Medicine and Pharmacology

Abstract: Autoimmune hemolytic anemia is a rare but potentially life-threatening disorder characterized by immune-mediated red blood cell destruction. Warm AIHA accounts for most pediatric cases and in childhood AIHA differs substantially from adult disease because of its stronger association with infections, immune dysregulation syndromes and inborn errors of immunity. The disease is clinically heterogeneous, ranging from self-limited episodes to severe chronic relapsing forms requiring prolonged immunosuppression. Diagnostic evaluation should not be limited to the direct antiglobulin test, but must include confirmation of hemolysis, exclusion of alternative causes of anemia, and a systematic search for underlying disorders. Corticosteroids (CS) remain the cornerstone of first-line therapy for warm AIHA, whereas rituximab has emerged as the preferred second-line treatment in CS-dependent or CS-refractory patients. Management of cold-antibody AIHA, paroxysmal cold hemoglobinuria, Evans syndrome, and AIHA associated with giant cell hepatitis requires specific diagnostic and therapeutic considerations. Novel targeted therapies directed against B cells, plasma cells, complement activation, Fc receptors, and intracellular signaling pathways are expanding the therapeutic landscape and may improve outcomes in refractory disease.

Abstract: ABO and Rhesus blood groups have been associated with COVID-19 susceptibility and severity in several international cohorts, but African data remain scarce his study evaluates the association between ABO/Rh blood groups and COVID-19 severity and mortality in Senegal. We conducted a retrospective study of RT-PCR-confirmed COVID-19 patients with available blood group data. Clinical severity (severe forms: Severe and Critical) and in-hospital mortality were analyzed by ABO group and Rhesus status using Fisher’s exact test with Bonferroni correction (×4 for ABO groups) and global Chi-square. Odds Ratios (OR) with 95% confidence intervals (Woolf method) were calculated. ABO distribution: O (47.8%), A (28.8%), B (16.9%), AB (6.4%); Rh+ 94.2%. Severe forms accounted for 27.1% and deaths for 10.2%. No statistically significant association was found between ABO/Rh and severe disease (Chi²=2.40; p=0.494) or mortality (Chi²=1.00; p=0.802). All ORs remained* non-significant after Bonferroni correction. A non-significant trend toward higher mortality in group B (14.0% vs 9.4%; OR=1.57; p=0.312) and zero deaths among Rh− patients (0/17) warrant cautious interpretation. ABO and Rhesus blood groups have no significant impact on COVID-19 severity or mortality in this Senegalese cohort, suggesting that the role of blood groups in COVID-19 outcomes may vary across population.

Abstract: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for hematological malignancies but is associated with severe neurological complications. Although cerebrovascular events are relatively uncommon after allo-HSCT, with reported rates of 2–8%, they are difficult to manage and may substantially increase mortality. Their epidemiology, timing, risk factors, and influence on transplantation outcomes remain insufficiently characterized. This study aimed to assess the impact of post-transplant stroke on transplantation outcomes in patients with hematological malignancies.

Abstract: Blood donation sustains an estimated 118 million annual donations worldwide, and while advances in infectious disease screening have greatly reduced recipient risk, the long-term health of repeat donors has received comparatively less attention. This cumulative narrative review synthesises current evidence on the principal acquired complications of regular blood donation across all modalities — whole blood, plasmapheresis, and plateletpheresis — addressing iron deficiency, plasma protein depletion, apheresis-related lymphopenia, clonal haematopoiesis of indeterminate potential (CHIP), and micronutrient deficiency. Iron deficiency affects 15–36% of frequent whole blood donors and is systematically underdetected by haemoglobin-based screening alone; ferritin-guided interval adjustment and oral supplementation are effective countermeasures. Regular plasmapheresis depletes immunoglobulins (IgG below normal in 5–15% of high-frequency donors), albumin, and coagulation factors, compounded by cumulative citrate-mediated hypocalcaemia. Plateletpheresis causes measurable subset-selective T-cell and NK-cell depletion, with CD4⁺ counts below clinically significant thresholds in a minority of the most frequent donors and attenuated vaccine responses documented in affected individuals. Emerging molecular data indicate that repeated haematopoietic stress selectively enriches low-risk, EPO-responsive DNMT3A clonal variants without increasing malignant risk. Regular blood donation if properly applied is a safe process. Across all domains, current eligibility criteria based on haemoglobin alone turn out to be inadequate; a shift to multiparameter, individualised and targeted donor monitoring — integrating ferritin, serum proteins, differential leucocyte counts, and micronutrient profiling — is both evidence-based and ethically imperative to sustain the long-term health of voluntary donor populations.

