Hemato doi: 10.3390/hemato7020011

Authors: Muhammad Aminu Idris Lucia Ruggieri Hafsat Rufai Ahmad Abdulaziz Hassan Ismaila Nda Ibrahim Jamil Abdullahi Faruk Niyi Mustapha Adebiyi Sani Awwalu Nasiru Usman Rabiu Wada Musa Muhammad Saidu Abdulkadir Fedele Bonifazi Wale Atoyebi Baba Psalm Duniya Inusa

Background: Sickle cell disease (SCD) patients have increased susceptibility to infections, particularly encapsulated bacterial pathogens such as Streptococcus pneumoniae and Haemophilus influenzae type b. Hyposplenism as well as immune defects in SCD result in increased risks for infections; these are the most frequent complications in individuals with SCD. This study was performed within the African Research and Innovative initiative for Sickle cell Education (ARISE, EC GA No 824021) project to develop best practices in the clinical management of SCD. In this retrospective study we aimed to determine the most prevalent reported infections among SCD patients’ records during clinic visits at Ahmadu Bello University Teaching Hospital, Zaria, Nigeria. Methods: The medical records of 1961 paediatric SCD patients from 1998 to 2023 were extracted and reviewed from a pilot electronic registry using a structural query. The data analysed patterns of infections reported during clinic visits at the ABUTH, Zaria, Nigeria. Results: 458 subjects (23.4%) manifesting at least one infection, of whom 392 (19.9%) subjects had a single infection (bacterial or parasitic) and 173 (8.8%) had more than one infection (bacterial and parasitic). Conclusions: Bacterial and parasitic infections are a significant complication of SCD patients attending a tertiary institution in northern Nigeria.

Hemato doi: 10.3390/hemato7020010

Authors: Annamaria Porreca Stefania Proietti Fabrizio Maturo Stefano Bonassi Ezio Zanon

Background: The co-existence of hemophilia and cancer presents one of the most complex clinical scenarios, demanding individualised therapeutic planning to balance oncologic efficacy and hemostatic safety. This study evaluated the ability of two Large Language Models (LLMs)—ChatGPT (GPT-4) and Microsoft Copilot (GPT-4–based)—to generate clinically appropriate recommendations for real cases of hemophilia with concurrent malignancy. Methods: Six consecutive adult cases of hemophilia and cancer, managed at the Hemophilia Centre of Padua, Italy, were selected for evaluation. Identical structured prompts were submitted to both LLMs. Two independent expert clinicians rated the model outputs across five domains (Decision/Rationale, Strategy, Selected Drug, Regimen, and Assessment) using a four-level ordinal scale. Results: LLMs demonstrated uneven performances. Outputs were consistently rated as highly reliable in domains involving high-level synthesis, such as Assessment and Strategy. However, substantial limitations were observed in the clinically demanding domains of Selected Drug and Regimen. Critically, in the Selected Drug domain, there was complete agreement between the two expert raters for neither system. This severe lack of concordance signifies that clinicians assigned different adequacy ratings to the same output in every case, reflecting ambiguity, lack of specificity, and inconsistent clinical interpretability of the drug-related information provided by LLMs. Conclusions: While LLMs possess the capacity for high-level reasoning and strategic planning, their inability to translate principles into precise, consistent, and clinically interpretable therapeutic plans—particularly regarding drug selection and treatment regimens—is a significant constraint. These deficiencies, highlighted by the minimal expert concordance in critical domains, necessitate rigorous clinical validation before the responsible integration of LLMs into the management of this uniquely vulnerable patient population.

Hemato doi: 10.3390/hemato7020009

Authors: Floriane Lanneretonne Lisa Boureau Marina Migeon Claudine Chollet Mélanie Martin Gourier Diane Lara Chloé Benard Gabriel Etienne Wendy Cuccuini Laurie Monier Julien Ecart François Lifermann Jean-Baptiste Gaillard Nathalie Nadal David Rizzo Julie Quessada Pascale Cornillet-Lefebvre Emilie Klein Estibaliz Lazaro Audrey Bidet

Myeloid/lymphoid neoplasms with tyrosine kinase rearrangements (MLN-TKs) are rare clonal eosinophilias driven by PDGFRA, PDGFRB and other kinase fusions, highly sensitive to tyrosine kinase inhibitors. Their detection remains challenging, particularly for cryptic PDGFRA rearrangements. We performed a large multicenter real-world validation of the generic quantitative RT-PCR assay (gPDGFR), which detects 3′ PDGFRA/PDGFRB overexpression independently of fusion partner. A total of 231 consecutive patients with hypereosinophilia from 12 French centers were analyzed, and assay robustness was further assessed in an independent heterogeneous cohort of 102 tyrosine kinase inhibitor (TKI)-treated patients. Twenty-two PDGFR-rearranged cases (14 PDGFRA-r, 8 PDGFRB-r) were identified. The assay demonstrated 100% sensitivity and 100% negative predictive value. For PDGFRA, positive predictive value and specificity reached 100%. In contrast, PDGFRB overexpression showed lower specificity due to borderline false-positive cases, underscoring the need for confirmatory testing. In selected patients, longitudinal gPDGFR kinetics paralleled fusion-specific RT-qPCR, supporting its use for molecular follow-up when dedicated assays are unavailable, although it does not provide quantitative measurable residual disease assessment. Overall, gPDGFR represents a robust, partner-independent first-line screening strategy that can be readily integrated into routine diagnostic workflows to enable timely identification of patients eligible for targeted therapy.

Hemato doi: 10.3390/hemato7010008

Authors: Johannes Bloehdorn Maria Siepen Martin Bommer

Angioimmunoblastic T-cell lymphoma (AITL) is a rare subtype of peripheral T-cell lymphoma (PTCL) and is frequently associated with autoimmune phenomena. Clinically, AITL shows an aggressive disease course and poor prognosis with currently available treatment strategies. We here report the case of a 64-year-old female patient who was diagnosed with AITL and showed a complicated clinical course due to concurrent immune-mediated thrombotic thrombocytopenic purpura (iTTP). To our knowledge, the presented case highlights a previously unreported association of both conditions. Treatment, including chemotherapy and iTTP-directed treatments, resulted in rapid clinical improvement and sustained remission of both the AITL and the concurrent iTTP. In AITL, transformed T-follicular helper cells (TFHs) are particularly thought to mediate hypersecretion of cytokines and excessive autoantibody production. Immunological disturbances to large parts mediated through these transformed TFHs are thought to trigger autoimmune conditions, as seen with iTTP in this patient. At 36 months post-treatment, the patient remains in complete remission for both AITL and iTTP. This case highlights the complex immunopathological relationship between AITL and autoimmune disorders possibly impeding diagnosis and treatment in a timely manner.

Hemato doi: 10.3390/hemato7010007

Authors: Musilimat H. Faleye Hadiza Lawal Olukemi Ajamufua Niyi M. Adebiyi Jamilu A. Faruk Zainab M. Hassan Hafsat R. Ahmad

Background: Sickle cell disease (SCD) is a hereditary blood disorder marked by the production of abnormally shaped, rigid red blood cells that obstruct blood flow, resulting in pain, organ damage, and increased infection risk. SCD poses a significant public health challenge in Nigeria, which has the highest global burden, with about 150,000 affected children born annually. The high prevalence is exacerbated by limited healthcare infrastructure, low public awareness, and socio-economic barriers, making effective disease management difficult. Understanding the knowledge of home-based caregivers is essential to identify gaps that may impact care quality. This study was performed within the African Research and Innovative Initiative for Sickle Cell Education (ARISE, EC GA No 824021) project to develop best practice in the clinical management of SCD. Aim: This study explores the knowledge, experiences, and educational needs of home-based caregivers of children with SCD attending the Paediatric Haematology Clinic, ABUTH, Zaria. Methods: A qualitative case study design was used, involving in-depth interviews with ten purposively selected caregivers. Interviews were conducted in Hausa, transcribed, and translated into English. Thematic analysis was performed. Results: Four themes emerged: 1. Understanding of SCD aetiology 2. Knowledge of symptoms 3. Awareness of complications and 4. Knowledge of SCD type. Conclusions: Home-based caregivers had limited knowledge of the genetic basis of the disease, but possess some knowledge of SCD key symptoms, enabling basic disease management and healthcare seeking. However, there is a need to enhance caregiver education to improve care quality and health-seeking behaviour for children with SCD.

Hemato doi: 10.3390/hemato7010006

Authors: Halime Tozak Yıldız Saim Özdamar

Objective: This study aimed to investigate erythrocyte morphological alterations in hematological malignancies, with particular emphasis on structural differences among leukemia subtypes and anemia. Materials and Methods: Peripheral blood samples were obtained from 60 patients, including individuals with anemia (n = 10), acute lymphoblastic leukemia (ALL, n = 15), acute myeloid leukemia (AML, n = 15), chronic lymphocytic leukemia (CLL, n = 15), and chronic myeloid leukemia (CML, n = 5), as well as 10 healthy controls. Erythrocyte morphology was evaluated using light microscopy and scanning electron microscopy. Morphological abnormalities, including loss of biconcavity, poikilocytosis, echinocyte transformation, burr cells, and stomatocytes, were assessed in accordance with International Council for Standardization in Haematology (ICSH)-based morphological definitions. Results: Distinct erythrocyte morphological alterations were observed across disease groups. AML cases demonstrated pronounced central depression-like or perforation-like structures and hypochromasia. Lymphoid malignancies, particularly ALL and CLL, exhibited increased echinocyte formation, whereas chronic leukemias showed a higher prevalence of stomatocytes and cup-shaped cells. Quantitative scoring indicated that loss of biconcavity was most prominent in anemia, followed by AML, CML, ALL, and CLL. Poikilocytosis was most frequent in anemia, followed by ALL, CLL, AML, and CML. Conclusions: The findings indicate that erythrocyte shape alterations are more heterogeneous and prominent in lymphoid leukemias, whereas myeloid leukemias exhibit distinct ultrastructural membrane abnormalities. Although studies focusing on erythrocyte morphology in leukemia remain limited, the present results provide a foundational morphological reference dataset that may support the development and validation of artificial intelligence-based diagnostic approaches. Further studies involving larger cohorts and expanded imaging analyses are warranted to improve diagnostic accuracy and translational applicability.

Hemato doi: 10.3390/hemato7010005

Authors: María José Robledo Rivera Adriana Margarita Trejos Tenorio José Ortega Ramírez Gustavo Ariel Fridenberg Manuel Sureda González

Marginal zone lymphomas (MZLs) are indolent mature B-cell neoplasms. Approximately 3.4% of gastrointestinal mucosa-associated lymphoid tissue (MALT) lymphomas involve the small bowel. Pseudoaneurysmal dilation has been reported in up to 35% of patients with small bowel MALT lymphoma. We report the case of a 73-year-old woman with ulcerative colitis in remission who presented with hematuria, constitutional symptoms, and progressive respiratory distress. Imaging incidentally revealed pseudoaneurysmal dilation of the small bowel and thoracic findings suggestive of pulmonary lymphangitic dissemination. A PET scan showed lung, nodal, and small bowel infiltration. Histopathological and flow cytometry examinations confirmed small bowel MZL, and bone marrow biopsy excluded marrow involvement. The patient was treated with R-CHOP chemotherapy and then R-Bendamustine, achieving complete clinical and radiological remission. This case illustrates a rare presentation of intestinal MALT lymphoma and emphasizes the diagnostic significance of correlating imaging and clinical findings in identifying pseudoaneurysmal dilatation and distinguishing it from other potential causes.

Hemato doi: 10.3390/hemato7010004

Authors: Palma Manduzio Luigi Ciccone Valeria Cosima Elisena Cardo Antonietta Faleo Antonietta Ferrara Lucia Simone Libera Padovano Tommaso Granato

Background: Feto-maternal hemorrhages (FMHs) due to placenta disruption and bleeding from fetal maternal circulation can lead to life-threatening fetal anemia. These hemorrhages are more often of small volume and remain unreported. Sensitization to fetal red blood cell (RBC) antigens can occur during pregnancy, at delivery, or after invasive procedures. The sensitized mother produces IgG antibodies (abs) that cross the placenta and cause the hemolysis of fetal RBCs, release of hemoglobin, and increased levels of unconjugated bilirubin in the fetus or neonate. The result is hemolytic disease of the fetus and newborn (HDFN). Methods: In this study, we aim to provide a structured overview of RBC alloimmunization in pregnancy. A literature search was conducted using PubMed. English articles published from January 2010 to October 2025 were selected by the authors. The contributing manuscripts focused on managing RBC alloimmunization in pregnancy, FMH screening and quantification, antenatal and postnatal testing, Rh immune globulin (Rh Ig or Anti-D) prophylaxis, and national registry data. Results: Frequencies of RBC abs vary among American, Caucasian, and Asian populations because of genetic diversity, different antibody detection and antibody identification methods, and FMH tests. More specifically, the erythrocyte rosette is a simple screening test for FMH. A positive rosette must be quantified by the Kleihauer–Betke (KB) or flow cytometry (FC). The KB results may be overestimated or underestimated. The advantages of FC include high accuracy, specificity, and repeatability. Ultimately, anti-D prophylaxis protocol varies from country to country. Conclusion: Maternal alloimmunization is an uncommon and highly variable event. Although introducing anti-D prophylaxis has decreased the Rh immunization rate, it is still an unmet medical need. In brief, mitigation strategies for RBC alloimmunization risk include accurate maternal and neonatal testing at different time points, adequate Rh immune globulin prophylaxis in D-negative pregnant women, preventing sensitizing events, adopting a conservative transfusion policy, and upfront ABO and Rh (C/c, E/e) and Kell matching in females under 50 years of age.

Hemato doi: 10.3390/hemato7010003

Authors: Hernycane Sosilya Muhammad Noor Diansyah Merlyna Savitri Putu Niken Ayu Amrita Pradana Zaky Romadhon Hermina Novida Nadya Luthfah Ami Ashariati Siprianus Ugroseno Yudho Bintoro

Background/Objectives: Tyrosine kinase inhibitors (TKIs) have transformed the treatment of chronic myeloid leukemia (CML), yet emerging evidence indicates an increased risk of vascular adverse events, particularly peripheral artery disease (PAD). Reliable biomarkers for early detection of TKI-related vascular toxicity are still lacking. Methods: A cross-sectional study was conducted on 78 patients with chronic-phase CML treated at Dr. Soetomo General Hospital, Surabaya. PAD was confirmed using ankle–brachial index. Serum oxidized low-density lipoprotein (OxLDL) and interleukin-10 (IL-10) levels were measured using ELISA. Results: PAD was detected in 20% of subjects. The PAD group showed significantly higher OxLDL, lower IL-10, and a markedly elevated OxLDL/IL-10 ratio (all p < 0.001). OxLDL remained independently associated with PAD after adjustment (adjusted OR = 1.132, 95% CI 1.020–1.255, p = 0.019). OxLDL/IL-10 ratio yielded a good diagnostic value (sensitivity 87.5% and specificity of 88.7%). Conclusions: Elevated OxLDL and an increased OxLDL/IL-10 ratio are associated with PAD in CML patients receiving TKI therapy and demonstrated a good diagnostic performance for early detection of TKI-induced vascular toxicity.

Hemato doi: 10.3390/hemato7010002

Authors: Sung-Nan Pei Caleb Gon-Shen Chen Hsiao-Wen Kao Huey-En Tzeng Ming-Lih Huang Chih-Cheng Chen Jasmine Hsiang-Wei Wang Lennex Hsueh-Lin Yu Hsin-An Hou

Introduction: Ropeginterferon alfa-2b is an emerging treatment for polycythemia vera, with growing interest in its application for essential thrombocythemia and early myelofibrosis due to its extended dosing intervals and favorable tolerability profile. However, real-world evidence regarding its dosing strategies and titration practices remains limited. Objective: This study examined seven younger patients, all under 60 years of age, who were treated with ropeginterferon alfa-2b. Materials and Methods: This study is a retrospective medical records review of consecutive patients from seven hospitals. Treatment was initiated at a dose of 250 micrograms, with a maintenance dose of 500 micrograms. Results: The regimen demonstrated good safety and tolerability in this real-world setting. Hematological responses were observed, along with a meaningful reduction in JAK2V617F variant allele frequency across the patient cohort. Conclusions: These findings show that the use of high-initial-dose accelerated titration (HIDAT) regimen of ropeginterferon alfa-2b is a safe and effective treatment option for younger patients with myeloproliferative neoplasms.

