HFE -related hemochromatosis (HC) is caused by hepcidin dysregulation and is characterized by excessive iron absorption and accumulation in the liver, heart, and endocrine glands, which leads to complications including arthropathy, cirrhosis, and hepatocellular carcinoma. Standard of care (SoC) typically involves phlebotomy, with iron chelators used less frequently. However, these therapies may cause side effects and negatively impact quality of life, making them troublesome for some patients. Using the Delphi methodology, a survey was developed to identify unmet needs and clinical challenges within the current therapeutic landscape of HC, and to establish consensus statements for its management. Consensus was defined as ≥75% agreement. Thirty-two HC specialists from Europe, Australia and the USA responded to the survey. After three rounds of survey refinement, final consensus statements were compiled. The Delphi process identified key unmet needs in HC, including lack of alternatives to phlebotomy, persistent symptoms, and burden related to the use of current SoC. The consensus process helped establish definitions for high phlebotomy treatment burden, intolerance, and suboptimal response to phlebotomy. The process also identified the subgroup of patients overly burdened by phlebotomy. Patient-reported outcomes were considered key to assessing phlebotomy’s impact, although they are rarely measured in clinical practice. The Delphi study highlighted the limitations of phlebotomy, with respondents identifying a high unmet need for patients who cannot be managed with or do not tolerate this approach. The study suggested exploring alternative therapy options for patients who experience high treatment burden or intolerance to phlebotomy.
Iron deficiency is the most common micronutrient deficiency worldwide, affecting approximately 2 billion individuals. Iron deficiency without anemia (IDNA), the stage in which iron stores are depleted but hemoglobin remains within the reference range, is estimated to affect approximately 1-2 billion individuals, although the precise prevalence varies by population, ferritin threshold, and inflammatory status. IDNA remains underrecognized because diagnostic evaluation often focuses on hemoglobin concentrations rather than iron stores. A growing body of evidence demonstrates that IDNA is associated with clinically significant fatigue, impaired cognitive function, anxiety, reduced exercise capacity, and diminished quality of life. Randomized controlled trials and meta-analyses of iron repletion in iron-deficient non-anemic cohorts demonstrate clinically meaningful reductions in fatigue. Emerging observational data have also identified an association between iron deficiency and colorectal neoplasia in selected higher-risk populations such as older adults, men, and postmenopausal women. However, the magnitude of this risk and the role of routine endoscopic evaluation in patients with IDNA remain incompletely defined. This narrative review examines the epidemiology, pathophysiology, origins of under-recognition, clinical manifestations, diagnostic approach, treatment, association with colorectal cancer, and future directions for IDNA in adults.
Background:Congenital methemoglobinemia is a rare inherited disorder caused by impaired reduction of methemoglobin to functional hemoglobin, resulting in functional hypoxia despite normal arterial oxygen tension. Due to its often-mild clinical phenotype, diagnosis is frequently delayed or made incidentally. Methods:This prospective case series of surgical patients was conducted at a tertiary care center in South India over a one-year period. Patients incidentally diagnosed with methemoglobinemia during perioperative or acute medical evaluation were included. Diagnosis was established using arterial blood gas analysis with co-oximetry and confirmed biochemically by erythrocyte NADH-cytochrome b5 reductase activity. Results:Ten surgical patients were identified, all originating from a single geographic region. Methemoglobin levels ranged from 14.4% to 29.1%. Most patients were asymptomatic or mildly symptomatic, with diagnosis prompted by refractory hypoxemia and a characteristic saturation gap. Enzyme assays confirmed Type I congenital methemoglobinemia in all cases. Management was largely supportive, with methylene blue reserved for symptomatic individuals. Conclusions:This case series highlights incidental perioperative detection as a key diagnostic opportunity and suggests possible regional clustering of congenital methemoglobinemia. Increased clinical awareness and targeted screening may improve the diagnosis of this underrecognized condition.
Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a transformative treatment for patients with relapsed or refractory hematologic malignancies, offering new possibilities beyond conventional transplantation. Since their approval in high-income countries, CAR-T products have demonstrated remarkable efficacy; however, their implementation in low- and middle-income countries (LMICs) remains limited due insufficient infrastructure, complex regulatory requirements and high costs. In some countries, like Mexico, these barriers are particularly pronounced, with limited access to clinical-grade vectors, early phase clinical research programs, and lack of government and private sector infrastructure and funding opportunities. Facing these challenges, there is a substantial patient population with B-cell acute lymphoblastic leukemia, multiple myeloma, or diffuse large B-cell lymphoma, who could benefit from CAR-T therapy. Advances in point-of-care manufacturing within academic settings -particularly the use of closed, semi-automated systems- have demonstrated feasibility in LMICs, by reducing costs and simplifying procedures, while maintaining product quality. These approaches may provide a viable alternative to commercial products, with the potential to lower the economic burden and increase accessibility. Regulatory innovation with the establishment of expert multidisciplinary oversight committees, will also be critical to ensure safe implementation. Ultimately, CAR-T therapy in LMICs is both a scientific and public health opportunity, and its integration into healthcare systems will depend on collaborative strategies that address financial, logistical, and policy barriers. By highlighting our experience, this review underscores the importance of developing locally adapted solutions to expand access to advanced cellular therapies in resource-constrained settings.