Abstract: Background/Objectives: Myeloproliferative neoplasms are a group of clonal myeloid malignancies that affect bone marrow and include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). PV is caused in most of patients by the JAK2-V617F mutation and is characterized at phenotypic level by overproduction and accumulation of red blood cells. PV is associated with significant morbidity, including risk of thrombotic events and of hematologic evolution (myelofibrotic or leukemic transformation) and reduced survival. In addition to JAK2-V617F mutation, PV patients display additional molecular abnormalities. The aim of this study is to review recent studies investigating molecular abnormalities observed in PV. Methods: An extensive search of the most recent literature was performed, selecting and critically analyzing the most relevant studies. Results: The studies carried out in the last years have provided an extensive molecular characterization of PV, showing its heterogeneity, characterized in many patients by the presence of additional cytogenetic and non-driver gene mutations that contribute to the disease development and evolution. Conclusions: PV is a complex disease that needs to be carefully characterized at molecular level at diagnosis, to be monitored in time to predict the risk for thrombotic complications and hematologic evolution and to receive an adequate treatment.

Abstract: Introduction and Clinical Significance: Older, frail patients with relapsed diffuse large B-cell lymphoma (DLBCL) face limited treatment options due to poor tolerance for standard cytotoxic chemotherapy. While novel chemotherapy-free regimens like polatuzumab vedotin plus rituximab (Pola-R) have emerged, optimizing their use requires careful evaluation of patient vulnerability via geriatric assessment (GA) and shared decision-making (SDM). Case presentation: We present the case of a male in his late 70s with multiply relapsed DLBCL who was classified as frail by a comprehensive geriatric assessment, complicated by cognitive impairment and functional decline. Due to his frailty and previous intolerance to cytotoxic chemotherapy, a safety-prioritized, chemotherapy-free Pola-R regimen was selected through an SDM process involving his family as surrogate decision-makers. The patient achieved a complete metabolic response without severe adverse events and has remained progression-free for 15 months. Conclusion: This case highlights the efficacy and safety of the chemotherapy-free Pola-R regimen for frail older patients with DLBCL, underscoring the critical role of integrating GA and SDM to individualize therapy and honor patient goals.

Abstract: Acute myeloid leukemia (AML) is cytogenetically and phenotypically heterogeneous, and this diversity contributes to differences in how patients respond to therapies that target apoptosis. Venetoclax, a selective BCL-2 inhibitor, has been shown to improve outcomes when used in combination with hypomethylating agents (HMAs) such as azacitidine or decitabine; however, clinical experience has shown resistance and relapse are common. This review examines the current evidence linking chromosomal abnormalities and cellular differentiation state to mitochondrial apoptotic pathways, with an emphasis on how these factors influence dependence on certain anti-apoptotic BCL-2 family proteins such as BCL-2, MCL-1, and BCL-XL. We summarize how specific cytogenetic subtypes and high-risk groups (including monosomy 7/del(7q) and complex karyotype/TP53-altered AML) frequently show stress-adaptive signaling and reliance on multiple anti-apoptotic pathways, which can limit the durability of response to BCL-2 inhibition. Lineage-associated dependencies are also examined, such as monocytic differentiation (which leads to increased MCL-1 reliance) and erythroid/megakaryocytic differentiation, which has been associated with increased BCL-XL dependence and venetoclax resistance. Resistance mechanisms can be grouped into three categories: primary resistance (low BCL-2 dependence), adaptive resistance (therapy-induced MCL-1/BCL-XL upregulation), and execution failure (impaired BAX/BAK function). Finally, we discuss the therapeutic implications of dependence mapping, including venetoclax combinations and direct MCL-1/BCL-XL targeting, and propose promising biomarker strategies that can detect dependence shifts early and guide appropriate treatment selection.

