and delay the initiation of the etiologic therapeutic strategy.

Massive bone marrow necrosis revealing an HIV-related primary bone marrow lymphoma: a diagnostic challenge.

Bone marrow necrosis (BMN) is a condition that can be difficult to diagnose, requiring a hematologist experienced in bone marrow morphology. This diagnostic challenge should alert the clinician of a severe disease or a possible underlying malignancy, either hematological or a solid tumor. We describe the concomitant presence of a primary bone marrow lymphoma (diffuse large B-cell lymphoma-DLBCL), along with an extensive BMN in an HIV patient for the first time in a living individual. HIV infection, BMN and DLBCL presented a multifactorial crossword of molecular events underlying the complex pathophysiology. The exact precipitating pathophysiological events resulting in BMN remain obscure and provide their clear impact for future research. The present report is instructive and also contains a critical review of the literature related to the case presented.

National registry of hemoglobinopathies in Greece: updated demographics, current trends in affected births, and causes of mortality.

National registries constitute an invaluable source of information and contribute to the improvement of hemoglobinopathy management. Herein, we present the second updated report of the National Registry for Haemoglobinopathies in Greece (NRHG) and critically discuss the time trends in demographics, affected births, and causes of mortality. Thirty-eight Greek hemoglobinopathy units reported data from diagnosis to the last follow-up or death by retrospectively completing an electronic form. Four thousand thirty-two patients were eligible for inclusion; more than half of them had thalassaemia major. Compared to the previous report, a reduction in the total number of all hemoglobinopathies except for hemoglobinopathy "Η" was evident. The total number of affected births was also reduced; most of them were attributable to diagnostic errors and lack of awareness. Importantly, data on iron overload are reported for the first time; although most patients had low or moderate liver iron concentration (LIC) values, a non-negligible proportion of patients had high LIC. The burden due to heart iron overload was less prominent. Cardiac- and liver-related complications are the major causes of morbidity and mortality. From 2000 to 2015, a decrease in heart-related deaths along with an increase in liver-associated fatalities was observed. The Hellenic Prevention Program along with advances in chelation regimens and iron status monitoring have resulted in improved patient outcomes. The NRHG gives insight into the effectiveness of prevention programs, the therapeutic management of hemoglobinopathies and associated outcomes. NRHG may contribute to the formulation of a roadmap for hemoglobinopathies in Europe and promote the implementation of effective public health policies.

Balloon pulmonary angioplasty is a promising option in thalassemic patients with inoperable chronic thromboembolic pulmonary hypertension.

Pulmonary hypertension (PH), a serious disorder with a high morbidity and mortality rate, is known to occur in a number of unrelated systemic diseases. ß-Thalassaemia, among other haematological disorders, develop PH which is not an infrequent finding and worsens the prognosis. Haemolysis, iron overload and hypercoagulable state are among the main pathogenetic mechanisms. Haemoglobinopathies and congenital haemolytic anaemia constitute a unique patients population more predisposed to developing chronic thromboembolic pulmonary hypertension (CTEPH). Although pulmonary endarterectomy is accepted as the best treatment for CTEPH, surgery in these patients poses significant practical challenges given the distinct nature of the disease. As drug therapy is not expected to offer relief from the mechanical obstructions of pulmonary arteries and the use of specific pulmonary arterial hypertension drugs is not established in thalassaemia patients, the novel technique of balloon pulmonary angioplasty (BPA) may emerge as a new therapeutic option for patients with inoperable CTEPH and thalassaemia. We are reporting the case of a thalassaemic patient with a history of splenectomy suffering from progressive severe pulmonary hypertension related to chronic thromboembolic disease, who was successfully treated by BPA with substantial improvement.

Iron chelation therapy of transfusion-dependent ß-thalassemia during pregnancy in the era of novel drugs: is deferasirox toxic?

The life expectancy of thalassemic patients has increased, and now approaches that of healthy individuals, thanks to improved treatment regimens. However, pregnancy in women with ß-Thalassemia Μajor remains a challenging condition. Recent advances in managing this haemoglobinopathy offer the potential for safe pregnancies with favorable outcome. However, clinical data regarding the use of chelation therapy during pregnancy are limited, and it is unclear whether these agents impose any risk to the developing fetus. Successful pregnancies following unintentional treatment with deferoxamine or deferasirox have rarely been reported. Generally, chelators are not recommended during pregnancy. Regarding the new oral chelators, data on fetotoxicity are lacking. In the present study, we describe the evolution and successful outcome of nine pregnancies in six Greek thalassemic women who received deferasirox inadvertently during early pregnancy, and review the literature regarding fetal anomalies due to chelators. Use of chelation before embarking upon a non-programmed pregnancy remains a difficult and unresolved question. In our study, chelation treatment during pregnancy did not prevent the delivery of healthy children. Nonetheless, the use of deferasirox is contraindicated in pregnant women, based on the product label. Deferasirox should only be used during pregnancy if the potential benefit outweighs the potential fetal risk.

Concurrent presentation of nodal myeloid sarcoma and bone marrow chronic lymphocytic leukemia/small lymphocytic lymphoma: a unique association.

Myeloid sarcoma (MS), previously known as granulocytic sarcoma, is a rare, localized, tumor mass composed of myeloid precursor cells, with or without maturation, and occurring at an anatomical site other than the bone marrow (BM). Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), in contrast, is a B-cell hematological malignancy. We describe the first reported case of concurrent presentation of nodal MS and of BM CLL/SLL in the same patient. Fatal leukemic central nervous system infiltration was the final outcome. We provide possible explanations and investigate the pathophysiology of this unique, previously unreported co-morbidity.

The role of Helicobacter pylori infection in hematological disorders.

Helicobacter pylori (H. pylori) is a Gram-negative spiral bacterium, classified as a carcinogen of class I, according to the World Health Organization (WHO). The infection is a major cause of gastritis, gastric and duodenal ulcer disease and increases the risk of gastric cancer. It has been implicated in the pathogenesis of several gastrointestinal, systemic or hematological diseases. The present review aims in deciphering the role of the bacterium in hematological disorders, increasing the awareness of gastroenterologists, hematologists and internal medicine practitioners, regarding the bacterium-associated hematological diseases. The efficacy of H. pylori eradication in increasing the platelet count in adult patients with primary immune thrombocytopenia (ITP) has been confirmed, linking the infection with the disease. Moreover, as the bacterium causes iron deficiency anemia (IDA) by several mechanisms, recent guidelines indicate H. pylori infection (Hp-I) to be sought in IDA patients if histology is negative and to be eradicated if present. Furthermore, it has been widely recognized that anti-H. pylori treatment causes regression of the low-grade B-cell gastric MALT lymphomas. Despite the well established associations of Hp-I with the aforementioned hematological disorders, we highlight the possible role of the infection to other hematological diseases or conditions such as non-Hodgkin lymphomas of the stomach, monoclonal gammopathy of undetermined significance, megaloblastic anemia and myelodysplastic syndromes. We finally underline the elevated risk of childhood leukemia and of hemorrhage in patients with coagulation disorders, due to the infection.