Background:VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is caused by somatic UBA1 mutations and frequently complicated by myelodysplastic syndrome (MDS). Conventional immunosuppressive and anti-inflammatory therapies are often ineffective, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the only curative treatment, although its optimal timing and donor selection remain uncertain. Case Presentation:A 67-year-old man with VEXAS syndrome and MDS harboring UBA1 (p.M41T) and EZH2 mutations, refractory to azacitidine and corticosteroids, successfully underwent allo-HSCT from a one-antigen-mismatched related donor. Post-transplant chronic graft-versus-host disease was well controlled with ruxolitinib. Methods and Results:We reviewed eight studies comprising 45 allo-HSCT recipients with VEXAS syndrome. The median age at transplantation was 59 years, and patients had received a median of five prior systemic therapies. MDS was present in 53.3% of cases, while 42.2% underwent transplantation for VEXAS without overt hematologic malignancy. The most frequent UBA1 variant was p.Met41Val (37.8%). At last follow-up, 84.4% of patients were alive, with resolution of inflammatory manifestations in most cases. Conclusion:Allo-HSCT represents a curative option for refractory VEXAS syndrome. Comprehensive genetic profiling may aid in identifying candidates for early transplantation. If early transplantation is required, human leukocyte antigen-mismatched donors may be selected.
Background:Multiple myeloma (MM) is an incurable hematological malignancy with increasing prevalence. While randomized controlled trials have demonstrated survival improvements, they underrepresent older and comorbid patients. Real-world data from observational cohorts are therefore essential. Objective:To assess the comparability of patient, hospitalization and center characteristics for patients treated in centers included in the French Epidemiology of Multiple MYeloma (EmmY) cohort with those treated in centers of the French-speaking Intergroupe Francophone du Myélome (IFM) network (including EmmY) and those treated in all centers treating MM in France between 2017-2023. Methods:We analyzed French national hospital discharge data (PMSI) to identify adults hospitalized with MM (ICD-10 C90) between August 2017 and December 2023. Patient demographics, comorbidities, hospitalization characteristics, and center profiles were compared between the three cohorts using standardized differences. Results:We identified 69,276 patients (including 50,243 IFM and 33,785 EmmY), 1,871,369 hospitalizations (including 1,484,288 IFM and 1,022,462 EmmY), and 323 centers (including 118 IFM and 70 EmmY). EmmY centers were larger and treated a higher mean proportion of MM patients (2.7%) per center than IFM (2.4%) and all MM centers (1.3%). No clinically meaningful differences were observed between EmmY and IFM centers regarding patient age, sex, comorbidities, treatment patterns, or hospitalization outcomes. Conclusions:The EmmY cohort is highly comparable to patients treated in specialized MM centers and those within the broader French MM population, supporting its validity as a robust real-world data source. It is well-suited for evaluating treatment pathways and outcomes in real-world MM populations, including patients underrepresented in randomized controlled trials.
Acute promyelocytic leukemia (APL) is frequently curable in the modern era using the chemotherapy-free regimen of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, rare disease manifestations and treatment complications may threaten these outcomes by requiring intensification or abbreviation of therapy. We present a unique case of a 36-year-old male with newly diagnosed low-risk APL with biopsy-confirmed leukemia cutis and isolated ATRA-associated myocarditis during induction therapy. Both APL leukemia cutis and ATRA-associated myocarditis are exceedingly rare, with each having less than 50 published cases to date. This report offers a comprehensive review of the literature, underscoring the importance of a comprehensive diagnostic evaluation and individualized care to ensure outstanding long-term outcomes for patients with APL.