Abstract: Human herpesvirus 8 (HHV-8), also known as Kaposi sarcoma–associated herpesvirus (KSHV), is a gamma-2 herpesvirus implicated in a distinctive group of lymphoproliferative disorders (LPD) and lymphomas, in several of which the neoplastic cells are concurrently infected with Epstein–Barr virus (EBV), a gamma-1 herpesvirus. This review summarizes the spectrum of HHV-8/EBV co-positive lymphoproliferations. We first outline the biology of both viruses—their latent and lytic life cycles and the viral gene products (including LANA, vFLIP and v-cyclin for HHV-8 and EBNA-1 and LMP-1 for EBV) through which they deregulate the cell cycle, inhibit apoptosis, and evade immune recognition and may create conditions permissive for B-cell transformation. We then place the principal KSHV/HHV8-associated entities—primary effusion lymphoma and its extracavitary presentation, KSHV/HHV8-positive germinotropic lymphoproliferative disorder, KSHV/HHV8-associated multicentric Castleman disease, and KSHV/HHV8-positive diffuse large B-cell lymphoma—within the current WHO-HAEM5 and ICC frameworks. PEL is frequently EBV-positive, and GLPD is characteristically dual-positive, whereas the KSHV/HHV8-positive lesional cells of MCD and KSHV/HHV8-positive DLBCL are usually EBV-negative. For the purposes of this review, dual positivity denotes demonstration of LANA and EBER within the same morphologically defined lesional cell population and is distinguished from concurrent viral positivity in separate or insufficiently characterized cell populations. Particular attention is given to rare atypical lesions with overlapping features. These cases suggest possible biological relationships among KSHV/HHV8-associated proliferations but do not yet establish a single continuous disease spectrum or a uniform mechanism of viral cooperation.

Abstract: Hereditary hemolytic anemias (HHAs) have quite similar clinical manifestations, complicating differential diagnosis and determining treatment, such as splenectomy. For the differential diagnosis of hereditary spherocytosis (HS), pyruvate kinase deficiency (PKD), and hereditary stomatocytosis (HSt), we proposed to measure erythrocyte filterability through membrane filters with a pore diameter of 3 or 3.5 μm. Our modified method provides improved reproducibility reducing the variation in results caused by differences in the filters used. The filterability of erythrocytes significantly differs in patients with HS, HSt and PKD (medians and 1.5 IQR were: 0.045 [0; 0.51] (n=88); 0.685 [0.46; 0.79] (n=12) and 0.75 [0.55; 0.86] (n=28) rel. un., respectively). The specificity of the filterability test for HS diagnosis was 100%, comparable to the best available tests, while its sensitivity (85.2%) was somewhat lower than that of some alternative methods. Only the filterability test could identify a second subgroup in HS patients (14.8%) with higher filterability (close to normal), but their HS diagnosis was confirmed by the decreased filterability by 3-µm pore filter. This subgroup requires further detailed study. The proposed filterability measurement method is promising for diagnosing HS. It has high sensitivity and specificity and can be performed quickly without expensive equipment.

Abstract: Acute myeloid leukemia (AML) produces more molecular, imaging, and clinical data per patient than any hematologist can hold in mind at once, and each revision of the WHO, ICC, and European LeukemiaNet (ELN) frameworks adds to the load. Artificial intelligence (AI) and machine learning (ML) now reach into every stage of AML care. Deep-learning models read therapy-relevant mutations directly from bone-marrow smears; automated flow-cytometry gating reproduces expert calls in under a minute; and the first AI pathology devices for hematology have cleared regulatory review and entered clinical use. Beyond diagnosis, ML captures the age-dependent weight of individual mutations that categorical ELN scoring misses, drug-response prediction for venetoclax–azacitidine has been validated across multiple external cohorts, and large language models are being tested for tumor-board support and trial matching. The next wave, from clonal-architecture modeling and single-cell foundation models to digital twins and reinforcement learning for adaptive dosing, could move AML management from reactive toward predictive, evolution-aware care. This review departs from existing AI-in-hematology surveys in three ways: we (i) restrict scope to AML and organize the field around clinical decision points rather than technology categories, (ii) grade every tool on a five-tier clinical-readiness level (CRL-AML 1–5), which exposes hundreds of models clustered at CRL-AML 1–2 and none yet in prospective clinical evaluation, and (iii) close with a numbered three-year agenda naming the consortia, datasets, and pragmatic trials needed to carry the field from publication to practice.