Hemato doi: 10.3390/hemato7010001

Authors: Pilar Palomo-Moraleda Sara Alonso-Álvarez Lucía Morais-Bras Christian Sordo-Bahamonde Rocío Granda-Díaz Joud Zanabili-Al-Sibai Sofía García-Ferreiro Marco Moro-García Estefanía Pérez-López Marco Hernández-Martín Ana J. González-Huerta Soledad González-Muñiz Ángel Ramírez-Payer J. María García-Gala Ariana Fonseca-Mourelle Segundo González Ana P. González-Rodríguez

Background: The emergence of therapy-related myelodysplastic syndrome (t-MN) after autologous stem cell transplantation (ASCT) is well documented. However, with the growing use of chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory B-cell malignancies, concerns about secondary myeloid neoplasms, particularly MN, have arisen. The mechanisms and cytogenetic features associated with post-CAR-T MN, especially chromosome 7 abnormalities, remain underexplored. Objectives: To compare the incidence, timing, and cytogenetic characteristics of MN developing after CAR-T-cell therapy versus ASCT, and to evaluate the potential association between CAR-T therapy, persistent cytopenias, and these specific alterations. Study Design: This was a retrospective, single-center study of 275 patients with B-cell malignancies treated between 2015 and 2024 at Hospital Universitario Central de Asturias (Spain). Of these, 259 patients underwent ASCT and 16 received CAR-T-cell therapy (axicabtageneciloleucel n = 13, tisagenlecleucel n = 2, brexucabtageneautoleucel n = 1). Clinical, cytogenetic, and laboratory data were collected and analyzed. Incidence rates were compared using Fisher’s exact test, and time-to-event outcomes was evaluated using the Mann–Whitney U test (given the small number of events). Statistical significance was set at p < 0.05. Results: Myeloid neoplasms were diagnosed in 3 of 259 ASCT patients (1.15%) and in 2 of 16 CAR-T-cell patients (12.5%) (p = 0.03). The median time to myeloid neoplasm diagnosis was numerically shorter in the CAR-T group (15.5 vs. 69 months, p = 0.096). All post-CAR-T cases presented persistent cytopenias and cytokine release syndrome (CRS). Cytogenetic analyses revealed de novo monosomy 7 and 7q deletion in both CAR-T-related cases, whereas no chromosome 7 abnormalities were detected in ASCT-related cases. Pre-treatment samples did not show these abnormalities, although limitations in the sensitivity of the assays preclude the definitive exclusion of minor pre-existing clones. Both affected CAR-T patients had prolonged CAR-T cell persistence and required transfusional support due to hematologic toxicity. One patient was diagnosed with high-risk MN with 5q and 7q deletion and the other with Clonal Cytopenia of Uncertain Significance (CCUS) with monosomy 7. Conclusions: CAR-T-cell therapy was associated with a significantly higher and earlier incidence of myeloid neoplasms compared to ASCT in this cohort. The development of post-CAR-T myeloid neoplasm was characterized by persistent cytopenias, prolonged CAR-T cell persistence, and de novo chromosome 7 alterations. While the small sample size necessitates cautious interpretation, these findings may suggest a distinct pathogenesis potentially linked to inflammation, immune toxicity, or the expansion of pre-existing clones. This highlights the need for long-term hematologic monitoring and evaluation for clonal hematopoiesis prior to CAR-T-cell therapy, especially in heavily pretreated patients.

Hemato doi: 10.3390/hemato6040044

Authors: María Martínez Miguel Ángel Muñoz Camila Riquelme Paulina Weisser Claudia Soto-Escobar Belén Larrañaga Bernabé Rivas Sebastián Alarcón

Background/Objectives: Understanding blood group antigen distribution is essential for transfusion safety and preventing alloimmunization in transfused patients. The ABO, RH1, and Kell blood group systems are among the most clinically significant due to their high immunogenic potential and their role in hemolytic transfusion reactions and hemolytic disease of the newborn. Despite their clinical significance, data on the phenotypic frequency of these samples in southern Chile are limited. This study aimed to identify the distribution of ABO, RH1, and Kell blood group systems among blood donors at the Centro de Sangre Concepción, adding regional data to the national transfusion medicine records. Methods: A retrospective, descriptive analysis was conducted using data from 59,318 blood donations collected in 2024 by the Concepción Blood Center, part of the Southern Transfusion Medicine Macronetwork in Chile. Blood typing for the ABO, RH1, and Kell antigen (KEL1) typing was performed in accordance with national regulations established by the Ministry of Health (MINSAL). Results: Blood group O was the most frequent (61.3%), followed by A (27.8%), B (9.0%), and AB (1.9%). RH1 positivity was observed in 94.47% of donors, and Kell positivity in 4.24%. The distribution of Kell phenotypes was comparable between men (4.38%) and women (4.11%), with the highest frequency in donors aged 27–52 years. Conclusions: The phenotypic distribution observed reflects national patterns and shows the genetic makeup of southern Chile. The low but important prevalence of Kell-positive donors emphasizes the need for systematic Kell antigen screening to prevent alloimmunization and improve transfusion safety.

Hemato doi: 10.3390/hemato6040043

Authors: Valeriia Tsekhovska Pietro Cimatti Bianca Allegra Govoni Lynnette Kyokunda Pier Paolo Piccaluga

Background: Malignant lymphomas are among the most common hematological neoplasms and include a heterogeneous group of entities characterized by distinct morphology, immunophenotype, genetics, and clinical features. Recent advances in molecular diagnostics have significantly improved our understanding of the genetic lesions and mechanisms underlying lymphomagenesis. Methods: This review summarizes key developments in molecular pathology relevant to B-cell lymphomas, including updates from the World Health Organization classification and recent progress in genomic, immunophenotypic, and clinical assessment. We highlight findings from next-generation sequencing studies and other molecular approaches used in routine and research settings. Results: Many molecular alterations are now routinely incorporated into diagnostic criteria and influence risk stratification, prognosis, and treatment selection. Although not all lesions are evaluated in everyday clinical practice, several changes have demonstrated prognostic significance and therapeutic relevance. Molecular subclassification has refined our ability to predict clinical behavior and response to targeted therapies. Conclusions: Advances in molecular diagnostics continue to reshape the clinical approach to lymphomas. Improved classification, better identification of therapeutic targets, and more accurate prognostic tools collectively enhance personalized treatment strategies. As a result, molecular tools increasingly guide clinical decision-making and contribute to improved outcomes in patients with B-cell lymphomas.

Hemato doi: 10.3390/hemato6040042

Authors: Monica Dugăeşescu Iulia Andrei-Bitere Marina-Raluca Baciu Eva Dănescu Alexandru Liţescu Simina-Teodora Vidroiu Andrei Manu Maria Magdalena Constantin Ioana Roșca Smaranda Stoleru Elena Poenaru

Background/Objectives: Complete blood count (CBC)-derived markers such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) have gained increasing attention as accessible indicators of systemic inflammation. These parameters, calculated from routine blood tests, are widely available in clinical settings and are potentially relevant for a variety of chronic diseases. This review aims to explore current evidence and highlight potential future directions regarding the use of hematologic inflammatory biomarkers in chronic disease. Methods: We performed an extensive literature search on PubMed to identify full-text original studies published in the past five years, focused on investigating the clinical applications of hematologic inflammatory markers in chronic conditions. Results: CBC-derived inflammatory markers have been studied in a wide range of chronic diseases, including autoimmune diseases, metabolic disorders, chronic kidney disease, chronic infections, psychiatric diseases, and other conditions. These markers have been evaluated for multiple clinical purposes, such as aiding diagnosis, monitoring disease status, assessing disease activity, disease subtype characterization, predicting prognosis, and evaluating associations with disease outcomes. Conclusions: As chronic diseases affect millions of individuals globally, placing a burden for the healthcare system, patients, and their families, simple and cost-efficient tools like CBC-derived inflammatory markers have the potential to improve clinical case management.

Hemato doi: 10.3390/hemato6040041

Authors: Bonaventure G. Ikediashi Tatiana Baglo-Agbodande Bernice Quenum Gisela Michel

Introduction: Disease knowledge and health literacy are important health competencies that individuals with chronic conditions like Sickle Cell Disease (SCD) need for self-management. This study aimed to: (I) describe and compare SCD knowledge and health literacy levels in adolescents and young adults (AYAs) with SCD in Benin; (II) examine associations between genotype, socio-demographic factors, health literacy, and SCD knowledge; and (III) examine the associations between patients SCD knowledge, health literacy, socio-demographic factors, and (a) frequency of hospitalisations and (b) frequency of occurrence of painful episodes. Methods: AYAs aged 14 to 25 years with SCD attending routine consultations at two Benin clinics—the National Sickle Cell Disease Centre (CPMI-NFED) and the Haematology clinic of the University Teaching Hospital (CUMAS), completed a questionnaire assessing SCD knowledge and health literacy (Health Literacy Measure for Adolescents, HELMA). Results: Most participants had inadequate health literacy: 72.1% at CPMI-NFED and 82.1% at CUMAS, with no significant differences between centres (t = 1.642, p = 0.200). CPMI-NFED participants had higher SCD knowledge than those at CUMAS (t = 4.303, p = 0.038). Higher SCD knowledge (β = 0.466; p < 0.001) and health literacy (β = 5.081; p < 0.001) were associated with older age. Tertiary-level education was associated with higher health literacy (β = 4.286; p = 0.023). Participants with high SCD knowledge experienced fewer painful episodes (IRR = 0.777, p = 0.046), but no significant differences in hospital admissions (IRR = 0.764, p = 0.162). Conclusions: Inadequate health literacy is common in AYAs with SCD in Benin. Having high SCD knowledge may have an impact on the occurrence of painful episodes.

Hemato doi: 10.3390/hemato6040040

Authors: Yana Gvozdeva Petya Georgieva Plamen Katsarov

Imatinib (IMT) is a small-molecule tyrosine kinase inhibitor that primarily targets platelet-derived growth factor receptor-β and related kinases. Beyond its established efficacy in chronic myeloid leukemia, IMT has also demonstrated therapeutic benefits in gastrointestinal stromal tumors, dermatofibrosarcoma, acute lymphoblastic leukemia, and as a second-line treatment for aggressive systemic mastocytosis or as an anti-Mycobacterium agent. From a physicochemical perspective, IMT exhibits poor aqueous solubility but high membrane permeability, classifying it as a Biopharmaceutics Classification System Class II compound. Pharmacokinetically, IMT shows variable oral absorption and a prolonged terminal half-life, resulting in dose-dependent systemic exposure. Despite relatively high oral bioavailability, its clinical use requires large doses to achieve therapeutic efficacy, underscoring the need for advanced drug delivery strategies. Nano- and microscale delivery systems offer promising approaches to enhance tumor-specific accumulation through the enhanced permeability and retention effect while mitigating resistance mechanisms. However, achieving high drug loading introduces formulation challenges, such as controlling particle size distribution, polydispersity, and scalability. Moreover, designing carriers capable of controlled release without premature leakage remains crucial for maintaining systemic bioavailability and therapeutic performance. Emerging delivery platforms—including polymeric, lipid-based, carbon-derived, and stimuli-responsive nanocarriers—have shown significant potential in overcoming these limitations. Such systems can enhance IMT’s bioavailability, improve selective tumor targeting, and minimize systemic toxicity, thereby advancing its translational potential. This review aims to highlight the different biomedical applications of IMT and off-label uses, and to discuss current advances in drug delivery to optimize its clinical efficacy and safety profile.

Hemato doi: 10.3390/hemato6040039

Authors: Pieter Sonneveld

This article represents a brief overview of the recent achievements in the treatment of multiple myeloma. New opportunities and treatment challenges are discussed in the context of risk factors regarding outcomes. The options for specific targeted treatments are discussed, and references are made to recent guidelines on the diagnosis and treatment of multiple myeloma.

Hemato doi: 10.3390/hemato6040038

Authors: Valentina De Santis Sabrina Mariani Giulia Pileggi Federica Lubrano Lobianco Esmeralda Conte Gianluca Maiorana Chiara Togni Monica Piedimonte Arianna Di Napoli Severino Persechino Evelina Rogges Agostino Tafuri

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy, typically presenting with systemic symptoms and mediastinal involvement. Leukemia cutis (LC) and renal infiltration are rare, especially at disease onset. A 27-year-old man presented with a solitary scalp lesion without systemic symptoms or hematologic abnormalities. Histopathology revealed a blastoid lymphoid infiltrate with a T-ALL immunophenotype. Two weeks later, laboratory tests showed leukocytosis, lymphocytosis, and renal dysfunction. Imaging revealed a large mediastinal mass, scalp soft tissue involvement, and bilateral renal infiltration. Bone marrow biopsy confirmed T-ALL with a mature phenotype. FISH identified TRAD:NKX2 rearrangement and CDKN2AB deletion. The patient received three cycles of pediatric-inspired chemotherapy, achieving complete molecular remission and resolution of extramedullary disease. He subsequently underwent allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-matched sibling. Post-transplant complications included febrile neutropenia and mucositis. On day +100, he remained in minimal residual disease (MRD)-negative remission. This case illustrates a rare presentation of T-ALL with isolated skin involvement and renal infiltration at diagnosis, highlighting the importance of early biopsy and immunophenotyping of atypical skin lesions. Intensive chemotherapy followed by HSCT represents a viable strategy for young adults with high-risk T-ALL and extramedullary disease.

Hemato doi: 10.3390/hemato6040037

Authors: Nikhil Vojjala Raj N. Shah Lakshmi Kattamuri Nagaishwarya Moka Geetha Krishnamoorthy Vijendra Singh

Introduction: Sickle cell anemia (SCA) is a hereditary hemoglobinopathy caused by a mutation in the beta-globin gene, resulting in the production of hemoglobin S. Intracranial hemorrhage (ICH) is a severe complication for patients with SCA, but there is a paucity of literature on its epidemiology, risk factors, and clinical outcomes. To address this knowledge gap, we conducted a comprehensive analysis using the Nationwide Inpatient Sample (NIS) database to evaluate the epidemiology, prevalence, predictors, and clinical outcomes of ICH in adults with SCA. Methods: We conducted a retrospective cohort study using the NIS database from 2016 to 2020 to identify hospitalizations with SCA, using the ICD-10-CM (International Classification of Diseases, Tenth Revision, Clinical Modification) codes. Subsequently, we derived the prevalence and predictors of ICH in SCA adults. Results: Out of 468,070 admissions of adult hospitalizations (Aged ≥ 18 years) with SCA between 2016 and 2020 in the United States, 825 (0.17%) had ICH (nontraumatic intraparenchymal and/or subarachnoid bleeding). 410 (49.7%) were males, and 380 (46.0%) belonged to the age group of more than 45 years. The mean length of stay was 14.9 days, and 210 deaths occurred during the index hospitalization, resulting in a 25.4% inpatient mortality rate as compared to 0.6% in SCA-non-ICH patients (p < 0.001). Across all adult SCA hospitalizations during 2016–2020 (n = 468,070), ICH accounted for 210 of 2940 inpatient SCA deaths (7.1%). On multivariate logistic regression analysis, hypertension (OR:2.08, 95% CI: 1.2–3.3), prior history of ischemic stroke (OR: 17.06, 95% CI: 7.5–38.5), and a Charlson comorbidity index of more than one (OR: 2.9, 95% CI: 2.4–3.5) are significant predictors of ICH in adults with SCA. Conclusions: This study highlights the high prevalence of ICH in addition to the well-known thrombotic phenomenon among SCA patients. Stroke prevention and hypertension control are of paramount importance for the prevention of this catastrophic event in patients with SCA.

Hemato doi: 10.3390/hemato6040036

Authors: Domenico Dell’Edera Brunilde Persia Francesco La Rocca Carmela Centoducati

Background: Haemoglobinopathies are among the most common monogenic disorders worldwide. Early identification of asymptomatic carriers through reliable screening and molecular diagnostics is crucial for prevention programmes, especially in high-prevalence regions such as Southern Italy. Methods: A total of 5243 individuals were analysed between 2013 and 2024 using both biochemical and genetic parameters. First-level screening included full blood count, iron status, and high-performance liquid chromatography (HPLC) for haemoglobin variant quantification. Molecular analyses were performed using next-generation sequencing (NGS) for the HBA1, HBA2, and HBB genes. Results: We identified 267 individuals (11.2%) as carriers of α-thalassaemia and 473 individuals (16.7%) as carriers of β-thalassaemia. Among them, 5 were compound heterozygotes and 3 homozygous for the α-3.7 deletion. A rare case of HbG Philadelphia in association with a triplicated α-gene was also observed. The most common β-globin mutations included c.118C>T (β039, 44%), IVS-I-110 (17.7%), IVS-I-6 (12.7%), and IVS-I-1 (12.3%). Among α-globin mutations, the most prevalent were -α3.7 (48%), α2 IVS1 -5nt (15.4%), -20.5 Kb (14.2%), and triplicated α (11%). In total, 18.7% of individuals were found to carry either α- or β-thalassaemia traits. Conclusion: Our findings highlight the limitations of traditional diagnostic methods—such as the osmotic fragility test—and the importance of integrating haematological, biochemical, and molecular data to accurately identify thalassaemia carriers. The variability of genotype–phenotype correlations, especially in the context of immigration and genetic diversity, underscores the need for comprehensive molecular analysis. We propose a three-step diagnostic algorithm combining first-level screening, iron status assessment, and NGS-based sequencing for inconclusive cases.

Hemato doi: 10.3390/hemato6040035

Authors: Hanane Ait Hammou Najwa Elhidar Mourad Ouhammou Wafa Sansar Samira Fazzani Touria El Dhimni Mohamed Sif Essalam

Background/Objectives: Erythrocyte alloimmunization is a critical complication impacting the efficacy of transfusion therapy in patients with thalassemia. This study seeks to evaluate the prevalence, characterization, and determinants of erythrocyte alloimmunization in multi-transfused thalassemia patients in south of Morocco. Methods: A retrospective study was conducted at the Moroccan Blood and Blood Derivatives Agency in Marrakech (Morocco) over 2 years, from June 2022 to June 2024, including 89 patients with beta-thalassemia receiving regular transfusions. The clinical, demographic, and transfusion characteristics of patients who developed alloimmunization were compared with those of non-alloimmunized patients. Results: Analysis of 89 β-thalassemia patients in the Marrakech region, mostly young and suffering from major form (67%), shows a significant male predominance (p = 0.004) and a high frequency of blood group O+ (49.4%). Alloimmunization mainly affects major forms and males and is associated with frequent annual transfusions (over 12 per year), usually resulting in the use of 24 to 60 packed red blood cell units annually. Alloimmunized patients mostly present anti-K and anti-E antibodies, indicating the involvement of the Kell and Rh systems. The direct Coombs test was more often positive in these patients (21.4% vs. 7.9%, p < 0.01). Conclusions: The high prevalence of alloimmunization in thalassemia patients in the Marrakech region highlights the need for a rigorous and personalized transfusion strategy, including molecular genotyping and alternative therapies.

Hemato doi: 10.3390/hemato6030034

Authors: Ugo Testa Elvira Pelosi Germana Castelli

Complete or partial deletions of chromosome 7 (-7/del7q) represent the most frequent chromosomal abnormalities observed in myeloid neoplasms (MNs) and are associated with a poor prognosis. -7/del7q is observed in 10–15% of adult patients with myelodysplasia (MDS) or with acute myeloid leukemia (AML). The occurrence of -7/del7q is particularly frequent in pediatric MDS, often associated with germline mutations of GATA2 or SAMD9/SAMD9L genes. The disease biology of -7/del7q and the genes driving leukemic development have not been completely elucidated, but the haploinsufficiency of tumor suppressor genes located in chromosome 7 deleted regions seems to play a relevant role. The response to standard treatments based either on chemotherapy or hypomethylating agents plus Venetoclax is limited. No approved targeted therapies exist for patients with -7/del7q; however, some recent studies have discovered some vulnerabilities of these myeloid neoplasms than can be efficiently targeted.