Background Chronic graft versus host disease (cGVHD) is a complex post-transplant complication resulting in varying degrees of musculoskeletal (MSK) manifestations, including sclerosis-type skin conditions, fasciitis, and osteopenia, avascular necrosis affecting the shoulder, elbow and hands apart from other joints of the body. A large proportion of these can often miss out on the expertise of upper limb therapists. Study Objectives This paper aims to outline upper limb cGVHD manifestations to raise awareness among upper limb physiotherapists and rehabilitation specialists, so that patients can receive more focused, optimal care. Methods An electronic search was conducted across a wide database covering the period from 1990 to 2025. Further manual search used Google Scholar to help identify relevant articles. Boolean operators ‘AND’ and ‘OR’ combined keywords such as chronic graft versus host disease, acute graft versus host disease, allogenic hematopoietic stem cell transplantation, hematopoietic cell transplantation, stem cell transplant, bone marrow transplant, physiotherapy, upper limb specialist, musculoskeletal, fasciitis, and scleroderma. Results A total of 4,393 titles were screened against the pre-set inclusion and exclusion criteria, and only 3 articles were found to be suitable for this narrative review. All 3 articles were case studies of upper limb cGVHD and rehabilitation reporting positive outcomes on patients’ upper and lower limb range of motion, function, and quality of life (QoL). Conclusion cGVHD can cause various MSK issues, especially in the upper limbs. It is important to collaborate with upper limb physiotherapy and occupational therapy experts to improve awareness and patient outcomes.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperimmune condition triggered by the pathological activation of T-cells, natural killer cells, and macrophages leading to a cytokine storm with widespread hyperinflammation affecting multiple organ systems, including the brain. This retrospective chart review characterizes the central nervous system (CNS) features in 22 pediatric HLH patients at a single center. CNS involvement was determined based on symptoms, exam, abnormal cerebrospinal fluid (CSF) studies, neuroimaging, and electroencephalogram (EEG) findings. Twenty-two children with HLH were analyzed, classifying them into primary HLH (pHLH) and secondary HLH (sHLH) based on genetic testing. Of 20 patients who underwent genetic testing, 6 (30%) had pathogenic pHLH mutations, while 14 were sHLH (8 with variants of unknown significance, 6 with no variants). CNS involvement was noted in 17 (77.2%) patients. Symptoms included generalized weakness, altered sensorium, seizures, and headaches. MRI abnormalities included patchy T2 FLAIR prolongation (85%) with and without contrast enhancement and subdural collection, diffuse brain atrophy (40%), microhemorrhages (15%) and diffusion restriction (15%) patients. CSF studies showed higher WBC counts in pHLH . Therapies amongst this cohort varied, with 47% receiving dexamethasone, etoposide and cyclosporine, and 29% undergoing HSCT. Mortality in the first year was 18%, with 75% of deaths involving patients with CNS involvement of HLH. Mean survival at six months was 167 days, with no further deaths in the 12-year follow-up. We conclude that frequent neurological abnormalities are noted in children with HLH highlighting the role for active surveillance of CNS involvement in this group of patients.
Factor XIII (FXIII) deficiency is a rare bleeding disorder characterized by unstable hemostatic clots due to defective fibrin cross‑linking. Congenital FXIII deficiency arises from variants in the F13A1 (FXIII-A subunit) or F13B (FXIII-B subunit) genes, and classically presents with delayed umbilical stump hemorrhage, soft‑tissue and intracranial bleeding, impaired wound healing, and recurrent pregnancy loss. Acquired deficiency stems from inhibitory autoantibodies or from reduced synthesis or consumption in critical illness and surgery. Routine coagulation screening tests are normal and diagnosis relies on quantitative FXIII activity assays with or without antigenic phenotyping and, when indicated, inhibitor testing and molecular confirmation. Plasma‑derived FXIII concentrate reduces spontaneous and intracranial bleeding; recombinant FXIII‑A2 is appropriate for F13A1 defects but not patients with F13B variants. Perioperative and obstetric care target activity thresholds suited to procedural risk and individual pharmacokinetics. This review synthesizes the molecular biology, epidemiology, clinical features, diagnostic methods, and evidence‑based management of FXIII deficiency, with practical guidance for assay selection, validation, and result interpretation.
Clonal Hematopoiesis of indeterminate potential (CHIP) has been increasingly recognised as a risk factor for cardiovascular disease (CVD). Recent epidemiological and experimental studies have linked CHIP as an independent risk factor for myocardial infarction, stroke, and coronary artery disease, with specific mutations carrying a higher CVD risk. During the aging process, somatic mutations in genes, including DNMT3A and TET2, accumulate in the hematopoietic stem cells (HSCs), conferring both epigenetic and metabolic advantages that not only drive hematopoiesis towards a pro-inflammatory myeloid lineage but also reprogram innate immune cells, promoting a persistent inflammatory state. These myeloid derivatives, via increased IL-1β and IL-6 production, establish a pro-atherogenic environment and contribute to plaque instability, leading to an increased thrombotic risk and accelerated vascular aging. Although routine screening is not recommended for asymptomatic adults, targeted detection in high-risk individuals could benefit from preventive strategies. Incorporating CHIP into risk models may enable precision prevention, but prospective trials are needed to determine whether CHIP-guided interventions improve cardiovascular outcomes.