Abstract:

Background: Multiple myeloma (MM) is a biologically heterogeneous plasma cell malignancy with variable responses to induction therapy that are not fully explained by current risk stratification systems. Mutations in RAS family genes are prevalent in MM, yet contemporary risk stratification systems do not include them despite their oncogenic potential. Our previous findings showed reduced tumor cell sensitivity to bortezomib-containing triplet induction regimens in the presence of RAS mutations. The aim of this study is to identify RAS pathway–related molecular targets and evaluate their relationship with clinical outcomes. Methods: Forty-four patients with newly diagnosed MM received bortezomib-based induction therapy (VCD or PAD/VCD). Bone marrow CD138+ plasma cells were isolated for transcriptome analysis. KRAS and NRAS gene mutations were identified by Sanger sequencing, and RNA sequencing was performed on the Illumina HiSeq 3000 platform. Gene expression was analyzed using Salmon and DESeq2. The clinical endpoints were depth of response, progression-free survival (PFS), and overall survival (OS). Results: Of 66 candidate RAS-pathway genes examined, five—CREM, NRL, IL-6, MMP14 and MEB2B—showed significantly higher expression in samples with KRAS and NRAS gene mutations (t-test, p < 0.05). Lower NRL gene expression was associated with achieving a deep response (CR/VGPR; p = 0.02). Elevated IL6 gene expression correlated with poorer OS (HR 3.18; p = 0.05), while increased CREM gene expression was associated with shorter PFS (HR 2.62; p = 0.01). Conclusions: Increased expression of NRL, CREM, and IL6 genes could serve as potential prognostic biomarkers in MM and may reflect the molecular mechanisms underlying the adverse effects of KRAS and NRAS gene mutations.

Abstract: Fms related receptor tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations occur in approximately 20–25% of patients with acute myeloid leukemia (AML) and are associated with increased relapse risk and inferior survival outcomes. Although measurable residual disease (MRD) has become a key prognostic tool for guiding post-remission treatment decisions, FLT3-ITD was historically considered a suboptimal MRD marker because of its subclonal nature, structural heterogeneity and dynamic behavior during disease evolution. Despite its strong diagnostic and prognostic relevance, FLT3-ITD has not yet been fully integrated into routine MRD monitoring also due to methodological limitations, and lack of standardized workflows. Recent evidence supports the use of ultra-high sensitivity (UHS) next-generation sequencing (NGS) approaches to detect FLT3-ITD MRD with improved precision, enabling reliable longitudinal tracking of patient-specific clones at very low variant allele frequencies (VAF), and potentially informing clinical decision-making. Indeed, although MRD evaluation is complicated by clonal heterogeneity and molecular instability, advances in high-sensitivity detection techniques have allowed more accurate monitoring of residual leukemic burden. The present review summarizes the biological underpinnings of FLT3-ITD mutated (FLT3-ITD^mut) AML, discusses the methodological challenges of MRD detection, and critically evaluates the evolving role of MRD in refining relapse prediction, supporting post-remission therapy tailoring, and contributing to a harmonized framework for FLT3-ITD^mut AML management.

Abstract: Background: Leg ulceration is a debilitating complication of thalassaemia syndromes, particularly among patients with non-transfusion-dependent thalassaemia (NTDT). Although chronic anaemia is considered a major contributor, clinically relevant haemoglobin (Hb) thresholds associated with ulcer development remain poorly defined. Methods: We conducted a retrospective longitudinal cohort study of patients managed at a specialised Adult and Adolescent Thalassaemia Care Centre established in 2011. Iterative generalised linear mixed-effects modelling (GLMM) with a logit link function was utilised across 84 patients to systematically identify high-risk longitudinal Hb thresholds for the entire cohort and stratified by genotype. A subsequent multi-exposure GLMM framework evaluated independent clinical risk factors, adjusted for sex and genotype. Results: Iterative threshold testing across the entire cohort identified an optimal biological and statistical cutoff at Hb < 5.0 g/dL, associated with a significant risk of ulceration (partially adjusted OR = 2.87, 95% CI: 1.15 - 7.14, P = 0.024). Genotype-stratified analysis revealed that this threshold effect was predominantly driven by the HbEβ-thalassaemia subpopulation, in which the risk escalated sharply between 4.5g/dL (OR = 33.28, P = 0.001) and 5.5g/dL (OR = 2.42, P = 0.023). In the fully adjusted multivariable model, an Hb < 5.0g/dL remained a robust, independent driver of ulceration (aOR = 2.67, 95%CI: 1.08 - 6.62, P = 0.034). Additionally, active follow-up duration (aOR = 1.17 per year, P < 0.001) and cumulative transfusion burden (aOR = 1.43 per unit, P = 0.004) were identified as independent risk factors. Gender and underlying genotype demonstrated no independent association (P > 0.05). Conclusions: A longitudinal hemoglobin level below 5.0g/dL represents a critical threshold for lower-extremity ulceration in thalassaemia, exhibiting a particularly profound risk in HbE/β-thalassaemia. Proactive clinical management targeted at sustaining Hb levels strictly above this threshold, while managing secondary complications reflected by transfusion burden, may optimise microvascular outcomes.