Hemato doi: 10.3390/hemato6030033

Authors: Seungjun Kim Kiwon Lee

Runt-related transcription factor 1 (RUNX1) is a key transcription factor in hematopoiesis, producing multiple major isoforms, RUNX1A, B, and C, via alternative promoter usage and splicing. These isoforms have distinct roles in hematopoiesis and leukemogenesis. Imbalances in isoform expression, such as RUNX1A overexpression or RUNX1C loss, contribute to leukemogenesis in disorders. RUNX1 isoform expression is regulated by transcriptional, epigenetic, and splicing mechanisms and is further influenced by genome architecture. Pathogenic variants, including truncations and fusion proteins, disrupt isoform homeostasis and transcriptional control for the target genes in hematopoiesis. Recent therapeutic strategies aim to restore isoform balance rather than inhibit RUNX1 globally. Approaches include splice-switching oligonucleotides, CRISPR-based promoter modulation, and enhancer-targeted therapies. Understanding isoform-specific RUNX1 biology offers new opportunities for precision treatment of hematologic malignancies.

Hemato doi: 10.3390/hemato6030032

Authors: Christian Ramos Peñafiel Álvaro Cabrera García Adolfo Martínez Tovar Daniela Pérez Sámano Isle Mendez Lomeli Ernesto Villagrán Carpintero Irma Olarte Carrillo Sayuri Midori Vargas Peña Adán Germán Gallardo Rodríguez

Background/Objectives: Adult acute lymphoblastic leukemia (ALL) often has poor outcomes, especially after relapse or treatment failure. Many patients eventually become ineligible for curative treatment and require only supportive care or low-intensity chemotherapy. However, data on prognosis and predictive factors in this context are limited. The study aim was to evaluate survival and identify prognostic factors in patients with relapsed/refractory ALL receiving supportive care. Methods: We conducted a retrospective observational study of 59 patients at two tertiary hospitals in Mexico. All patients had exhausted curative treatment options. Clinical variables at diagnosis and relapse were analyzed, including age, leukocyte counts, relapse timing, prior treatment lines, transfusion needs, and use of prognostic scores. Kaplan–Meier analysis was used to estimate survival, and multivariate models were applied to identify predictors of overall survival. Results: Fifty-nine patients were included (median age 31 years, balanced gender). Most received two prior high-intensity chemotherapy lines. Median overall survival was 137 days, with transfusion requirements being the only significant prognostic factor; neither the Palliative Prognostic Index nor the Charlson Comorbidity Index demonstrated predictive value. Conclusions: In patients with relapsed/refractory ALL managed with supportive care, survival remains limited. Transfusion dependence is a strong adverse prognostic factor, likely reflecting disease burden and logistical barriers to outpatient care. These findings highlight the need for earlier integration of palliative care and the development of tailored prognostic tools for this population.

Hemato doi: 10.3390/hemato6030031

Authors: Luca Collodel Enza Coluccia Stefania Guaita Michela Pivetta Ileana Vaccara Gianluca Gessoni

Background: Today, in Western countries, patients with allo-antibodies to high-frequency antigens or with complex antibody mixtures represent one of the most significant challenges in transfusion medicine. Another important aspect is the prevention of allo-immunization of patients who lack high-frequency antigens. In these conditions, the availability of a bank of a rare red blood cell group, supported by a database of donors subjected to extensive erythrocyte typing (preferably using erythrogenomic study), can constitute a resource of great value. Materials and Methods: Repeat Caucasian blood donors of group A or O, with selected Rh phenotypes (CCDee, ccDEE, ccdee, ccDee), aged under 52 years, were considered for typing. Moreover, we selected all non-Caucasian repeat blood donors for typing. For extended phenotyping and genotyping we adopted commercial methods supplied by Grfols and Werfen, respectively. For cryopreservation, we selected a high glycerol method in −80 °C electric freezer; blood unit processing was performed using a Haemonetics ACP 215 automated cell processor with close circuit devices. Results: We considered the five patients as follows: PA was massively transfused for a road trauma, developed multiple allo-antibodies (anti-D, anti-k), and required compatible blood units for an elective cardiac surgery; PB was a pregnant woman with anti-Coa (a high frequency antigen) monitored during pregnancy and in which it was necessary to proceed with the transfusion of the newborn; PC was a poly-transfused patient with myelo dysplastic syndrome who developed multiple allo-antibodies (anti-k, anti-CW, anti-Lea) and required continuous supportive therapy, including the procurement of compatible units and the implementation of therapeutic actions in an attempt to reduce the transfusion requirement using luspatercept; PD was a patient with sickle cell disease. They had a Fy (null) genotype, making it very difficult to find compatible units; and PE was interesting for the complexity of the immunohematological and erythrogenomic study performed to characterize a recipient with a rare phenotype and thus allow the transfusion of compatible units, preventing allo-immunization. Discussion: In this report, we have maintained a narrative approach. Starting with five patients representing as many clinical situations as possible, we have illustrated the approach followed for the immune-hematological study and the choices made to try to guarantee effective and safe transfusion therapy.

Hemato doi: 10.3390/hemato6030030

Authors: Mohamed Abdelkarim Inès Limam Emna Berred Rachid Kharrat Brigitte Sola Fatma Ben Aissa-Fennira

Background/Objectives: Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of abnormal plasma cells in bone marrow, predominantly affecting individuals over 65 years of age. Despite recent therapeutic advances, MM remains largely incurable due to frequent relapses and the emergence of drug resistance. MicroRNAs have emerged as key post-transcriptional regulators implicated in cancer progression, with miR-429 exhibiting context-dependent oncogenic or tumor-suppressive roles in various cancers. However, its function in MM has not been thoroughly investigated. Methods: miR-429 expression was evaluated in MM cells and patient samples by qRT-PCR. Functional effects were assessed through inhibition studies, proliferation/apoptosis assays, and co-culture with stromal cells. Results: In this study, we found that miR-429 expression is significantly downregulated in MM cell lines and primary malignant plasma cells compared to normal plasma cells. The functional inhibition of miR-429 in U266 cells led to a significant increase in cell proliferation without affecting spontaneous apoptosis, as confirmed in both MM cell lines and patient-derived plasma cells. Additionally, the inhibition of miR-429 in HS-5 stromal cells enhanced the proliferation of co-cultured MM cells, highlighting the role of the bone marrow microenvironment in disease progression. Conclusions: These findings suggest that miR-429 may act as a tumor suppressor by modulating MM cell proliferation. Although preliminary, our results support the need for further investigation into miR-429 as a potential biomarker or therapeutic target.

Hemato doi: 10.3390/hemato6030029

Authors: Henry Sutanto Pradana Zaky Romadhon Vembi Rizky Fatmawati Alief Waitupu Bagus Aditya Ansharullah Betty Rachma Elisa Elisa Laras Pratiwi Galih Januar Adytia

Multiple myeloma (MM) is a malignant plasma cell disorder that evolves from precursor conditions including monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Understanding the biological continuum and the molecular drivers of disease progression is crucial for early diagnosis and risk-adapted therapy. Recent advances in next-generation sequencing have identified recurrent mutations in the RAS/MAPK, TP53, and MYC pathways, along with epigenetic alterations that contribute to clonal evolution and therapeutic resistance. Novel diagnostic tools including minimal residual disease (MRD) assessment, gene expression profiling, and advanced imaging have improved risk stratification. Therapeutically, the integration of proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies has dramatically improved patient outcomes. In parallel, emerging immunotherapies such as CAR-T cells, bispecific T-cell engagers, and antibody–drug conjugates are expanding treatment options, especially in relapsed or refractory settings. Future directions aim to personalize treatment using genomics, target the tumor microenvironment, and leverage synthetic lethality and epigenetic vulnerabilities. This review highlights the evolving landscape of plasma cell disorders from molecular pathogenesis to cutting-edge therapeutic innovations, emphasizing the need for precision medicine approaches to improve survival and quality of life for patients with MM and its precursors.

Hemato doi: 10.3390/hemato6030028

Authors: Claudia Moriello Chiara De Rosa Stefania D’Angelo Perrone Pasquale

Background/Objectives: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the BCR–ABL fusion gene, whose constitutive tyrosine kinase activity drives leukemogenesis. Although tyrosine kinase inhibitors (TKIs) have revolutionized treatment, drug resistance and leukemic stem cell persistence remain major challenges. Natural compounds such as polyphenols have shown potential in modulating key oncogenic pathways in CML. Results: Polyphenols such as resveratrol, quercetin, curcumin, and epigallocatechin gallate (EGCG) demonstrated significant antiproliferative and pro-apoptotic effects in CML cell lines, including imatinib-resistant models. These effects were mediated through the modulation of signaling pathways, including PI3K/Akt, STAT5, and MAPK; inhibition of BCR–ABL expression; induction of oxidative stress; and the enhancement of apoptosis via mitochondrial and caspase-dependent mechanisms. Some polyphenols also showed synergistic activity with TKIs, potentiating their efficacy and overcoming resistance. Conclusions: Preclinical evidence supports the role of polyphenols as potential adjuvants in CML therapy, particularly in drug-resistant contexts. Their pleiotropic molecular actions and low toxicity profile make them promising candidates for integrative oncology. Nonetheless, clinical translation requires further investigation through well-designed trials assessing efficacy, safety, and pharmacokinetics.

Hemato doi: 10.3390/hemato6030027

Authors: Fabio Bertani Francesco Faiella Claudia Di Franco Raffaella Milani Antonella Gualdoni Cinzia Fulceri Elena Costa

Monoclonal B Lymphocytosis (MBL) is considered the pre-malignant state of chronic lymphocytic leukemia (CLL) and atypical chronic lymphocytic leukemia (aCLL). Both entities are rarely found in association with other hematological tumors; still, they naturally tend to progress to more aggressive lymphomas. This manuscript reports the case of an 81-year-old Caucasian male under follow up for MBL who presented to the Emergency Department with severe anemia and thrombocytopenia. A complete diagnostic workup revealed the simultaneous presence of atypical CLL and B-acute lymphoblastic leukemia, with minimal blast presence in peripheral blood.

Hemato doi: 10.3390/hemato6030026

Authors: Humza Mallick Samir Dalia

Background/Objectives: Pica, the compulsive ingestion of non-nutritive substances, has long been observed in patients with iron deficiency anemia (IDA). This behavior is particularly noted in adults, including pregnant women, and poses both diagnostic and management challenges. We conducted a review of studies from the past decade to evaluate the epidemiology and nature of pica in adult IDA patients and the outcome of various treatment strategies on anemia and pica behaviors. Methods: We searched PubMed, Scopus, and Cochrane Library for peer-reviewed articles (including observational studies, clinical trials, and reviews) published in English between 2015 and 2025. Inclusion criteria targeted studies of adult populations with IDA that reported on pica prevalence, characteristics, or treatment outcomes. We also reviewed clinical guidelines and meta-analyses on IDA treatment in adults for recommended management approaches. Results: Pica was found to be a prevalent symptom among individuals with IDA, but was readily treatable with appropriate iron deficiency treatment. Among treatment options, both oral and parenteral iron supplementation were found to be effective in resolving iron deficiency and pica. Choice of treatment depends on tolerance to oral iron, speed of resolution required, and comorbid conditions. Conclusions: Pica is closely intertwined with IDA; our review highlighted the prevalence of pica among individuals with IDA, which serves as both a clinical clue to underlying anemia and a potential source of complications. Crucially, the treatment of IDA is also effective for pica. We recommend oral iron therapy on alternate-day dosing as first-line therapy to minimize side effects, alongside dietary optimization. If IDA and pica are resistant to oral iron supplementation or oral iron cannot be tolerated, parenteral iron therapy can be considered.

Hemato doi: 10.3390/hemato6030025

Authors: Eros Cerantola Laura Forlani Marco Pizzi Renzo Manara Mauro Alaibac Federica Lessi Angelo Paolo Dei Tos Chiara Briani Carmela Gurrieri

Introduction: Acute Myeloid Leukemia (AML) is a hematologic malignancy characterized by the clonal expansion of myeloid progenitors. While it primarily affects the bone marrow, extramedullary relapse occurs in 3–5% of cases, and it is linked to poor prognosis. Central nervous system (CNS) involvement presents diagnostic challenges due to nonspecific symptoms. CNS manifestations include leptomeningeal dissemination, nerve infiltration, parenchymal lesions, and myeloid sarcoma, occurring at any disease stage and frequently asymptomatic. Methods: A 62-year-old man with a recent history of AML in remission presented with diplopia and aching paresthesias in the left periorbital region spreading to the left frontal area. The diagnostic workup included neurological and hematological evaluation, lumbar puncture, brain CT, brain magnetic resonance imaging (MRI) with contrast, and dermatological evaluation with skin biopsy due to the appearance of nodular skin lesions on the abdomen and thorax. Results: Neurological evaluation showed hypoesthesia in the left mandibular region, consistent with left trigeminal nerve involvement, extending to the periorbital and frontal areas, and impaired adduction of the left eye with divergent strabismus in the primary position due to left oculomotor nerve palsy. Brain MRI showed an equivocal thickening of the left oculomotor nerve without enhancement. Cerebrospinal fluid (CSF) analysis initially showed elevated protein (47 mg/dL) with negative cytology; a repeat lumbar puncture one week later detected leukemic cells. Skin biopsy revealed cutaneous AML localization. A diagnosis of AML relapse with CNS and cutaneous localization was made. Salvage therapy with FLAG-IDA-VEN (fludarabine, cytarabine, idarubicin, venetoclax) and intrathecal methotrexate, cytarabine, and dexamethasone was started. Subsequent lumbar punctures were negative for leukemic cells. Due to high-risk status and extramedullary disease, the patient underwent allogeneic hematopoietic stem cell transplantation. Post-transplant aplasia was complicated by septic shock; the patient succumbed to an invasive fungal infection. Conclusions: This case illustrates the diagnostic complexity and poor prognosis of extramedullary AML relapse involving the CNS. Early recognition of neurological signs, including cranial nerve dysfunction, is crucial for timely diagnosis and management. Although initial investigations were negative, further analyses—including repeated CSF examinations and skin biopsy—led to the identification of leukemic involvement. Although neuroleukemiosis cannot be confirmed without nerve biopsy, the combination of clinical presentation, neuroimaging, and CSF data strongly supports the diagnosis of extramedullary relapse of AML. Multidisciplinary evaluation remains essential for detecting extramedullary relapse. Despite treatment achieving CSF clearance, the prognosis remains unfavorable, underscoring the need for vigilant clinical suspicion in hematologic patients presenting with neurological symptoms.

Hemato doi: 10.3390/hemato6030024

Authors: Elsa Vitale Roberto Lupo Stefano Botti Chiara Ianne Alessia Lezzi Giorgio De Nunzio Donato Cascio Ivan Rubbi Simone Zacchino Gianandrea Pasquinelli Doria Valentini Valeria Soffientini Valentina De Cecco Chiara Cannici Marco Cioce Luana Conte

Background: It is estimated that in Italy, there were 364,000 new diagnoses of neoplasms each year and that the overall incidence of blood cancers was 10% of these. Leukemia and lymphomas represented the ninth and eighth places, respectively, among the causes of death from neoplasia. Hematopoietic stem cell transplantation represented an effective treatment option for many of these malignancies, and not only that: benign and congenital diseases could also be treated. Objective: To assess knowledge among the Apulian population regarding stem cell donation and factors that could influence this choice, focusing especially on the knowledge of the residents of Puglia, Italy on how stem cells were harvested and their functions, their reasons for joining the National Registry, and the reasons that hold them back from making such a choice. Study Design: An observational and cross-sectional study was conducted, through snowball sampling methodology, until data saturation. An online survey was conducted, which included several Italian associations. The questionnaire administered contained five main sections, such as sociodemographic data, knowledge of the existence of National Registries and their adherence, the nationwide presence of various associations that promote donation, knowledge with respect to the structure, use and functions of stem cells, sources of procurement, such as bone marrow, peripheral blood and umbilical cord, and related procedures, beliefs, attitudes, values, and opinions of the Italian population regarding the topic, and degree of information and education regarding bone marrow donation. Results: A total of 567 Apulian citizens were enrolled. Of these, 75.3% were female and 96.8% were aged between 18 and 65 years. Most of participants were single (46.9%) and married (47.3%) and had a diploma (44.4%), and less had a degree (35.8%). Significant differences were recorded between gender, singles, and married participants, and participants with a diploma or a degree and the items proposed. Conclusions: A true culture of donation in our region was not clearly spread. Although something has been accomplished in recent years in terms of deceased donor donation, still a great deal needs to be achieved for living donation, which encountered a great deal of resistance. It has been deemed necessary to seek winning solutions to this issue in terms of communication and information campaigns, raising awareness and empowering citizens to express consciously their concerns about organs and tissues and to stand in solidarity with those who suffered.

Hemato doi: 10.3390/hemato6030023

Authors: Mariah N. Hafiz Anshoo Agarwal Nida Suhail Zakariya M. S. Mohammed Sanaa A. Mohammed Hibah A. Almasmoum Mohammed M. Jawad Wesam Nofal

Background: Iron deficiency anemia (IDA) represents a significant public health concern, particularly among female populations. Various demographic factors, including age and socioeconomic status, have a substantial impact on overall health outcomes, contributing to the prevalence of IDA. The primary objective of this study was to assess the knowledge and awareness of iron deficiency anemia among the adult population and to examine its correlation with various sociodemographic factors. Methods: A cross-sectional study was conducted in the Northern Region of Saudi Arabia between October and December 2024. Data were collected using a structured questionnaire from 385 participants aged 18 years and older. The Chi-square test was utilized to assess the association between categorical variables. Results: In this study, 42.5% of participants demonstrated good knowledge of IDA, 48.1% had moderate knowledge, and 9.4% showed poor knowledge. Knowledge levels were significantly associated with gender, age, education, and self-perceived IDA status. Women, older individuals, and those with higher levels of education had a greater knowledge of IDA. Regarding attitude, 93% of participants had a positive attitude, while only 7% exhibited a negative attitude. Interestingly, none of the explanatory variables were significantly linked to attitude, suggesting that positive attitude toward IDA was consistent across all demographic groups. Conclusions: This study highlights the need for targeted health initiatives focusing on diet, supplementation, symptom recognition, and prevention to effectively reduce the burden of IDA. Prioritizing education through symposiums and medical programs in high-prevalence regions is crucial.