Abstract: Background: Relapsed/refractory multiple myeloma is marked by frequent triple-class refractoriness and poor survival, whereas bispecific antibodies targeting BCMA, GPRC5D, or FcRH5 show meaningful activity even in heavily pretreated and post-BCMA disease.This meta-analysis evaluates and compares the efficacy and safety of these agents in RRMM using direct and indirect evidence. Methods: We manually searched 7 databases and identified 44 studies for quantitative analysis. Forest plots were created using R 4.1.x software. Results: Versus SOC, odds of ORR were higher with Talquetamab, Teclistamab, Elranatamab, and Linvoseltamab (5.73, 4.86, 3.84, 2.63). PFS improved with Teclistamab (HR 0.50, 95% CI 0.36–0.55), Talquetamab (0.50, 0.36–0.55), Elranatamab (0.45, 0.36–0.55), and Linvoseltamab (0.23, 0.17–0.31). Linoseltamab and Elranatamab showed numerically longer OS relative to SOC ( HR 0.41, 0.24–0.70) and (HR 0.58, 0.43–0.78), but numerically shorter OS with Teclistamab (HR 1.82, 1.37–2.42) and Talquetamab (HR 1.75, 1.20–2.57). In pooled single‑arm data, Talquetamab had the highest ORR (72%) and CRS (68%); Teclistamab showed ORR of 61% with CRS 61% and Linvoseltamab showed ORR of 60% with CRS 51%. Cevostamab and Elranatamab had ORR 49% and 56% with CRS 61% and 52%, respectively. Conclusion: In RRMM, all bispecific antibodies showed superior ORR along with improved PFS as compared to SOC. Linoseltamab and Elranatamab showed numerically longer OS relative to SOC, whereas Talquetamab and Teclistamab showed numerically shorter OS versus SOC, within the constraints of adjusted cross-trial comparisons.

Abstract: The introduction of Bruton tyrosine kinase inhibitors (BTKis) has significantly improved prognosis in the treatment of MCL. BTK inhibitors have demonstrated strong activity in the treatment of relapsed/refractory patients with mantle cell lymphoma (MCL), and several trials indicate that they also have potential as first-line treatment. Furthermore, combining BTKis with immunochemotherapy has enabled time-limited therapy as an alternative for continuous treatment with BTK inhibitors alone. In 2013, ibrutinib became the first BTK inhibitor to be approved by the FDA for previously-treated MCL. The TRIANGLE study found ibrutinib to improve the efficacy of standard immunochemotherapy and reduce the need for autologous stem cell transplantation (ASCT) in younger patients; however, its findings do not conclusively confirm whether ASCT enhanced the activity of the ibrutinib-containing regimen in treatment-naïve patients. The next-generation covalent, irreversible BTK inhibitors acalabrutinib and zanubrutinib demonstrate greater selectivity and better pharmacological characteristics than ibrutinib. The FDA approved acalabrutinib and zanubrutinib as single drugs for the treatment of R/R patients with MCL who have received at least one prior therapy. Acalabrutinib combined with bendamustine and rituximab was also approved for TN MCL unsuitable for ASCT. Pirtobrutinib, a first-in-class noncovalent reversible BTK inhibitor, was approved for the treatment of R/R MCL patients, including those resistant to covalent BTK inhibitors. Several other covalent and non-covalent BTK inhibitors are currently under investigation in MCL. Finally, BTK degraders have entered early clinical trials in B-cell lymphoid malignancies, and some of them in MCL.