Hemato doi: 10.3390/hemato6030022

Authors: Ugo Testa Elvira Pelosi Pelosi Germana Castelli

Acute myeloid leukemia (AML), a heterogeneous and aggressive clonal disease, is predominantly observed in older individuals, with a median age at diagnosis of 68–69 years. With the aging population, there is a significant increase in the occurrence of some genetic alterations, including detrimental gene mutations and cytogenetic abnormalities, and a higher incidence of secondary AML (s-AML) and therapy-related AML (t-AML), compared to younger AML patients. Outcomes of AML patients and their response to therapy are associated with the molecular features of AML subtypes and with individual variables. The current criteria for risk classification predict outcomes in younger AML patients treated with intensive chemotherapy but are less predictive for older AML patients treated with lower-intensity treatments. Thus, this review analyzes and discusses the development of new risk stratification models adapted to the study of older AML patients and how these new criteria may significantly contribute to a more rational classification and treatment of older AML patients.

Hemato doi: 10.3390/hemato6030021

Authors: Sophie Vlayen Tim Dierckx Marino Caruso Swell Sieben Kim De Keersmaecker Dirk Daelemans Michel Delforge

Background/Objectives: The treatment of multiple myeloma (MM) remains a challenge, as almost all patients will eventually relapse. Proteasome inhibitors are a cornerstone in the management of MM. Unfortunately, validated biomarkers predicting drug response are largely missing. Therefore, we aimed to identify genes associated with drug resistance or sensitization to proteasome inhibitors. Methods: We performed genome-wide CRISPR-Cas9 knockout (KO) screens in human KMS-28-BM myeloma cells to identify genetic determinants associated with resistance or sensitization to proteasome inhibitors. Results: We show that KO of KLF13 and PSMC4 induces drug resistance, while NUDCD2, OSER1 and HERC1 KO cause drug sensitization. Subsequently, we focused on top sensitization hit, NUDCD2, which acts as a co-chaperone of Hsp90 to regulate the LIS1/dynein complex. RNA sequencing showed downregulation of genes involved in the ERAD pathway and in ER-associated ubiquitin-dependent protein catabolic processes in both untreated and carfilzomib-treated NUDCD2 KO cells, suggesting that NUDCD2 depletion alters protein degradation. Furthermore, bortezomib-treated NUDCD2 KO cells showed a decreased expression of genes that have a function in oxidative phosphorylation and the mitochondrial membrane, such as Carnitine Palmitoyltransferase 1A (CPT1A). CPT1A catalyzes the uptake of long chain fatty acids into mitochondria. Mitochondrial lipid metabolism has recently been reported as a possible therapeutic target for MM drug sensitivity. Conclusions: These results contribute to the search for therapeutic targets that can sensitize MM patients to proteasome inhibitors.

Hemato doi: 10.3390/hemato6030020

Authors: Antonino Carbone Mohamed Nazem Alibrahim Annunziata Gloghini

In recent decades, significant progress in medicine has improved the outcomes for Hodgkin lymphoma (HL), a malignancy affecting approximately 8570 new patients annually in the United States and causing around 910 deaths per year [...]

Hemato doi: 10.3390/hemato6030019

Authors: María Hidalgo Eduardo Ramos-Elbal José Antonio Galián Helios Martínez-Banaclocha Mercedes Plaza Victoria Martínez-Sánchez Ana María Galera Irene Jiménez María Esther Llinares Mar Bermúdez Alfredo Minguela José Luis Fuster

Background/Objectives: Intrachromosomal amplification of chromosome 21 (iAMP21) represents a rare and heterogeneous distinct cytogenetic subgroup of B-cell precursor acute lymphoblastic leukemia (ALL) initially associated with a poor prognosis. Treatment intensification with additional doses of methotrexate and asparaginase was associated with better treatment outcomes. Methods: In this retrospective single-center study, we evaluated the impact of iAMP21 on treatment outcome in a cohort of pediatric patients treated with an intensified asparaginase regimen and describe the genomic landscape of four patients with iAMP21. Results: Four out of 89 patients > 1 year old were classified as iAMP21 positive. Five-year event-free survival (EFS) was inferior in the iAMP21-positive group: 25% versus 85.6% (p = 0.001). The cumulative incidence of relapse and treatment-related mortality were 50% vs. 9.9% and 0% vs. 2.38%, respectively, in the iAMP21-positive and non-iAMP21 groups (p = 0.02 and 0.76, respectively). These results did not translate into a significant difference in overall survival: 100% vs. 93.7% (p = 0.6). The presence of iAMP21 (HR 7.68, 95% CI 2.04–29.05; p = 0.002) and a measurable residual disease ≥1% after induction on day +33 (HR 8.82, 95% CI 2.6–29.91; p = 0.001) retained significant negative impact on EFS in multivariate analysis. Conclusions: We found an independent significant prognostic impact of iAMP21 on EFS among pediatric patients with ALL, and clinical presentation and early treatment response did not classify these patients as HR. Diverse genetic backgrounds among iAMP21-positive patients might influence the treatment response and outcome of this heterogeneous disease.

Hemato doi: 10.3390/hemato6030018

Authors: Giulia Pileggi Sabrina Mariani Valentina De Santis Gianluca Maiorana Federica Lubrano Lobianco Chiara Togni Monica Piedimonte Caterina Tatarelli Esmeralda Conte Arianna di Napoli Emanuela Pilozzi Evelina Rogges Agostino Tafuri Giovanna Palumbo

Langerhans cell sarcoma (LCS) is a rare and aggressive neoplasm characterized by a clonal proliferation of Langerhans cells (LCs), with multi-organ involvement and poor prognosis. Diagnostic challenges arise from its rarity and overlapping features with Langerhans cell histiocytosis (LCH), requiring immunophenotypic and histological analysis for differentiation. This case report discusses a 67-year-old male with multi-organ LCS involvement. Diagnosis was confirmed via liver biopsy and genetic analysis, revealing a MAP2K1 mutation. Treatment with subcutaneous cladribine and dexamethasone resulted in significant clinical and radiological improvement, despite hematological toxicity due to an underlying myelodysplastic neoplasm (MDS). This case proves the potential efficacy of cladribine for disseminated LCS and highlights the necessity for further research into optimal therapeutic approaches for this rare malignancy.

Hemato doi: 10.3390/hemato6020017

Authors: Velizar Shivarov Stefan Lozenov

Myeloid/lymphoid neoplasms with tyrosine kinase gene fusions (MLN-TK) represent a distinct group of hematologic malignancies recognized in the latest WHO classification due to shared clinical, morphological, and molecular features, and their responsiveness to tyrosine kinase inhibitors (TKIs). Among these, fusions involving the SYK gene, such as ETV6::SYK and ITK::SYK, have emerged as rare but potentially targetable genetic events in both myeloid and lymphoid neoplasms. SYK, a non-receptor tyrosine kinase critical for hematopoietic signalling, can become constitutively activated through gene fusions, driving oncogenesis via the PI3K/AKT, MAPK, and JAK-STAT pathways. ETV6::SYK has been primarily associated with myeloid neoplasms, often presenting with eosinophilia, bone marrow dysplasia, and skin involvement. In vitro and in vivo models confirm its leukemogenic potential and identify SYK as a therapeutic target. Although SYK inhibitors like fostamatinib have shown transient efficacy, resistance mechanisms, possibly involving alternative pathway activation, remain a challenge. The ITK::SYK fusion, on the other hand, has been identified in peripheral T-cell lymphomas, particularly of the follicular helper T-cell subtype, with similar pathway activation and potential for targeted intervention. Additional rare SYK fusions, such as PML::SYK and CTLC::SYK, have been reported in myeloid neoplasms and juvenile xanthogranuloma, respectively, expanding the spectrum of SYK-driven diseases. Accumulating evidence supports the inclusion of SYK fusions in future classification systems and highlights the need for broader molecular screening and clinical evaluation of SYK-targeted therapies.

Hemato doi: 10.3390/hemato6020016

Authors: Aditi Sharma Danielle Blake Jay Yang

The treatment of acute myeloid leukemia (AML) in Jehovah’s Witness (JW) patients poses unique challenges due to their refusal of blood transfusions. This case series reports the outcomes of four older JW patients with AML treated with azacitidine (Aza) and venetoclax (Ven), including two with hyperleukocytosis and FLT3-ITD mutations. Three patients achieved initial remission; one of these patients subsequently received gilteritinib in combination with Ven and Aza, also achieving remission. All but one therapy cycle was administered in an outpatient setting, and hematologic recovery occurred in all patients without bleeding, ischemic events, or fungal infections. Three patients experienced disease relapse at 179, 301, and 392 days post-diagnosis, while one patient remains alive 706 days post-diagnosis. This report is among the first to demonstrate that Ven and Aza can safely achieve remissions, some of which were durable, in older JW patients with AML, even those with proliferative features like hyperleukocytosis and FLT3-ITD mutations. Our central finding is that Ven and Aza represent safe and effective transfusion-sparing therapeutic options in this population, with triplet therapy incorporating gilteritinib also proving feasible with dose modifications. These findings underscore the clinical relevance of such approaches, suggesting that transfusion refusal should not preclude treatment initiation, offering meaningful clinical outcomes and potentially enhancing quality of life in this population.

Hemato doi: 10.3390/hemato6020015

Authors: Mario Biglietto Giusy Peluso Cristina Luise Diletta Tripi Maria Francesca Conforti Valeria Filipponi Luisa Bizzoni Stefania Trasarti

Hemolytic anemias (HAs) encompasses a heterogeneous group of disorders with either congenital or acquired etiologies. We present a complex case of a 27-year-old woman with hemolytic anemia of multifactorial origin, involving both inherited RBC membrane defects and multiple autoimmune comorbidities. Genetic testing identified heterozygous variants in SPTA1 and SBDS, consistent with carrier status for hereditary elliptocytosis and Shwachman–Diamond syndrome. The patient was also diagnosed with Caspr2-positive Isaacs syndrome, systemic lupus erythematosus, seronegative antiphospholipid syndrome, and anti-aquaporin-4 antibody-positive optic neuritis. Despite extensive immunosuppressive and immunotherapic treatment and splenectomy, the clinical course was marked by recurrent hemolytic crises, thrombotic complications, and progressive neurological involvement, ultimately leading to death. Our experience highlights the challenges posed by the diagnosis and management of HAs, underlining the relevance of a multidisciplinary and personalized approach.

Hemato doi: 10.3390/hemato6020014

Authors: Erin M. Drengler Audrey L. Smith Sydney A. Skupa Elizabeth Schmitz Eslam Mohamed Dalia El-Gamal

Background: Myeloid-derived suppressor cells (MDSCs) contribute to immune suppression observed in chronic lymphocytic leukemia (CLL). MDSCs are immature myeloid cells that are hijacked during development and further reprogrammed by the tumor microenvironment (TME) to harbor immune-suppressive properties and inhibit T-cell functions. Bromodomain and extraterminal domain (BET) proteins, including BRD4, are epigenetic modulators that regulate genes implicated in CLL pathogenesis and TME interactions. Previously, we investigated how the novel BET inhibitor OPN-51107 (OPN5) prevents CLL disease expansion, modulates T-cell immune function, and alters gene expression related to MDSCs. In turn, we hypothesize that BET proteins such as BRD4 regulate MDSC functions, and subsequent pharmacological inhibition of BRD4 will alleviate MDSC-mediated immune suppression in CLL. Methods: Utilizing the Eµ-TCL1 mouse model of CLL, we evaluated BRD4 protein expression in MDSCs derived from the bone marrow of transgenic and age-matched wild-type (WT) mice. We then investigated the ex vivo functionality of OPN5-treated MDSCs, expanded from Eµ-TCL1 and WT bone marrow in MDSC-supportive medium. Finally, we conducted an in vivo study utilizing the Eµ-TCL1 adoptive transfer mouse model to determine the in vivo effects of OPN5 on MDSCs and other immune populations. Results: Through the course of this study, we found that MDSCs isolated from Eμ-TCL1 mice upregulate BRD4 expression and are more immune-suppressive than their WT counterparts. Furthermore, we demonstrated ex vivo OPN5 treatment reverses the immune-suppressive capacity of MDSCs isolated from leukemic mice, evident via enhanced T-cell proliferation and IFNγ production. Finally, we showed in vivo OPN5 treatment slows CLL disease progression and modulates immune cell populations, including MDSCs. Conclusions: Altogether, these data support BET inhibition as a useful therapeutic approach to reverse MDSC-mediated immune suppression in CLL.

Hemato doi: 10.3390/hemato6020013

Authors: Zana Radic Savic Natasa Bogavac-Stanojevic Dragana Malcic-Zanic Sinisa Stankovic Natasa Egeljic-Mihailovic Đorđe Stojisavljević Miron Sopić Bosa Mirjanic-Azaric

Numerous studies point to the significance of cathepsin B (CTSB) in the development of carcinoma. Therefore, the aim of this pilot study was to investigate the levels of cathepsin B (CTSB) and the expression of CTSB mRNA in the plasma of non-Hodgkin lymphoma (NHL) patients. Methods: The study included 44 newly diagnosed NHL patients and 35 healthy volunteers comprising the control group. CTSB in the plasma samples were detected using the enzyme-linked immunosorbent assay (ELISA). Results: The level of CTSB was significantly higher in NHL patients compared to control subjects: 15.28 (11.68–17.23) versus 11.57 (10.12–13.41), p = 0.003. In addition, a positive correlation between plasma CTSB mRNA and CTSB after therapy was observed (rho = 0.591, p = 0.026). Regarding redox parameters, we found a negative correlation between CTSB and the total antioxidant status (TAS) (rho = −0.499, p = 0.035), as well as a positive correlation with the total oxidant status (TOS) (rho = 0.576, p = 0.012). Conclusions: Targeting CTSB might have significant clinical relevance in the diagnostics of NHL.

Hemato doi: 10.3390/hemato6020012

Authors: Mohamed Nazem Alibrahim Hussein Hammam Antonino Carbone Noor Alsaleh Annunziata Gloghini

Background/Objectives: Classic Hodgkin lymphoma (cHL) is a predominantly curable B-cell malignancy. However, primary refractory and relapsed (R/R) cHL remain therapeutic challenges, especially in regions with high tuberculosis (TB) prevalence, where clinical and radiologic features overlap and can obscure the correct diagnosis. This article, presenting a case of R/R cHL mimicking disseminated TB, reviews the evolving paradigm in R/R cHL management. Methods: A 30-year-old Middle Eastern male with advanced nodular sclerosis cHL initially achieved a complete remission (CR) with escalated BEACOPP chemotherapy. Shortly afterward, he developed respiratory symptoms and diffuse miliary pulmonary nodules, highly suggestive of disseminated TB. Despite extensive negative TB workup, including QuantiFERON-TB Gold testing, sputum acid-fast bacilli (AFB) staining, and PCR, his imaging raised concern for recurrent cHL. Due to the small size and diffuse distribution of nodules, biopsy was unfeasible, prompting empiric salvage therapy with DEHAP-Carbo, brentuximab vedotin (BV), and nivolumab. Results: The rapid and robust metabolic response on PET/CT supported lymphoma relapse rather than TB. Following four cycles of this combined regimen, he proceeded to autologous stem cell transplantation and achieved a second CR. Conclusions: This case highlights the diagnostic difficulties in differentiating cHL relapse from TB in endemic regions, emphasizes the critical role of PET/CT in guiding therapy when histopathological confirmation is impractical, and illustrates the impact of novel immunotherapies in improving outcomes. By underscoring the importance of early diagnostic suspicion and multimodal assessment, this article also reviews the evolving paradigm in R/R cHL management, where personalized approaches and targeted agents increasingly complement or replace traditional chemotherapy regimens.

Hemato doi: 10.3390/hemato6020011

Authors: Gabriela Micurova Kristina Maria Belakova Tomas Simurda Miroslava Drotarova Jan Stasko Branislav Kolarovszki

Background: Hemophilia A is an X-linked recessive bleeding disorder associated with high risk for intracranial hemorrhage, requiring complicated neurosurgical interventions. Perioperative management is based on quick factor replacement therapy, control of hemostasis, and deciding whether surgery will be beneficial. Methods: We report the case of a 49-year-old male with severe hemophilia A who had purulent secernation via a skin fistula as a late complication of decompressive craniectomy for epidural hematoma at younger age. Results: Revision surgery was successfully managed with perioperative administration of clotting factor VIII, and the patient showed indications of titanium cranioplasty. Conclusions: A direct preoperative preparation prior to surgery in a postoperative period with controlled hemostasis has been shown to reduce hemorrhagic complications in hemophilic patients, increasing the quality of life and significant neurological complications.

Hemato doi: 10.3390/hemato6020010

Authors: Ugo Testa Germana Castelli Elvira Pelosi

Clonal hematopoiesis (CH) is an age-related process in which hematopoietic stem/progenitor cells increase their fitness due to the acquisition of mutations that lead to a proliferative advantage and to clonal expansion. Its frequency increases with age, and it mostly affects people older than 70 years. The most mutated genes in CH are epigenetic regulators, DNA damage response genes, and splicing factors, which are all involved in the development of myeloid neoplasia. Some risk factors, including age, smoking, and prior cytotoxic therapy, increase the risk of developing CH or increase the fitness of CH. Various types of CH have been observed, associated or not with cytopenias or monocytosis. CH represents a risk factor for many pathological conditions and particularly for hematologic malignancies. A better understanding of the risks related to CH has triggered the development of research, translational, and clinical programs for the monitoring, prevention, and treatment of CH.

Hemato doi: 10.3390/hemato6020009

Authors: Paul A. Valle Luis N. Coria Yolocuauhtli Salazar Corina Plata Luis A. Ramirez

Background: This work presents a mechanistic nonlinear model, formulated as a system of first-order Ordinary Differential Equations, to investigate the dynamics of Chronic Lymphocytic Leukemia (CLL) under combined chemoimmunotherapy using CAR-T cells and chlorambucil. Methods: Leveraging nonlinear dynamical systems theory and a model-based design approach, we derive optimal dosing strategies through extensive in silico simulations, providing hemato-oncologists with actionable tools to refine CLL treatment. The model captures the short- and long-term impacts of both therapies on leukemia cell populations, enabling precise predictions of therapeutic outcomes. Results: By analyzing local and global system dynamics, we establish sufficient conditions for dosing and protocol design, offering a framework to optimize therapies based on individual patient responses. Comparisons of dose-escalation and -de-escalation strategies further demonstrate potential trajectories, such as complete eradication, partial response, or relapse, providing data-driven guidance for improving patient care. Conclusions: This study highlights the power of mathematical modeling in blood cancer research, enhancing the development of personalized and effective CLL treatment regimens.

Hemato doi: 10.3390/hemato6020008

Authors: Evgenia Papakonstantinou Athanasios Tragiannidis Mirella Ampatzidou Nikolaos Katzilakis Maria Nikita Georgios Totikidis Kleoniki I. Athanasiadou Vasiliki Antari Charikleia Kelaidi Iordanis Pelagiadis Dimitrios Doganis Margarita Mpaka Helen Kosmidis Antonis Kattamis Eftychia Stiakaki Vassilios Papadakis Emmanouel Hatzipantelis Sophia Polychronopoulou

Background/Objectives: Down syndrome (DS), affecting 1 in 1000 births, has been linked to an increased risk of acute leukemia (AL). Patients with DS–acute lymphoblastic leukemia (DS-ALL) have historically had inferior outcomes when they have received risk-adapted therapy. Transient abnormal myelopoiesis (TAM) constitutes a transient leukemia with spontaneous remission in the neonatal period or represents a preleukemic state, preceding DS–acute myeloid leukemia (DS-AML). DS-AML has a better prognosis than that of AML without DS (NDS-AML) due to genetic and biological underlying features, a better response to chemotherapeutic agents, and a lower frequency of relapses. Methods: This retrospective cohort study presents the DS-AL outcomes from a nationwide survey in pediatric oncology centers. A total of 20 patients were studied, 10 with DS-ALL, 4 with DS-AML, 5 with TAM, and 1 with DS-AML after TAM, at median follow-ups of 9.25 (0.6–17.42) years and 7.25 (0.25–18.25) years for DS-ALL and DS-AML, respectively. Results: The median age at diagnosis was 4.7 (1.16–13.83) and 1.92 (1.25–3) years for ALL and AML, respectively. All DS-ALL patients had B-cell precursor ALL and achieved complete remission (CR). One patient relapsed and succumbed due to a severe infection. Three DS-AML patients had AMKL. All DS-AML patients achieved CR. One patient with TAM demanded treatment, all achieved CR, and one progressed to DS-AML. The overall survival (OS) was 70% and 80% for DS-ALL and DS-AML. Conclusions: The improved survival rates of our patients have been due to new protocols with less toxic therapies and better supportive care.

Hemato doi: 10.3390/hemato6010007

Authors: Marialuisa Zedde Rosario Pascarella

Thalassemia, once associated with limited survival, now sees extended life expectancy due to treatment advancements, but new complications such as pseudoxanthoma elasticum (PXE)-like syndrome are emerging. In fact, thalassemia patients develop PXE-like features more frequently than the general population. These features include skin lesions, ocular changes, and vascular issues like arterial calcifications, all linked to oxidative damage from iron overload. PXE-like syndrome in thalassemia mimics inherited PXE but is acquired. The underlying cause is thought to be oxidative stress due to iron overload, which induces free radicals and damages elastic tissues. Unlike inherited PXE, this form does not involve mutations in the ABCC6 gene, suggesting different pathogenic mechanisms, including abnormal fibroblast metabolism and oxidative processes. The vascular calcification seen in this syndrome often follows elastic fiber degeneration, with proteoglycans and glycoproteins acting as nucleation sites for mineralization. The condition can lead to severe cardiovascular and gastrointestinal complications. Studies have shown a significant incidence of PXE-like skin lesions in thalassemia patients, with some dying from cardiovascular complications. Research on ABCC6, a transporter protein involved in ectopic mineralization, has highlighted its role in various conditions, including PXE, beta-thalassemia, and generalized arterial calcification of infancy. ABCC6 mutations or reduced expression led to ectopic mineralization, affecting cardiovascular, ocular, and dermal tissues. The exact molecular mechanisms linking ABCC6 deficiency to ectopic mineralization remain unclear, though it is known to influence calcification-modulating proteins. This review focuses on the role of ABCC6 in the pathogenesis of calcifications, especially intracranial vascular calcifications in PXE and beta-thalassemia.

Hemato doi: 10.3390/hemato6010006

Authors: Imran Rangraze Mohamed El-Tanani Adil Farooq Wali Manfredi Rizzo

Background: Chronic myeloid leukemia (CML) relates to the abnormal presence of the Philadelphia chromosome, which originates the production of the BCR-ABL1 fusion protein and therefore leads to neoplastic transformation and unregulated cell growth. The advent of tyrosine kinase inhibitors (TKIs) has resulted in tremendous improvements in CML scenarios; however, there are practical difficulties, especially considering the late stages of the disease. This review examines recently developed strategies that are intended to increase the efficiency of treatment by overcoming TKI resistance. Methods: We performed a literature review of such databases as PubMed, Scopus, Web of Science, and Embase for the last ten years. The following keywords were used in the studies: ‘CML’, ‘TKI resistance’, ‘novel therapies’, ‘immunotherapy’, ‘targeted agents’, and ‘combination therapies’. Only those studies were included that were clinical trials and preclinical across-the-board developmental programs that attempt to target the tumor at multiple levels and not just focus on basic first-line TKIs. Results: In CML patients who do not respond to TKIs, novel therapeutics encompass ponatinib, asciminib, CAR-T immunotherapy, and BCL-2 and mTOR inhibition in conjunction with TKI therapy. This addresses both BCR-ABL1-dependent and independent resistance mechanisms, increasing the chance of achieving deeper molecular response and reduced toxicity. Nonetheless, they exhibit diverse characteristics regarding efficacy, safety, cost, and quality of life effects. Discussion: Nonetheless, numerous challenges remain regarding the understanding of the mechanisms of resistance, the long-term efficacy of novel medicines, and the ideal combinations to attain optimal outcomes. Areas of future research include the search for other patterns of molecular resistance, tailoring specific treatments to patients, and incorporating AI to improve diagnosis and monitoring. Conclusion: The introduction of novel therapeutic techniques into clinical practice needs a collaborative approach and persistent dynamism to new findings from research. Our analysis indicates that the challenges posed by resistant CML disease are complex and require further improvements in therapeutic and clinical protocol development.

Hemato doi: 10.3390/hemato6010005

Authors: Stefano Mancin Marco Sguanci Gaetano Ferrara Riccardo Caccialanza Emanuele Cereda Alessio Lo Cascio Mauro Parozzi Fabio Petrelli Giovanni Cangelosi Sara Morales Palomares

Background/Aim: Omega-3 fatty acids, a key component of immunonutrition, have been used to modulate immune responses and improve clinical outcomes in various settings, including hematological patients undergoing hematopoietic stem cell transplantation (HSCT). This study aimed to summarize the effects of omega-3 supplementation on inflammation, long-term survival, and post-transplant complications, such as graft-versus-host disease (GVHD) and mucositis. Additionally, its impact on nutritional status and immune function was considered. Methods: A narrative review was conducted. The PubMed, Embase, and CINAHL databases were searched, along with sources of gray literature. From 2607 records, five studies met the inclusion criteria and were analyzed Results: The available literature suggests that omega-3 supplementation provides significant benefits, including reduced inflammation, lower C-reactive protein levels, and improved long-term survival. Furthermore, a reduction in GVHD and mucositis incidence was observed. The safety profile of omega-3 was favorable, with no serious adverse events reported. However, the evidence remains limited and heterogeneous, emphasizing the need for further well-designed trials to validate and expand upon these findings. Conclusions: Omega-3 fatty acids appear to be a promising intervention for improving clinical outcomes in HSCT patients. Additional research is essential to optimize treatment protocols and confirm its immunomodulatory role.

Hemato doi: 10.3390/hemato6010004

Authors: Nazanin Talebabadi Eusni Rahayu Mohd Tohit Maha Abdullah Siti Yazmin Zahari Sham Nur Fatin Zalikha Zailan Syafinaz Amin Nordin Irmi Zarina Ismail Ahmad Mahfuz Gazali Masriana Hassan

Obesity is among the most prevalent risk factors in the severe forms of Coronavirus disease 2019 (COVID-19) infection. COVID-19 patients with obesity often face severe complications that might be associated with overexpression of adiponectin, inflammatory cytokines, and angiotensin-converting enzyme 2 (ACE2) receptors in visceral fat. The pre-existing subclinical inflammation associated with obesity can also lead to severe inflammatory responses. Elevation of proinflammatory cytokines considerably activates coagulation cascades, including the tissue factor (TF) pathway. The hypercoagulable state in COVID-19 is presented with severe pulmonary complications such as venous thromboembolism (VTE), disseminated intravascular coagulation (DIC), and disruption of vascular endothelial cells, which can lead to severe complications and death. The interaction between inflammatory response and coagulation mechanism in COVID-19 patients with obesity warrants a further understanding of prognosis and potential therapeutic approaches. This review discusses the crosstalk between inflammation and coagulopathy in obesity-related severe COVID-19 infection.

Hemato doi: 10.3390/hemato6010003

Authors: Aishwarya Sridhar Thomas S. Gunning Alexandra Della Pia Xiaopei Zhang Jaeil Ahn Brittany Sinclaire Brittany Lukasik Christina Cho Michele L. Donato Sukhdeep Kaur Hyung C. Suh Lori A. Leslie Tatyana A. Feldman Andre H. Goy Andrew Ip

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common diagnosed aggressive B-cell lymphoma, with poor outcomes in those who experience relapsed or refractory (R/R) disease. Landmark clinical trials have demonstrated the efficacy and safety of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for patients with R/R DLBCL, though further exploration of real-world outcomes (RWOs) and safety data is warranted. Methods: A retrospective chart review was performed to collect patient and disease characteristics from patients with R/R DLBCL receiving CAR T-cell therapy for third-line treatment or beyond at the John Theurer Cancer Center as the standard of care. Results: We report on 82 patients with R/R DLBCL that successfully completed an infusion of an anti-CD19 CAR T-cell product at our institution. Best overall and complete response rates were 74.4% (95% CI, 64.9 to 83.8) and 67.1% (95% CI, 56.9 to 77.2), respectively. From the time of CAR T-cell infusion, median PFS was 26.5 months (95% CI, 8.6 months could not be estimated) and OS was not reached. Subgroup analyses revealed no statistical differences in outcomes by use of bridging therapy, Karnofsky performance status, transformed DLBCL status, and the type of CAR T-cell product used for this study. CAR T-cell therapy was well tolerated, with 58 patients (70.7%) experiencing cytokine-release syndrome and 17 patients (20.7%) experiencing immune effector cell-associated neurotoxicity syndrome. Conclusions: These results of RWOs in third-line patients with R/R DLBCL receiving anti-CD19 CAR T-cell therapy are comparable or superior to prior clinical trials and studies of RWOs, validating the strong efficacy and manageable toxicities of CAR T-cell therapy.

Hemato doi: 10.3390/hemato6010002

Authors: Giulia De Fusco Gianluca Gessoni

Background: Extracorporeal photopheresis (ECP) consists of the collection of a patient’s peripheral blood mononuclear cells (MNCs) that, after incubation with a photosensitive molecule, are exposed to ultraviolet-A (UVA) and then reinfused into the patient. There are two methods for performing the ECP procedure: the “in-line” methods and the “off-line” methods. In the “in-line” method, all the phases of ECP (leukapheresis, photoactivation, and reinfusion) are achieved sequentially in extracorporeal circulation using a single instrument and a single sterile disposable kit without disconnection from the patient’s blood circulation. In this paper, we report our real-life experience with a recently licensed in-line ECP system proposed by Fresenius-Kabi. Methods: The ECP procedures (n = 211) were performed using an Amicus cell separator and a Phelix UV irradiator with Amicus software 4.51 and Phelix software 1.0. A targeted 2000 mL of whole blood (WB) was processed, and 1.5 J/cm2 of UVA light was delivered to the collected mononuclear cells (MNCs). Results: From May 2023 to April 2024, we performed 211 ECP procedures in 11 patients with graft-versus-host disease (GvHD). The processed blood volume was between 1992 and 2000 mL, and the blood flow speed during the procedures was highly variable (from 30 to 50 mL/min), so the total duration of the procedure was quite variable (from 92 to 118 min). The collection efficiency (CE2) for mononuclear cells was always satisfactory (from 55% to 73%), with a minimal presence of RBCs and PLTs. Conclusions: In our experience, the Amicus system-based ECP procedure is safe and well tolerated as we observed only one side effect. The duration of the procedure was always under two hours. The collection efficiency (CE2) for MNCs was satisfactory, with minimal platelet and RBC product contamination.

Hemato doi: 10.3390/hemato6010001

Authors: Luciano Carideo Rosaria Meucci Giuseppe Campagna Vincenzo Marcello Russo Enrico D’Ippolito Maria Rinzivillo Francesco Panzuto Daniela Prosperi

Background/Objectives: Lutathera® ([177Lu]Lu-DOTA-TATE) is the first radiolabelled somatostatin (SST) analog approved for the treatment of patients with well-differentiated (G1 and G2) unresectable or metastatic gastro-entero-pancreatic neuro-endocrine-neoplasms (GEP-NENs). The bone marrow and kidneys are critical organs for RLT with [177Lu]Lu-DOTA-TATE. Our purpose was to evaluate hematological and renal toxicity in 29 patients (18 males, 11 females) treated with Lutathera®. Methods: According to standard protocols, four cycles of (177Lu)Lu-DOTA-TATE were administered every eight/nine weeks. Patients received pre-medication with anti-emetic and anti-acid drugs and a slow amino acid infusion for renal protection. Blood count and serum creatinine data were collected at three time points: before the first cycle, after the second cycle, and at the end of treatment. Results: We found that almost all hematological parameters significantly decreased between the baseline and/or interim and post-therapy evaluation, although without a clinical impact. The presence of total tumor load or bone metastases had no influence on these findings, while male patients showed less hematological toxicity than females. Conversely, creatinine levels did not vary during treatment. Conclusions: Our study confirms that [177Lu]Lu-DOTATATE RLT is safe and well tolerated despite some minor (grade 1) hematological toxicity.

Hemato doi: 10.3390/hemato5040035

Authors: Chiara Marcon Marta Medeot Alessio Michelazzi Valentina Simeon Alessandra Poz Sara Cmet Elisabetta Fontanini Anna Rosa Cussigh Marianna Chiozzotto Giovanni Barillari

Hereditary hemochromatosis (HH) related to HFE-gene mutations is a well-known condition, yet its understanding remains complex. The BIOIRON classification emphasizes that only homozygosity for the C282Y mutation should be considered pathogenic. The penetrance of HFE-related HH is highly variable. Symptoms are often challenging to recognize at the time of presentation, and the systemic involvement may overlap with other diseases. Hyperferritinemia and elevated transferrin saturation levels are still the milestones in HH diagnosis, but they are also common findings in many other clinical conditions. Furthermore, current diagnostic and therapeutic guidelines are not always unequivocal in defining HH patients’ characteristics, as well as treatment management and goals. Our work provides a concise overview of the latest evidence regarding pathogenic mechanisms, clinical picture, differential diagnosis and diagnostic tools. Alongside this, it summarizes and compares the main recommendations from principal guidelines issued by the 2017 Hemochromatosis International Meeting, the American College of Gastroenterology, the European Association for the Study of the Liver, the European Molecular Genetics Quality Network, the DUTCH guidelines, and the British Society for Haematology. Summarizing tables for quick consultation are also provided.

Hemato doi: 10.3390/hemato5040034

Authors: Maria Ntoumpara Elpis Mantadakis Lemonia Skoura Paraskevi Panagopoulou Elpida Emmanouilidou-Fotoulaki Eleftheria Parasidou Paraskevoula Koutra Maria Fotoulaki

Background: Hypophosphatemia is a known side-effect of parenteral iron administration, especially after intravenous ferric carboxymaltose (FCM). Fibroblast growth factor 23 (FGF23) is thought to play an important role in the pathophysiology of serum phosphate homeostasis. This study aimed to investigate the effects of FCM on FGF23 serum levels in FCM-treated pediatric patients with iron deficiency (ID)/iron deficiency anemia (IDA) caused by gastrointestinal diseases. Methods: Over 30 months, FGF23 serum levels were assessed prospectively in children with ID/IDA due to gastrointestinal diseases and treated with FCM infusion. Serum levels of intact FGF23 (iFGF23) were assessed and correlated to phosphate serum levels and factors of bone metabolism. Blood sampling was performed in three phases: before FCM infusion, 7–10 days after FCM infusion, and 6–8 weeks after FCM infusion. Results: A total of 42 FCM infusions were given to 35 children (20 girls) with a mean age (±SD) of 12.2 (±4.03) years (range: 2–16 years). The median levels of iFGF23 did not show a significant difference across the three phases (p = 0.56). No significant correlation was found between iFGF23 levels and 25-hydroxyvitamin D/parathyroid hormone/serum phosphate/serum calcium/alkaline phosphatase. No significant change was noted between pre- and post-treatment serum phosphate levels. However, four children (11.42%) developed asymptomatic and transient hypophosphatemia. Conclusions: No significant difference was found between pre-and post-FCM infusion serum iFGF23 levels and bone metabolism parameters. An increase of iFGF23 serum levels 7–10 days after FCM infusion was noted in patients with hypophosphatemia.