Abstract: Obstructive sleep apnoea (OSA) is associated with substantially elevated cardiovascular, neurodegenerative, and metabolic morbidity, yet the mechanistic chain linking nocturnal intermittent hypoxia to these clinical consequences remains incompletely understood. We highlight three apparent contradictions in the existing OSA erythrocyte literature: (i) accelerated erythropoiesis with normal haemoglobin concentration; (ii) unchanged daytime P50 and 2,3-diphosphoglycerate concentrations compared to non-OSA controls; yet (iii) consistently elevated systemic oxidative stress, vascular inflammation, oxidized low-density lipoprotein, and accelerated brain ageing. These observations are not easily reconciled within frameworks that treat OSA erythrocytes as a stable hypoxia-adapted phenotype. We propose the perpetual erythrocyte cohort churning hypothesis: OSA erythrocytes constitute a dynamically mixed population in which newly produced cells attempting to adopt a hypoxia-adapted phenotype are continually subjected to neocytolysis upon return to daytime normoxia. The molecular substrate is the miR-21-mediated catalase suppression demonstrated by Song and Prchal: the same molecular programme that fits cells for nocturnal hypoxia also embeds the antioxidant vulnerability that triggers their daytime clearance. The resulting cycle of production and lysis—occurring each twenty-four hours over years to decades—releases cell-free haemoglobin, free iron, membrane phospholipid fragments, and extracellular vesicles into the systemic circulation, generating a chronic background of oxidative stress that we propose drives the downstream cardiovascular and neurodegenerative consequences. The hypothesis is positioned within the Red Blood Cell Triphenotype Classification (RTC v2.0) as a paradigmatic case of dynamic mixed phenotype—a state in which a single individual harbours multiple coexisting erythrocyte functional phenotypes whose proportions vary diurnally. Four falsifiable predictions are advanced: erythrocyte churning intensity will distinguish OSA from controls and scale with severity; churning will correlate more strongly with downstream oxidative and inflammatory markers than the apnoea-hypopnoea index itself; CPAP therapy will attenuate churning, with residual churning identifying patients at continued cardiovascular risk; and individuals with disproportionately high churning despite moderate AHI will be at elevated long-term morbidity. A multicentre prospective observational study (CSMUH-OSA-RTC-2026-01) has been designed to test these predictions.

Abstract: Erythrocytes are routinely characterized in clinical medicine by three twentieth-century parameters: haemoglobin concentration, haematocrit, and mean corpuscular volume. This framework reflects an outdated view of the red cell as a passive oxygen carrier. Recent landmark findings—including the 2026 demonstration that erythrocytes function as a primary glucose sink during chronic hypoxia, the 2021 elucidation of the band 3 N-terminus as a bidirectional metabolic switch, and the molecular characterization of neocytolysis as an evolutionary retirement mechanism for hypoxia-adapted erythrocytes—collectively reveal a fundamentally different picture: the erythrocyte is a programmable metabolic entity whose functional phenotype is determined by its oxygen exposure history and is dynamically modulated by ongoing physiological state. We propose the Red Blood Cell Triphenotype Classification (RTC), a hypothesis-driven framework that organizes erythrocyte function along three orthogonal axes: Glucose Sink Capacity (GSC), reflecting contribution to systemic glucose disposal; Oxygen Kinetics State (OKS), reflecting position on the oxygen-release-versus-retention spectrum; and Antioxidant Reserve State (ARS), reflecting capacity to withstand oxidative stress. Combining low/medium/high levels along each axis yields ten clinically distinguishable phenotype categories—Types α (baseline) through κ (quantity-quality dissociated)—each linked to specific molecular signatures and clinical contexts spanning altitude adaptation, cyanotic congenital heart disease, chronic mountain sickness, obstructive sleep apnoea, critical illness, sepsis, and rare disorders such as voxelotor-treated sickle cell disease. RTC is intended as both a heuristic for clinical interpretation and a hypothesis generator for empirical research. A Level 1 measurement protocol using existing clinical laboratory infrastructure—flow cytometric GLUT1 quantification, 2,3-diphosphoglycerate, methaemoglobin, and reticulocyte count—is proposed for immediate application. Four testable predictions are advanced. We argue that RTC offers the missing conceptual bridge between molecular erythrocyte biology and the clinical interpretation of haematological, metabolic, and oxygenation data. A planned multi-centre clustering validation study (CSMUH-RTC-2026-01) is described.