Hemato doi: 10.3390/hemato5040033

Authors: Antonino Carbone Annunziata Gloghini

The clinicopathologic spectrum of nodular lymphocyte-predominant Hodgkin lymphoma, now termed “nodular lymphocyte-predominant B-cell lymphoma” (NLPBCL), may include incipient, typical and transformed forms. On the basis of its clinicopathologic spectrum, NLPBCL is very similar to follicular lymphoma not associated with BCL2 translocation. In addition, NLPBCL, based on biopathologic features (gene profiling signature, and phenotypic and morphotypic characteristics), is a germinal center-derived B-cell neoplasm; therefore, it could be included in the follicular lymphoma group of non-Hodgkin lymphoma.

Hemato doi: 10.3390/hemato5040032

Authors: Paola Muggeo Vito Michele Rosario Muggeo Massimo Grassi Teresa Perillo Jessica Forte Celeste Raguseo Nicola Santoro

Background: Serum albumin is crucial for critically ill patients. To date, several reports have focused on the influence of lower albumin levels on poorer prognosis and disease outcome in different subsets of critical clinical conditions varying from sepsis, to cirrhosis, renal failure, and cancer. In the last few years, investigators reported the role of serum albumin levels in predicting the thrombotic risk in patients with nephrotic syndrome, and, in particular, the degree of hypoalbuminemia seemed to influence the risk of thromboembolism. Decreased serum albumin has been associated with the risk of venous thromboembolism and mortality in adult cancer patients after ending chemotherapy for different malignancies. Aims: We aimed to investigate the role of serum albumin in a cohort of children diagnosed as having VTE (venous thromboembolism) during their treatment for acute lymphoblastic leukemia (ALL) compared to ALL children who did not experience VTE. Methods: A nested case-control study was conducted at the Pediatric Oncology and Hematology Department, University Hospital of Bari. A total of 167 patients were diagnosed as having ALL and treated according to AIEOP-BFM ALL 2000-R2006 protocol. Among these, 12 cases of VTE were recorded and matched to 31 controls, for a total of 43 ALL patients (30 males, aged 1.2–16.6 years) enrolled in the present study. Serum albumin level was collected at diagnosis—before the start of any treatment—(time point 0) and at the moment of the VTE or corresponding time point of the protocol (time point 1). Information on inherited thrombophilia genotype were also recorded. Results: Patients presenting VTE showed a marked reduction of average albumin levels as compared to the control children: t0–t1 1.1 IC (95%) = (0.55, 1.65) vs. 0.31 IC (95%) = (0.08, 0.55); p < 0.005. Conclusions: The reduction of serum albumin levels in our cohort might be an expression of altered vascular and endothelial homeostasis, likely predisposing to VTE. This important clinical observation warrants further larger studies.

Hemato doi: 10.3390/hemato5040031

Authors: Alessandra Trojani Luca Emanuele Bossi Roberto Cairoli

Background: This review aims to provide an overview of the potential impact of fasting and diet on cancer, and in particular, on chronic lymphocytic leukemia (CLL), which is the most frequent form of leukemia in the Western world. Methods: Experimental and clinical studies have provided evidence of the crucial role of fasting in enhancing cancer treatment and improving outcomes for oncological patients, particularly at the early stages of the disease. Results: Emerging evidence highlights that fasting creates a differential stress response under critical conditions by fostering the survival of normal cells while limiting the survival and growth of cancer cells. Pivotal studies on CLL have highlighted the potential of fasting and dietary components to influence the stromal microenvironment and certain metabolic pathways, thereby affecting cancer cell apoptosis and immune response. In addition, explorative and initial clinical studies suggest that fasting and specific diets can mitigate the toxicity of chemotherapy. Conclusions: Clinical trials are needed to evaluate the efficacy and safety of nutritional and fasting approaches in cancer and CLL. Future investigations could provide new insights into the potential role of diet and fasting in the prevention and treatment of cancer, potentially leading to more effective and personalized therapeutic strategies.

Hemato doi: 10.3390/hemato5040030

Authors: Lisa Blackburn Anthony Mansour Qiuhong Zhao Francesca Cottini Abdullah Khan Naresh Bumma Srinivas Devarakonda Elvira Umyarova Ashley E. Rosko Jennifer Vaughn Nidhi Sharma Don M. Benson

Background—Autologous stem cell transplant (ASCT) is integral to the treatment of multiple myeloma (MM), although its absolute necessity in first remission has been recently questioned. We report real-world factors that influence clinical decision-making and outcomes from ASCT in 733 patients with MM. Results—Similar to recent prospective data, we found a significant progression-free survival (PFS) benefit with early versus deferred ASCT (median PFS of 5.1 years versus 2.6 years, p < 0.001); however, there was no significant difference in overall survival (median OS of 8.3 years and 8.6 years, p = 0.21). Patient preference, age, marital status, body mass index, and comorbidities influence ASCT timing. Conclusion—These findings highlight the emerging role of an individualized, shared decision-making model regarding the timing of ASCT between patients and physicians with the myriad of treatment options available in the contemporary era.

Hemato doi: 10.3390/hemato5040029

Authors: Mahat Taybi Zineb Khammar Noufissa Alami Drideb Rhizlane Berrady Sanae Benmiloud Laila Bouguennouch Sanae Elfakir Laila Tahiri Mohammed Majdoub Laila Chbani Nawal Hammas

Background: High-grade B-cell lymphoma with c-MYC and BCL2 and/or BCL6 rearrangements (HGBL-DHL/THL) is a recently identified category in the most recent World Health Organization (WHO) classification. For all tumors displaying the appearance of diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL), it is necessary to perform fluorescence in situ hybridization (FISH) in order to achieve an accurate diagnosis. The findings of FISH and immunohistochemistry (IHC) examinations from 50 DLBCL/HGBL samples obtained from Hassan II University Hospital in Fez/Morocco are reported. Methods: This retrospective study included 50 patients diagnosed with DLBCL/HGBL over a period of nine years (2013–2022) and treated with RCHOP chemotherapy protocol. All patients underwent a histological study followed by an immunohistochemical study to confirm the diagnosis and to classify patients according to cell of origin into non-GCB and GCB subtypes; then, a cytogenetic study using FISH was performed to classify patients according to the presence or absence of rearrangements in the c-MYC, BCL2 and BCL6 genes. A comparison was made between the molecular subtypes of DLBCL/HGBL in relation to clinicopathological features and outcomes. Results: Among the 50 cases studied in our population, we found 5 cases of HGBL with DLBCL morphology and 45 cases of DLBCL, which consisted of 13 cases (28.89%) of GCB subtype and 32 cases (71.11%) of non-GCB subtype based on the immunohistochemistry Hans algorithm. After FISH testing of all cases, we found three cases of double-hit lymphoma (DHL) and one case of triple-hit lymphoma (THL). Thus, HGBL-DHL/THL accounted for 8% of the cases. Furthermore, two cases were detected with only one rearrangement in the BCL2 gene and one case harboring a rearrangement in the BCL6 gene. DHL and THL patients and patients with a single rearrangement (BCL2 or BCL6) have a worse prognosis than patients with no rearrangement. Conclusions: DHL and THL are an aggressive entity of HGBL with poorer outcomes in comparison to DLBCL/HGBL NOS. First-line treatment with the RCHOP chemotherapy protocol may not be effective for all aggressive DLBCL cases. More targeted treatment is crucial for better patient outcomes.

Hemato doi: 10.3390/hemato5040028

Authors: Chiara Togni Giacinto La Verde Sabrina Pelliccia Maria Paola Bianchi Arianna Di Napoli Tiziana Lanzolla Marta Zerunian Andrea Laghi Gianluca Maiorana Ambra Taglietti Agostino Tafuri

Introduction: Primary bone lymphoma (PBL) is a rare clinical entity, accounting for less than 5% of all extranodal non-Hodgkin lymphomas and approximately 5% of primary bone tumors. Diffuse large B-cell lymphoma (DLBCL) is the most common histotype, accounting for about 80% of all PBL cases. Conversely, the incidence of indolent primary bone lymphomas (iPBL) represents less than 1% of all reported PBL cases, and data on these rarer lymphomas are scarce. Drawing on diagnostic criteria developed by the World Health Organization (WHO) and the International Extranodal Lymphoma Study Group (IELSG), we report a rare case of primary bone follicular lymphoma, focusing specifically on the clinical presentation and treatment. Discussion: Additionally, we provide a systematic review of the literature data on this very rare lymphoproliferative entity.

Hemato doi: 10.3390/hemato5040027

Authors: Teresa Perillo Marco de Giorgi Claudia Giorgio Carmine Frasca Renato Cuocolo Antonio Pinto

Background: Hematologic malignancies are a group of heterogeneous neoplasms which originate from hematopoietic cells. The most common among them are leukemia, lymphoma, and multiple myeloma. Machine learning (ML) is a subfield of artificial intelligence that enables the analysis of large amounts of data, possibly finding hidden patterns. Methods: We performed a narrative review about recent applications of ML in the most common hematological malignancies. We focused on the most recent scientific literature about this topic. Results: ML tools have proved useful in the most common hematological malignancies, in particular to enhance diagnostic work-up and guide treatment. Conclusions: Although ML has multiple possible applications in this field, there are some issue that have to be fixed before they can be used in daily clinical practice.

Hemato doi: 10.3390/hemato5030026

Authors: A. Nicolae E. Sabattini M. Ponzoni M. Paulli M. Lucioni T. Salviato A. Carbone

A two-day meeting on controversial topics in hematopathology was held in Bologna, Italy, on 19–20 January 2024. The meeting primarily targeted pathologists lacking experience in hematological neoplasms and pathologists in training. The course aimed to highlight practical diagnostic challenges faced by pathologists and discuss solutions through the application of conventional histology, along with appropriate immunohistological, genetic, and molecular findings. The teaching program included lectures and slide seminars presented by a team of expert hematopathologists who were co-authors of the WHO classification of hematolymphoid tumors. Special interest revolved around “lymphadenitis and lymphoma mimickers”, “a rational approach to low-grade B-cell lymphomas”, and “advancements in defining Hodgkin lymphoma”. A key aspect emphasized by the faculty team was the use of the fifth edition of the WHO Bluebook and the International Consensus Classification (ICC 2022) of lymphomas.

Hemato doi: 10.3390/hemato5030025

Authors: Muhammad Aminu Idris Lucia Ruggieri Hafsat Rufai Ahmad Abdulaziz Hassan Ismaila Nda Ibrahim Faruk Jamil Adullahi Sani Awwalu Usman Nasiru Fedele Bonifazi Baba P. D. Inusa

Background: Sickle cell disease (SCD) is an autosomal recessive haemoglobin disorder, affecting about 7.74 million individuals worldwide, but it is more prevalent among Africans and Asians. SCD is characterised by many complications, and it is a major health issue in Nigeria, the country with the largest burden of the disease globally. This work aims to present the design and implementation of electronic registries (ER) for SCD in a tertiary hospital in Nigeria. Methods: Registry design was initiated during a staff exchange programme within the ARISE initiative (EU grant agreement no. 824021). Ethical approval was obtained, and paper records were retrieved and transferred into one adult and one paediatric database, developed with Microsoft Access. Results: Data from 2659 SCD patients were entered in the ERs, including 698 (26.3%) adults and 1961 (73.7%) children. There were 287 (41%) male adults, 404 (58%) female and 7 (1%) patients whose gender was missing. There were 1041 (53.1%) male children, 906 (46.2%) female and 14 (0.7%) whose gender was missing. Information on phenotype was available for 2385 subjects, and most of them (2082, 87.3%) were SS. The most prevalent SCD-related complication was painful events (26.6% in adults and 68.7% in children, considering valid cases). Conclusions: About 60% of SCD patients in the centre were included in the ERs providing useful, hands-on recommendations for future ER design in SCD. These ERs might be an appropriate tool for collecting and analysing SCD patients’ data.

Hemato doi: 10.3390/hemato5030024

Authors: Alexandria P. Eiken Elizabeth Schmitz Erin M. Drengler Audrey L. Smith Sydney A. Skupa Kabhilan Mohan Sandeep Rana Sarbjit Singh Jayapal Reddy Mallareddy Grinu Mathew Amarnath Natarajan Dalia El-Gamal

Background: B-cell receptor (BCR) signaling is a central driver in chronic lymphocytic leukemia (CLL), along with the activation of pro-survival pathways (e.g., NF-κB) and aberrant anti-apoptotic mechanisms (e.g., BCL2) culminating to CLL cell survival and drug resistance. Front-line targeted therapies such as ibrutinib (BTK inhibitor) and venetoclax (BCL2 inhibitor) have radically improved CLL management. Yet, persisting CLL cells lead to relapse in ~20% of patients, signifying the unmet need of inhibitor-resistant refractory CLL. SpiD3 is a novel spirocyclic dimer of analog 19 that displays NF-κB inhibitory activity and preclinical anti-cancer properties. Recently, we have shown that SpiD3 inhibits CLL cell proliferation and induces cytotoxicity by promoting futile activation of the unfolded protein response (UPR) pathway and generation of reactive oxygen species (ROS), resulting in the inhibition of protein synthesis in CLL cells. Methods: We performed RNA-sequencing using CLL cells rendered resistant to ibrutinib and venetoclax to explore potential vulnerabilities in inhibitor-resistant and SpiD3-treated CLL cells. Results: The transcriptomic analysis of ibrutinib- or venetoclax-resistant CLL cell lines revealed ferroptosis, UPR signaling, and oxidative stress to be among the top pathways modulated by SpiD3 treatment. By examining SpiD3-induced protein aggregation, ROS production, and ferroptosis in inhibitor-resistant CLL cells, our findings demonstrate cytotoxicity following SpiD3 treatment in cell lines resistant to current front-line CLL therapeutics. Conclusions: Our results substantiate the development of SpiD3 as a novel therapeutic agent for relapsed/refractory CLL disease.

Hemato doi: 10.3390/hemato5030023

Authors: Marialuisa Zedde Micol Quaresima Isabella Capodanno Ilaria Grisendi Federica Assenza Manuela Napoli Claudio Moratti Claudio Pavone Lara Bonacini Giovanna Di Cecco Serena D’Aniello Franco Valzania Francesco Merli Rosario Pascarella

Sickle cell disease (SCD) is a hereditary blood disorder characterized by abnormal hemoglobin, leading to the sickle shape of red blood cells. It has several vascular complications and the cerebrovascular ones are among the most frequent and severe both in children and in adults. This review summarizes the main neurovascular manifestations of SCD, including acute stroke, silent cerebral infarction, large-vessel diseases (moyamoya arteriopathy and aneurysms), and brain bleeding. Both epidemiology, pathophysiology, and treatment issues are addressed and prevention of cerebrovascular events, including silent cerebral infarctions, is particularly relevant in SCD patients, being associated to poor functional outcome and cognitive complaints. Transfusions and hydroxyurea are the main available therapy at the moment, but contraindications, availability, and complications might prevent their long term use, particularly in low-income countries. The role of transcranial Doppler in monitoring the patients (mainly children) is analyzed and a practical approach has been selected in order to give the main messages from the current literature for a better management of SCD patients.

Hemato doi: 10.3390/hemato5030022

Authors: Velizar Shivarov Denitsa Grigorova Mira Nedeva Todor Milkov Albena Zlatareva Angel Yordanov

Background: In the last two decades, tyrosine kinase inhibitors (TKIs) and advances in molecular diagnostics have revolutionized management and long-term clinical outcomes in chronic myeloid leukemia (CML). Real-world data from different countries allow for the identification of country-specific issues in the clinical management and development of specific plans for improvement. Here, we aimed to analyze the trend in overall survival in Bulgarian CML patients since 2000. Methods: We retrieved publicly available Bulgarian CML data from several sources such as the Bulgarian National Cancer Registry, Bulgarian National Statistical Institute, and National Health Insurance Fund since 2000. We used the retrieved data of a total of 1513 Bulgarian CML patients to describe the trends in overall survival (OS), conditional overall survival, life expectancy, and life years lost over five time periods. We also described the trends in healthcare expenditures for TKIs and CML patients’ coverage with TKIs since 2014. Results: In both uni- and multivariate models, we found a constant increase in OS over the three 5-year periods until 2014. The period 2015–2019 was not associated with an additional increase in OS. Identical dynamics in the improvement in life expectancy (LE) and in life years lost (LYLs) was observed. Additionally, conditional 5-year survival did not improve during 2015–2019 in comparison to 2010–2014. Population-level data did not show consistent changes in the documented number of deaths due to CML since 2013. The period after 2013 is marked by a constant increase in the annual expenditures for TKIs, reaching to about 2.0 EUR/capita. The number of patients who received at least one TKI also increased during that period. Conclusions: After the initial significant improvement in the clinical outcomes for Bulgarian CML patients until 2014, subsequent periods did not bring further benefit in spite of the improved coverage with second- and third-line TKIs. Multiple factors may contribute to these suboptimal outcomes. Therefore, one can propose several additional measures at the country level, which could lead to additional improvement in the OS of Bulgarian CML patients.

Hemato doi: 10.3390/hemato5030021

Authors: Giacomo Malipiero Anna Ermacora Chiara Pratesi Antonino Carbone Adolfo Rogato Simonetta Prosdocimo Rita De Rosa Paolo Doretto

Refractoriness to standard first-line therapy in immune thrombocytopenia (ITP) should foster additional diagnostic work-up to exclude hematological clonal disease, mostly myelodysplatic syndrome (MDS) or clonal cytopenia of unknown significance (CCUS), which may present with isolated thrombocytopenia of immune or non-immune origin. We herein report on a patient who showed a transient leukoerythroblastic reaction (LEB) associated with bone marrow myelofibrosis upon rompilostim treatment, challenging a diagnosis of primary ITP and requiring additional investigations. RUNX-1-mutated myelodysplastic syndrome was eventually diagnosed. Even though LEB and marrow fibrosis have already been rarely reported during romiplostim treatment for ITP, this is the first case to our knowledge in which a background clonal hematopoiesis was diagnosed and deemed potentially involved in the abnormal response to this thrombopoietin receptor agonist (TPO-RA).