Abstract: Background: Hemophagocytic lymphohistiocytosis is a life-threatening hyperinflammatory syndrome that can mimic sepsis in adults, delaying diagnosis and treatment. Methods: We reviewed three adult patients admitted to a high-complexity referral hospital in Colombia, all initially managed as sepsis, analyzing clinical findings, laboratory results, bone marrow studies, diagnostic approach, and outcomes. Results: All patients had persistent fever, cytopenias, organomegaly, hyperferritinemia, and hypertriglyceridemia, with ongoing inflammation despite appropriate antimicrobial therapy. Bone marrow examination showed hemophagocytosis in all cases. One case was associated with acute myeloid leukemia and had a poor outcome, while two infection-related cases, triggered by disseminated histoplasmosis and visceral leishmaniasis, improved with targeted therapy and supportive care. Conclusions: Persistent inflammation, cytopenias, and markedly elevated ferritin despite standard sepsis treatment should prompt early consideration of hemophagocytic lymphohistiocytosis and investigation of the underlying trigger.

Abstract:

Background/Objectives: Acute Myeloid Leukemia (AML) with myelodysplasia-related gene mutations (AML-MR), often referred to as secondary AML (s-AML) or AML-MRC, is an aggressive form of leukemia that typically arises from an antecedent myelodysplastic syndrome (MDS) but may originate also de novo. It is characterized by mutations in key genes associated with MDS that include some epigenetic regulators (ASXL1, EZH2), splicing factors (SF3B1, SRSF2, U2AF1, ZRSR2) and transcription factors (BCOR, RUNX1, STAG2). The main objective of this review paper consists in analyzing recent studies that have improved the criteria for characterization, definition and classification of AML-MR. Methods: An extensive search of the most recent literature on the topic was performed, selecting and critically analyzing the most relevant studies. Results. The studies carried out in the last years have provided an extensive molecular characterization of AML-MR, supporting more sound criteria for their identification and for a better definition with respect to other AML subtypes, particularly with respect to TP53-mutant AML. Conclusions: A unifying classification of AML-MR is now possible, allowing its identification as a unique, well-defined and separate entity.

Abstract: Background: Diffuse large B-cell lymphoma (DLBCL) with TP53 abnormalities, corresponding to the LymphGen A53 molecular subtype, represents a biologically high-risk group associated with primary resistance to standard R-CHOP therapy. Epigenetic sensitization using hypomethylating agents may enhance chemosensitivity in this setting. We prospectively evaluated the clinical activity and safety of a molecularly adapted DAC-R-CHOP regimen in newly diagnosed A53-DLBCL. Methods: In this single-center prospective pilot cohort study, 70 consecutive patients with newly diagnosed DLBCL underwent targeted next-generation sequencing using a 60-gene panel with integrated copy number variation analysis. Six patients (8.5%) were classified as the A53 subtype. All patients received one cycle of standard R-CHOP. From cycle 2 onward, A53 patients received decitabine (10 mg/m² IV, days 1–5) prior to R-CHOP (DAC-R-CHOP), for a total of six cycles. The primary endpoint was complete metabolic response (CMR) according to Lugano 2014 criteria. Exact 95% confidence intervals (CI) were calculated. Results: The median age of the A53 cohort was 65 years. CMR was achieved in all six patients (100%; 95% CI, 54%–100%). At a median follow-up of 6 months, all patients remained alive in confirmed CMR. Grade III–IV hematologic toxicity occurred in all cases. Febrile neutropenia developed in 100% of patients, requiring mandatory G-CSF support and anti-infective therapy; no treatment-related mortality or permanent dose reductions were observed. Two patients (33%) experienced gastrointestinal bleeding related to local tumor lysis, which was managed conservatively without protocol discontinuation. Conclusions: In this prospective molecularly stratified pilot cohort, integration of decitabine into front-line immunochemotherapy showed promising clinical activity in A53-DLBCL, albeit at the cost of substantial hematologic toxicity requiring intensive supportive care. Given the small sample size, short follow-up, and absence of a comparator arm, these findings should be considered hypothesis-generating and warrant validation in larger multicenter phase II studies with integrated translational biomarker analyses.