Hemato doi: 10.3390/hemato5030020

Authors: Tulasi Geevar Peter J. B. Sabatini Tong Zhang Ali Sakhdari

We present a case of adult-onset systemic chronic active EBV disease (CAEBV) in a 40-year-old woman with chronic HBV hepatitis. Initial symptoms resembled a viral illness, progressing to recurrent fever, transaminitis, and anasarca. Investigations revealed high-level EBV viremia and an abnormal T-cell population in the liver and bone marrow, indicative of CAEBV. The liver biopsy showed CD3+ T-cells lacking TCRbeta and displaying dim/negative CD5, with elevated EBV-infected T-cells. Next-generation sequencing identified rare variants in CREBBP, SPEN, TP73, and PLCG2, suggesting potential contributions to disease pathogenesis. This case underscores the diagnostic challenges and management complexities of adult-onset CAEBV, particularly with underlying chronic HBV infection. Genomic profiling offers crucial insights into the molecular landscape of rare lymphoid malignancies, highlighting the importance of personalized treatment strategies. The distinct immunophenotypic features underscore the heterogeneity in EBV-associated T-cell LPDs, urging further research for optimized clinical management.

Hemato doi: 10.3390/hemato5030019

Authors: Arturo Bonometti Simone Zanella Daoud Rahal Chiara Milanesi Rossella Caselli Matteo Giovanni Della Porta Silvia Uccella Sara Fraticelli

Diagnosis of myeloid neoplasm is currently performed according to the presence of a predetermined set of clinical, morphological, and molecular diagnostic criteria agreed upon by a consensus of experts. Even strictly adhering to these criteria, it is possible to encounter patients who present features that are not easily ascribable to a single disease category. This is the case, e.g., of patients with de novo myeloid neoplasms with features intermediate between primary myelofibrosis (PMF) and chronic myelomonocytic leukemia (CMML). In this study, we retrospectively searched the pathological database of IRCCS Humanitas Research Hospital to identify cases of chronic myeloid neoplasm with monocytosis with a driver mutation of classic myeloproliferative neoplasms (MPN) and showing morphological MPN features. For each case, we assessed all epidemiological, clinical, histopathological, and molecular data. Then, we carried out a literature review, searching for cases with features similar to those of our patients. We retrieved a total of 13 cases presenting such criteria (9 from the literature review and 4 from our institution); in all of them, there was a coexistence of clinical, histopathological, and molecular myelodysplastic and myeloproliferative features. To date, according to current classifications (World Health Organization and International Consensus Classification), given the presence/absence of essential features for PMF or CMML, these patients should be formally diagnosed as myelodysplastic/myeloproliferative neoplasm unclassified/not otherwise specified (U/NOS). This review aims to summarize the features of these difficult cases and discuss their differential diagnosis and their classification according to the novel classifications and the existing literature on overlapping myeloid neoplasms.

Hemato doi: 10.3390/hemato5030018

Authors: Pilar Solves Alcaina Pedro Asensi Cantó

Monoclonal antibody (MoAb) therapy has been increasingly used in recent years for hematologic malignancies. The MoAbs anti-CD38 and anti-CD47 are immunoglobulins directed against epitopes that are highly expressed not only on cancer cells, but also on red blood cells (RBCs), as well as platelets. Additionally, producing an off-target effect interferes in pre-transfusion testing, having the potential to unchain hemolytic anemia. Blood banks must assure the availability and safety of blood products for patients in need. Thus, MoAbs have become a challenge for blood banks, since methods to overcome interferences must be adopted. Several strategies have been proposed to mitigate pan-reactivity in pre-transfusion indirect antiglobulin tests, such as the treatment of reagent RBCs with enzymes or reducing agents, allogeneic RBC adsorptions, and drug-specific neutralization assays. All of these have some kind of limitation. This review summarizes the interferences of MoAbs in pre-transfusion testing, focusing on the available strategies to mitigate them in order to provide a safe transfusion.

Hemato doi: 10.3390/hemato5020017

Authors: Sakditad Saowapa Natchaya Polpichai Manasawee Tanariyakul Thanathip Suenghataiphorn Narathorn Kulthamrongsri Maireigh McCullough Mariana Goncalves Damasceno Moreira Pharit Siladech Lukman Tijani

Background: Autoimmune disorders (ADs) are prevalent among patients with myelodysplastic syndrome (MDS), yet their impact on MDS outcomes, including overall survival (OS), mortality, and transformation to acute myeloid leukemia (AML), is not well defined. Methods: We conducted a systematic review of articles published up to April 2024, sourced from PubMed, Web of Science, Embase, and Google Scholar, focusing on the influence of ADs on survival and AML transformation rates in MDS patients. The methodological quality of each study was assessed using the Newcastle Ottawa Scale. Results: From 8 studies that met the inclusion criteria, ADs were present in 17.5% (3074/17,481) of MDS patients. Data analysis indicated mortality rates ranging from 15.3% to 67% in MDS patients with ADs and 12% to 69% in those without. The rate of AML transformation varied from 0% to 23% in patients with ADs compared to 4% to 30% in those without. Conclusions: The influence of ADs on survival and AML transformation in MDS patients appears variable. This systematic review highlights the need for further large-scale prospective studies to clarify the relationship between ADs and MDS outcomes.

Hemato doi: 10.3390/hemato5020016

Authors: Annunziata Gloghini Antonino Carbone

Classic Hodgkin lymphoma (cHL) is a B-cell lymphoma in which tumour cells, the so-called Hodgkin Reed–Sternberg (HRS) cells, are admixed with non-malignant cell types that are a functional part of the disease. Immune cells, fibroblasts, specialised mesenchymal cells, and microvasculature together make up the tumour microenvironment and have functional interactions with tumour cells. HRS cells are surrounded by T and B cells admixed with plasma cells, macrophages, eosinophils, and mast cells. A cross-talk occurs between HRS cells and immune cells of the TME. This cross-talk is mediated either by a large network of cytokines and chemokines expressed by HRS cells or molecules produced by different cell types of the TME, i.e., CD30/CD30L, CD40/CD40L, OX40L/OX40, Il- 3/Il-3R, CCR5/CCL5, CD74 macrophage migration inhibitory factor/macrophages, and PD-L1/PD-1. The over-expression of CD30 and CD40, members of the TNF receptor family, is a hallmark of HRS cells. This review highlights the current development of newer therapeutic strategies as a means of immune checkpoint blockade and suggests that further research should explore innovative molecules aimed at targeting components of HL that are involved in cancer cell growth and/or immune escape. Hopefully, this will influence sensitivity or resistance to checkpoint inhibitor therapy in an individual patient.

Hemato doi: 10.3390/hemato5020015

Authors: Gianluca Maiorana Giusy Antolino Giacinto La Verde Agostino Tafuri

Multiple Myeloma is a hematological neoplasm that, over the recent few years, has benefited from numerous therapeutic options. Among the latter, CAR-T stands out as the most recent and one of the most promising treatments currently available. Despite its recent introduction, multiple CAR-T products have already been approved, and research regarding cellular therapy is rapidly increasing. We conducted a comprehensive search and review of the available literature, including published studies and abstracts from recent meetings (ASH, ASCO, ASTCT, IMS), regarding Multiple Myeloma and CAR-T therapy. We describe the discovery and research regarding promising targets like the B-Cell Maturation Antigen (BCMA) and others, the origin and nature of CAR-T cells, and the recent introduction of anti-BCMA CAR-Ts Idecabtagene-vicleucel and Ciltacabtagene-autoleucel, which are currently the only approved CAR-T products for MM. Additionally, we discuss non-BCMA-targeting CAR-Ts and their clinical implications. Given the significant impact of cellular therapy, we provide an overview of its limitations and possible adverse implications, as well as related resistance mechanisms. Finally, we describe the current research aimed at improving CAR-T therapy in MM, including structural innovations and new therapeutic approaches, such as in the earlier lines of treatment and maintenance therapy.

Hemato doi: 10.3390/hemato5020014

Authors: Paula Rodriguez-Otero Thomas Martin

The treatment of relapsed and refractory multiple myeloma has improved substantially in the last 5–10 years based on the development and use of several novel classes of drugs and drug combinations. These advances have led to improvements in progression-free and overall survival as well as quality of life. The general tendency has been to advance drugs/combinations that have performed well in advanced disease to the earlier line settings (frontline, first/early relapse). There are several triplet drug combinations that, when used as part of first or early relapse, can provide remission durations of 3 years or longer. More recently, impressive responses have been seen with the use of targeted immunotherapeutics (chimeric antigen receptor T-cells and bispecific antibodies) in heavily pretreated patients with MM. These treatments, however, have been associated with some new and occasionally severe toxicities, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and severe infections, including opportunistic infections and profound cytopenias. These potential toxicities bring into question whether these immune-targeting drugs should remain as late-line therapeutics or whether the high single-agent overall response rates mandate that these agents be used in earlier line settings. Herein, the authors provide a point and counterpoint about the future use of these agents.

Hemato doi: 10.3390/hemato5020013

Authors: Elaine S. Jaffe Antonino Carbone

The World Health Organization (WHO) “Classification of Tumours of Haematopoietic and Lymphoid Tissues”, published in 2001 and subsequently updated in 2008 and 2017, defined disease entities based on morphologic and phenotypic characteristics, clinical features, and genomic findings. Recently, the criteria for the diagnosis of many lymphoma entities have been refined in a proposal by the International Consensus Classification (ICC). Some provisional categories have now been recognized as “definite” entities, while other categories have undergone major revision. This article reports on the major revisions in the criteria and definition of B- and T-/NK-cell lymphomas by the ICC system.

Hemato doi: 10.3390/hemato5020012

Authors: Paul G. Richardson

High-dose melphalan (HDM) plus autologous stem cell transplant (ASCT) remains a standard-of-care treatment approach for eligible patients with newly diagnosed multiple myeloma (NDMM) based on demonstrated superiority in terms of progression-free survival (PFS) versus nontransplant approaches. Very high rates of minimal residual disease (MRD)-negative responses are also being seen with novel triplet and quadruplet induction regimens plus HDM-ASCT. However, recent clinical trials have shown no overall survival benefit with transplant versus nontransplant approaches. Furthermore, HDM is associated with several important downsides, including acute and long-term toxicities, transient decreases in quality of life, the need for hospitalization, an increased mutational burden at relapse, and an elevated risk of second primary malignancies. In this context, given the highly heterogeneous nature of MM in the NDMM patient population, as well as the continued emergence of novel agents and treatment approaches, there is an increasing rationale for considering deferred HDM-ASCT approaches in selected patients. Approaches under investigation include MRD-adapted therapy and the use of novel immune-based therapies as alternatives to HDM-ASCT. Ongoing developments in understanding the pathobiology and prognostic factors in NDMM, plus immune profiling and routine MRD evaluation, will result in novel, HDM-sparing treatment paradigms, enabling further improvement in patient outcomes.

Hemato doi: 10.3390/hemato5020011

Authors: Joaquim Carreras Naoya Nakamura

Background: Artificial intelligence in medicine is a field that is rapidly evolving. Machine learning and deep learning are used to improve disease identification and diagnosis, personalize disease treatment, analyze medical images, evaluate clinical trials, and speed drug development. Methods: First, relevant aspects of AI are revised in a comprehensive manner, including the classification of hematopoietic neoplasms, types of AI, applications in medicine and hematological neoplasia, generative pre-trained transformers (GPTs), and the architecture and interpretation of feedforward neural net-works (multilayer perceptron). Second, a series of 233 diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab-CHOP from the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) was analyzed. Results: Using conventional statistics, the high expression of MYC and BCL2 was associated with poor survival, but high BCL6 was associated with a favorable overall survival of the patients. Then, a neural network predicted MYC, BCL2, and BCL6 with high accuracy using a pan-cancer panel of 758 genes of immuno-oncology and translational research that includes clinically relevant actionable genes and pathways. A comparable analysis was performed using gene set enrichment analysis (GSEA). Conclusions: The mathematical way in which neural networks reach conclusions has been considered a black box, but a careful understanding and evaluation of the architectural design allows us to interpret the results logically. In diffuse large B-cell lymphoma, neural networks are a plausible data analysis approach.

Hemato doi: 10.3390/hemato5020010

Authors: Salomon Manier Thierry Facon

Multiple myeloma (MM) presents unique challenges in the elderly population due to increased frailty and comorbidities. Balancing treatment efficacy, safety, and quality of life is essential in managing elderly patients. While two-drug regimens were often favored for elderly patients, recent studies show promising outcomes with anti-CD38 antibody-based therapies, particularly daratumumab and lenalidomide with minimal dexamethasone. Continuous low-intensity treatments have shown improved progression-free survival and overall survival, with significant benefits observed in elderly patients. The DRd combination has now emerged as the standard of care for elderly MM patients, offering a favorable balance of efficacy, safety, and convenience. Ongoing trials are evaluating the addition of bortezomib in an induction phase for fit patients. New-generation immunotherapies hold promise for further refining treatment approaches, potentially leading to treatment discontinuation in select patient populations with sustained minimal residual disease negativity.

Hemato doi: 10.3390/hemato5020009

Authors: Pilar Solves Ana Bataller Ana Belén Gálvez Pedro Asensi Cantó Marta Santiago María José Moreno Inés Gómez-Seguí Javier de la Rubia

Background: Selective IgA deficiency (IgA-D) has been historically considered a high-risk entity for developing allergic/anaphylactic reactions after blood transfusion (AATRs). However, it has been suggested that the IgA-D-related anaphylactic transfusion reaction is not evidence-based. Methods: We conducted three different approaches to collect evidence about epidemiology, AATRs, and transfusion management of patients with IgA-D at La Fe University Hospital. Firstly, we analysed the prevalence of IgA-D in a population of patients diagnosed with acute leukaemia, The second approach consisted of collecting transfusion data from IgA-D patients. Finally, we reviewed the IgA levels of patients recorded in the hemovigilance system suffering an AATR. Results: IgA-D prevalence was 1 in 334 patients. At least one blood component was transfused to 23 patients diagnosed with IgA-D. Plasma was transfused to eight IgA-D patients, while six patients received red blood cells, platelets, and plasma. No adverse reactions were reported in any patient. AATRs occurred in 325 men and 264 women with a median age of 52 years. Severe reactions occurred in 56 patients (1/14,520 components). Mean IgA levels were 215 mg/dL (4–5570) for mild reactions and 214 mg/dL (14–824) for severe reactions (p = ns). Washed platelets were administered to two patients who developed severe and repeated AATRs. Both had normal IgA levels. Conclusions: Since the AATRs related to IgA-D are extremely low, as reported in current hemovigilance systems, IgA-D should not be considered a high-risk entity to develop AATRs. On the contrary, our findings support standard transfusion management of IgA-D patients.

Hemato doi: 10.3390/hemato5010008

Authors: Michael Dennis Weaver Bianca Glass Chance Aplanalp Gauri Patel Jeshrine Mazhil Isabella Wang Samir Dalia

Eosinophils are a type of granulocyte key to immune system modulation seen in a number of disease processes. Nearly every major organ system can be connected to peripheral eosinophilia through a number of different disease processes, ranging from benign conditions to malignancy. In this paper, we review both common and rare causes of peripheral eosinophilia, their symptoms, and a framework for the workup of peripheral eosinophilia of unknown etiology.

Hemato doi: 10.3390/hemato5010007

Authors: Natalia Wojciechowska Kaci Orr Karen Albritton Kenneth Heym Kelly Vallance Lauren Murray Rocio Aguilar Anish Ray

Immunotherapy has emerged as a promising treatment approach in oncology, as it is specifically designed to boost the strength and accuracy of the immune system, allowing it to target tumor cells but spare non-tumor tissue. This treatment not only demonstrates potential for improved clinical outcomes but may also be associated with fewer adverse effects compared to traditional therapies. Despite its early success, the application of immunotherapy has largely been limited to adult cancer patients, with slow adoption noted in the treatment of pediatric cancer patients. Our objective is to demonstrate a single institution’s experience with immunotherapy in pediatric cancer patients and to discuss the use of these treatment modalities in this unique patient population. We performed a retrospective chart review and identified patients who received immune checkpoint inhibitors (ICIs) and/or underwent immunohistochemistry (IHC) testing for programmed death ligand 1 (PD-L1), quantification of tumor mutational burden (TMB), and classification of microsatellite instability (MSI) status. In total, we identified seven pediatric cancer patients who received therapy with ICIs. Four of these patients demonstrated positive PD-L1 expression, high TMB, and/or MSI-high status. These patients were treated with nivolumab alone or in combination with ipilimumab or brentuximab. The diagnoses included: multifocal epithelioid and spindle cell hemangioma (n = 1); metastatic melanoma (n = 2); histiocytic sarcoma (n = 1); rectal adenocarcinoma in the setting of constitutional mismatch repair deficiency syndrome (CMMRD) (n = 1); and Hodgkin lymphoma (n = 2). The patients received between four and nineteen cycles of immunotherapy. Immunotherapy-related adverse events included: mild allergic reaction; prodromal symptoms; anemia; neutropenia; transaminitis; endocrinopathies; and self-limiting neuritis. Of the seven patients, three are still being treated with immunotherapy (the patients with rectal adenocarcinoma, metastatic melanoma, and multifocal epithelioid and spindle cell hemangioma) with positive treatment responses observed on imaging, one is being treated with other modalities (the patient with Hodgkin lymphoma), two have achieved remission (the patients with metastatic melanoma and Hodgkin lymphoma), and one has relapsed (the patient with histiocytic sarcoma). The three patients who completed their immunotherapy regimens have been followed for 1 month, 4 months, and 10 months, respectively. This report of a single-institution experience with immunotherapy in pediatric cancer patients highlights the positive impact immunotherapy can have, especially when utilized to treat relapsed/refractory malignancies, as tumor regression or stabilization of disease burden was achieved in six of the patients described (CR = 2; PR = 4). Further research is needed to accurately identify pediatric oncology patients who could benefit from immunotherapy.

Hemato doi: 10.3390/hemato5010006

Authors: Rabea Möller Katharina Kaiser Ulrich Baulain Björn Petersen Carsten Detering Mahnaz Ekhlasi-Hundrieser Richard Zimmermann Christian Mühlfeld Mario von Depka Prondzinski Christiane Pfarrer Stefanie Lehner

Pregnancy and the oestrus cycle are challenging for female patients suffering from von Willebrand disease (VWD). Therefore, our study aimed to investigate the changes in von Willebrand factor (VWF) and factor VIII (FVIII) during pregnancy and the oestrus cycle in our porcine model of von Willebrand disease compared with the wild-type. Plasma analyses regarding primary hemostasis, secondary hemostasis, and VWF multimers, as well as immunohistochemistry analyses of VWF in the uterus and ovary, were performed. For levels of VWF and FVIII activities, significant elevations were seen in the last trimester. Primary hemostasis improved towards the end of pregnancy. In the oestrus cycle, significantly lower VWF values can be seen in the immunohistochemistry of the ovaries during the oestrus, while values were highest in the metoestrus. VWF multimer patterns in pigs were similar to the ones in human VWD patients. In summary, the course of VWF and FVIII during pregnancy and the oestrus cycle in porcine VWD were investigated for the first time. The porcine model seems to be suitable for haemostaseological studies on VWD. This provides an advantage for investigating reproduction-related bleeding and understanding the underlying mechanisms of post-partum hemorrhage or miscarriage in women with VWD.

Hemato doi: 10.3390/hemato5010005

Authors: Elpis Mantadakis Sonia Alexiadou Panagiota Zikidou

Iron deficiency (ID) is by far the most common nutritional disorder in developing and developed countries. When left untreated, ID leads to anemia. Although the usually recommended treatment for iron deficiency anemia (IDA) is oral iron therapy with countless products, such therapy necessitates administration for >3–6 months with questionable patient compliance since most oral iron products have an unpleasant metallic aftertaste and cause intestinal side effects. In addition, in certain gastrointestinal conditions, such as inflammatory bowel diseases or untreated gluten-sensitive enteropathy, oral iron therapy is contraindicated or unsuccessful. Intravenous iron is considered safe in adults, where adverse events are mild and easily managed. The experience with parenteral iron in children is much more limited, and many pediatricians appear reluctant to use it because of uncorroborated fears of serious anaphylactic reactions. In the current article, we thoroughly review the available pediatric literature on the use of all commercially available parenteral iron products except ferumoxytol, which was recently removed from the market. We conclude that parenteral iron appears to be safe in children; it works faster than oral iron, and the newer third-generation products allow replacement of the total iron deficit in a single sitting.

Hemato doi: 10.3390/hemato5010004

Authors: Aditi Sharma Amit Dahiya Asif Alavi Indryas Woldie Aditya Sharma Jeffrey Karson Vijendra Singh

Background: Transfusional iron overload causes significant morbidity and mortality in sickle cell disease (SCD). Nevertheless, red blood cell transfusions continue to be essential in its management. This study describes the transfusion patterns among SCD hospitalizations. Methods: Hospitalizations for SCD in the 2017–2018 Nationwide Readmissions Database were divided into two groups based on whether they received transfusions. Descriptive analysis was performed to compare their demographics and complications. Multivariable logistic regression was performed to determine the factors associated with transfusions. Results: Out of 109,783 hospitalizations, 28,300 were transfused, and 81,483 were not transfused. Females and older individuals were higher in the transfused category than the non-transfused category (59.49% vs. 53.52% and 28.86% vs. 21.27%, respectively; p < 0.001 for both). The wealthiest population was more likely to be in the transfused category (11.27% vs. 8.34%; p < 0.001). Admissions to teaching hospitals, large metropolitan hospitals, and highest-volume hospitals were higher in the non-transfused category vs. transfused category (79.89% vs. 72.17%; p < 0.001, 69.26% vs. 65.35%; p 0.003 and 74.71% vs. 63.51%; p < 0.001, respectively). Most admissions were transfused once, with three or more transfusions being given more in the non-teaching hospitals than the teaching hospitals (1.27% vs. 0.41%; p 0.01). Furthermore, a higher proportion of early transfusions occurred in the non-teaching hospitals (65.6% vs. 57.82% for admission days 1 and 2; p < 0.001). Admission to a teaching hospital was associated with lower blood transfusion odds than a non-teaching hospital. Conclusion: A quarter of admissions for SCD receive a blood transfusion. In addition to performing more frequent and early transfusions, the odds of being transfused are higher in non-teaching hospitals.

Hemato doi: 10.3390/hemato5010003

Authors: Alessandro Cellini Andrea Visentin Alessandro Salvalaggio Mario Cacciavillani Sergio Ferrari Chiara Briani

The dysregulation of the immune system in Chronic Lymphocytic Leukemia (CLL) often allows for the development of immune-mediated diseases. Among them, autoimmune cytopenias are the most common, but cases of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have been reported. We herein report on a patient who developed a CIDP while undergoing ibrutinib treatment for CLL, prompting drug discontinuation. Steroid treatment and a rituximab course proved to be ineffective at obtaining long-term control of CIDP, but therapy with venetoclax and rituximab, which was started due to CLL progression, led to the progressive amelioration of the symptoms up to complete remission of the neurological disease.

Hemato doi: 10.3390/hemato5010002

Authors: Francisco Alejandro Lagunas-Rangel Venice Chávez-Valencia

Acute lymphoblastic leukemia (ALL), a remarkable cancer that mainly affects children, has seen commendable advances in its treatment. However, the occurrence of relapses after initial treatments poses a major threat and is one of the leading causes of cancer-related mortality in pediatric patients. To address this problem, innovative therapeutic approaches for ALL need to be continuously developed and refined. Synthetic lethality, an interaction between genes in which alteration of only one allows survival, but simultaneous alteration of both leads to inviability, is emerging as a promising therapeutic approach against ALL and other cancers. In this regard, the review aims to examine the documented cases of synthetic lethality in ALL reported to date (2023) and to elucidate the molecular mechanisms underlying this phenomenon. Furthermore, this review explores possible targets that have so far gone unnoticed, justifying their importance in this context.

Hemato doi: 10.3390/hemato5010001

Authors: Antonino Carbone

Hemato (ISSN 2673-6357) is an open access, peer-reviewed journal that publishes original articles and reviews highlighting important advances in the fundamental areas of Hematology [...]

Hemato doi: 10.3390/hemato4040029

Authors: Lívia de Oliveira Sales Lais Lacerda Brasil de Oliveira Jean Breno Silveira da Silva Manoel Odorico de Moraes Filho Maria Elisabete Amaral de Moraes Raquel Carvalho Montenegro Caroline Aquino Moreira-Nunes

The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in China and is responsible for Coronavirus disease (COVID-19). Despite being well tolerated by most patients, a fraction of cases evolve into a potentially fatal condition requiring intensive care. In addition to respiratory complications, several studies have reported cases of patients who developed intense thrombosis, including acute myocardial infarction and ischemic stroke, as well as the presence of elevated coagulation markers. Evidence has shown that the virus can interact directly with platelets and modulate their thrombotic and inflammatory functions, with significant prognostic implications. It is important to highlight that the emerging literature shows that when hyperactive these cells can act as pro-viral infections both in transporting their particles and in increasing inflammation, leading to a hyperinflammatory state and consequent clinical worsening. In this review, we searched for studies available in public databases and discussed the interaction of platelet biomarkers in the pathogenesis of COVID-19. In this context, understanding the mechanism of SARS-CoV-2 and these cells in different clinical conditions could help us to understand the coagulation and inflammation profiles of critically ill patients with the disease, guiding faster clinical management and enabling the reuse and targeting of more efficient therapies.

Hemato doi: 10.3390/hemato4040028

Authors: Guillermo A. Herrera Jiamin Teng Chun Zeng Luis Del Pozo-Yauner Bing Liu Elba A. Turbat-Herrera

The process of light-chain-associated amyloid (AL-Am) fibril formation in unique organelles (fibril-forming organelles) with lysosomal features has been documented in vitro in renal mesangial cells incubated with amyloidogenic light chains using electron microscopy and lysosomal gradient centrifugation to visualize intricate interactions between monoclonal light chains and endosomes/lysosomes. It is important to determine whether this process also occurs in vivo in the human renal mesangium. The present study analyzes 13 renal biopsies from patients with renal AL-amyloidosis and utilizes ultrastructural labeling techniques to define the nature and function of these organelles. Organelles were labeled for lysosomal-associated membrane protein (LAMP) and CD-68 (a macrophage marker). Furthermore, lambda was also localized inside these structures in transformed mesangial cells with a macrophage phenotype. These 11 cases from renal biopsies with a diagnosis of AL-amyloidosis (5 kappa and 8 lambda light-chain-associated) were examined ultrastructurally. All of the cases exhibited numerous fibrils forming organelles in approximately 40–50% of the remaining mesangial cells. All of the cases revealed mesangial cells engaged in active amyloidogenesis. Fibril-forming organelles are organelles with morphological/immunohistochemical and biochemical characteristics of lysosomes but with a unique, peculiar morphology. Five cases of other glomerular disorders used as controls were also carefully scrutinized for fibril-forming organelles and failed to show any. In the AL-amyloid renal cases, there was an intricate interaction between the fibril-forming organelles and lambda-/kappa-containing amyloid fibrils, supporting the notion that the monoclonal light chains participated in their formation.

Hemato doi: 10.3390/hemato4040027

Authors: Karina P. Verma Rebecca Steuer Camille V. Edwards

Monoclonal gammopathy of undetermined significance (MGUS) is a pre-malignant plasma cell disorder with an etiology that is incompletely understood. Modifiable risk factors and genetic predispositions likely interact to increase MGUS risk in specific individuals and populations. Identifying geographic prevalence patterns and modifiable risk factors is critical for understanding the etiology of MGUS. The aim of this review was to outline original research on MGUS prevalence across geographic locations and modifiable risk factors. We conducted a systematic review of 39 eligible studies from PubMed®, Embase®, and Web of Science® written in English and published by February 2023. Our protocol was registered in accordance with PROSPERO guidelines. Studies were synthesized using Research Electronic Data Capture and appraised using the National Heart, Lung, and Blood Institute study quality assessment tools. The prevalence of MGUS ranged from 0.24% to 9% across geographic locations. Modifiable risk factors for MGUS include infections, autoimmune diseases, chronic inflammatory conditions, lifestyle factors, environmental exposures, and ionizing radiation. Therefore, the development of MGUS may be related to chronic antigenic stimulation and genetic aberrations that promote clonal proliferation of plasma cells. Prospective studies assessing gene–environment interactions are needed to further define risk factors for MGUS and inform screening and preventative strategies.

Hemato doi: 10.3390/hemato4040026

Authors: Chiara Marvisi Elena Galli Caterina Ricordi Rexhep Durmo Massimo Roncali Francesco Muratore Carlo Salvarani Annibale Versari

The role of 18F-fluorodeoxyglucose (FDG) positron emission tomography (18F-FDG PET) in the diagnosis of large vessel vasculitis (LVV) is well established. It permits us to assess the extent and the grade of vascular involvement and to rule out the other causes in clinical scenarios characterized by less specific symptoms. The advantages of 18F-FDG PET are far less clear in monitoring disease activity over time. Studies looking for the role of 18F-FDG PET as a potential biomarker had conflicting results and whether and when to repeat it during follow-up is based on clinical experience. A comprehensive assessment, including clinical, laboratory and morphological imaging is still required to monitor patients with large-vessel vasculitis over time. The aim of this review is to present more recent data about the utility of 18 F-FDG PET in the diagnosis and follow-up of LVV.

Hemato doi: 10.3390/hemato4040025

Authors: David Bared Dukenik Deborah Soong Wenhui Li Ellen Madarang Justin Watts Justin Taylor

We describe a case of a female patient with acute lymphoblastic leukemia treated with high-dose systemic methotrexate and intrathecal methotrexate for leukemic relapse of the central nervous system. She developed complete bilateral lower-limb paralysis that was not attributable to any other cause. She was treated with folic acid, vitamin B12, methionine, S-adenosylmethionine, leucovorin, and dextromethorphan. After a 3-month period of paraplegia, she began to slowly recover motor function. She can now ambulate with assistance and continues to improve. There is a paucity of literature on methotrexate-induced subacute combined degeneration, which is typically described as irreversible. In addition to reporting our unique case, we review the published literature and call for more awareness and research in this area.

Hemato doi: 10.3390/hemato4040024

Authors: Leigh A. Madden Rebecca V. Vince Victoria C. Edwards Vivienne M. Lee Desmond M. Connolly

The blood coagulation response to decompression stress in humans has yet to be fully investigated. Here we utilised calibrated automated thrombogram (CAT) on samples from healthy volunteers exposed to decompression stress to investigate real-time thrombin generation. To induce decompression stress, fifteen apparently healthy males (age 20–50 yr) were exposed to two consecutive ascents to 25,000 ft for 60 min (1st ascent) and then 90 min (2nd ascent) while breathing 100% oxygen. Citrated blood samples were taken prior to exposure (T0), following the 2nd ascent (T8) and at 24 h (T24). Thrombin generation curves were obtained using ThrombinoscopeTM. Parameters determined were lag time (LAG), time to peak (TTP), peak thrombin (PEAK), endogenous thrombin potential (ETP) and velocity index (VEL). Of the 15 subjects, 12 had validated coagulation profiles. TTP and ETP showed no significant differences. However, there was a significant increase in VEL from T0 to T8 (p = 0.025) and from T8 to T24 (p = 0.043). A non-significant trend of an overall increase in PEAK was also observed from T0 to T8 (p = 0.069) and from T8 to T24 (p = 0.098). PEAK and VEL were found to be correlated. Taken together, these two parameters suggest an overall shift towards a more procoagulant profile following hypobaric stress.

Hemato doi: 10.3390/hemato4040023

Authors: Ringo Manta Chiara Lauri Maurizio Taurino Alberto Signore

Diagnosis of vascular graft/endograft infection (VGEI) is a challenge for clinicians due to the heterogeneity of clinical presentation and the complexity of its management. Microbiological culture is the gold standard, but it often fails to isolate the causative microorganism. A non-invasive imaging approach is therefore needed to assess VGEI. CTA is currently the first-choice imaging modality. Nuclear medicine techniques are recommended in case of negative or doubtful CTA results with persisting clinical suspicion. This review aims to summarize data from original studies published in the last decades regarding the role of both white blood cell (WBC) scans and fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT), their respective diagnostic performances, and their integration into the diagnostic approach for patients with a suspicion of VGEI.

Hemato doi: 10.3390/hemato4030022

Authors: Giacomo Malipiero Piernicola Machin Anna Ermacora Chiara Pratesi Antonino Carbone Desre’ Ethel Fontana Kathreena Paul Vattamattathil Rita De Rosa Paolo Doretto

Kikuchi–Fujimoto disease (KFD) is a rare, benign lymphoproliferative disease of uncertain origin that can mimic other inflammatory or clonal lymphoproliferative disorders. Given the lack of available blood biomarkers, diagnosis is based on the biopsy of an affected lymph node. In recent years, evidence has been mounting that a dysregulated type I INF innate immune response plays a pivotal role in the pathogenesis of the disease and might be a future therapeutic target. Nonetheless, laboratory assays measuring the expression of interferon alpha (INFα) and INF-stimulated genes (ISGs) are cumbersome and not widely available, limiting their use in clinical and translational research and encouraging the use of more convenient surrogate markers. In this study, a rapid flow cytometry assay detected increased levels of expression of CD169 (Siglec-1), an INFα-induced surface protein involved in innate immunity regulation, on circulating monocytes from two patients with KFD. Our results are in line with previous experiences and set the stage for a more extended investigation into the use of this assay in exploring the pathophysiology of KFD.

Hemato doi: 10.3390/hemato4030021

Authors: Tina Bagratuni Alexandra Papadimou Kostantina Taouxi Meletios A. Dimopoulos Efstathios Kastritis

High frequencies of MYD88L265P mutation are observed in IgM monoclonal gammopathies, and specifically in Waldenström macroglobulinemia (WM), indicating this mutation as a potential disease biomarker. Given the fact that MYD88L265P mutation has been described as a key driver mutation, has increased our understanding of the biology behind MYD88 signaling and helped us to identify the functional components which could be targeted. On the other hand, the absence of the MYD88L265P mutation in patients with IgM monoclonal gammopathies has been associated with a higher risk of transformation to aggressive lymphomas, resistance to several therapies, and shorter overall survival. The present review focuses on the molecular mechanisms that shape the signaling pattern in MYD88WT cells, as well as on the clinical implications and therapeutic challenges of WM patients that harbor the MYD88WT genotype.

Hemato doi: 10.3390/hemato4030020

Authors: Mario Tiribelli Giuseppe Petruzzellis Giulia Battaglia Martina Pucillo Marta Lisa Battista Michela Cerno Antonella Geromin Gabriele Facchin Umberto Pizzano Daniela Damiani Renato Fanin Francesca Patriarca

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML), granting patients a life expectancy close to that of the normal population and, in a subset of patients, the possibility to discontinue therapy. Nonetheless, for a not negligible minority of patients, TKIs are not able to control CML. Allogeneic hematopoietic cell transplantation (HCT) has long been a pivotal therapy for CML. At present, allogeneic HCT is considered an option in CML patients diagnosed or progressing to blast phase (BP), for those in chronic phase (CP) resistant to multiple lines of TKI therapy or for those experiencing severe toxicity, mostly hematologic, under TKIs. Moving from real-world cases, we reviewed the results of allogeneic HCT in the setting of advanced-phase CML or failure of TKIs, with a focus on the progresses in transplant technology that has extended transplant options in elderly CML patients and in those lacking a sibling donor, and on the post-HCT strategies for prevention and treatment of disease relapse.