The use of proteasome inhibitors (PI) and immunomodulatory drugs (IMiD) such as lenalidomide (Len) in early lines of therapy in multiple myeloma (MM) has resulted in a high proportion of patients with relapsed or refractory multiple myeloma (RRMM) being Len-refractory. Len refractoriness is associated with inferior outcomes, constituting an unmet need in clinical practice. This retrospective single-center study aimed to provide real-world characteristics and outcomes in RRMM previously exposed to PI and Len during 1-3 prior lines of therapy (LOT), stratified by Len refractoriness. RRMM patients between Jan 2017 and May 2023 were included. We studied clinical characteristics, treatments and survival outcomes. A total of 218 patients were included (n=85 Len refractory). The median progression-free survival was 13.6 months in Len-refractory versus 14.9 months in Len non-refractory patients. The median overall survival was 20.3 months in Len refractory, and not reached in Len non-refractory patients. The overall response rates to the subsequent LOT were 58.8% and 61.7% in Len refractory and non-refractory cohorts, respectively. IMiD-based and anti-CD38 monoclonal antibody-containing regimens were the most frequent subsequent LOT, 44% and 41%, respectively. This study shows suboptimal outcomes in Len refractory RRMM patients, highlighting the need to develop effective treatment options.
Spleen tyrosine kinase (SYK) and Bruton's tyrosine kinase (BTK) inhibitors have emerged as promising targeted therapies for adult immune thrombocytopenia (ITP). However, a comprehensive synthesis of their benefits compared to placebo has not been previously conducted. This study aims to analyze the efficacy and safety of SYK and BTK inhibitors in comparison to placebo for the treatment of adult patients with ITP. A systematic search was performed across four major databases (Medline, Europe PMC, Scopus, and ClinicalTrials.gov) for randomized controlled trials (RCTs) evaluating SYK and/or BTK inhibitors versus placebo in adults with ITP. We utilized random-effects models to evaluate the risk ratio (RR) and mean difference (MD) for the occurrence of outcomes. Five RCTs across four publications were included. Both SYK and BTK inhibitors significantly improved overall platelet response (RR 3.95; 95%CI: 2.68 - 5.81, p<0.00001) and durable response rates (RR 12.50; 95%CI: 3.99 - 39.18, p<0.0001) compared to placebo. Treatment also resulted in shorter time to response and reduced need for rescue interventions. Although total AEs and rash were more common in the intervention group, these were predominantly grade 1-2 and did not lead to increased discontinuation or serious AE rates. No significant differences were observed in the specific events such as gastrointestinal symptoms, cytopenias, liver enzyme elevations, infections, or hypertension. SYK and BTK inhibitors demonstrate superior efficacy over placebo in improving platelet outcomes in adult ITP without compromising safety. These findings support their role as effective treatment options, especially for patients unresponsive to other therapies.
Ramadan fasting induces significant physiological adaptations that can affect patients with hematological disorders. While fasting is generally safe for healthy individuals, reduced hydration and nutritional intake during the 13-18 hour fasting period can pose risks for those with anemia, coagulopathies, or malignancies. High-risk patients - such as those on intensive chemotherapy, post stem-cell transplantation, or with severe anemia (hemoglobin <8 g/dL) - are advised not to fast to avoid complications (e.g. vaso-occlusive crises, thrombotic events, or worsening anemia). Patients with stable hematologic conditions, however, may fast safely with careful pre-Ramadan evaluation, medication timing adjustments, and strict hydration and nutrition plans. Given the limited clinical data, an individualized risk stratification approach is essential. Shared decision-making, balancing religious aspirations with medical safety, is encouraged. Future studies are needed to establish evidence-based guidelines, but until then, thorough risk assessment, proactive monitoring, and patient education form the cornerstone of safe Ramadan fasting for individuals with hematological disorders.
Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm with highly variable, multisystem manifestations that present significant diagnostic and therapeutic challenges. This retrospective multicenter case series included 11 adult patients diagnosed with biopsy-proven ECD across Canada between January 2015 and June 2024. The cohort comprised six females and five males with a median age of 55 years (range 41-74). PET-CT was used for disease staging and treatment monitoring in nine cases. The most commonly involved sites were bone (n=8), kidney (n=6), and lungs (n=5). BRAF V600E mutations were detected in seven patients. Treatments included vemurafenib, interferon, tocilizumab, cladribine, cobimetinib, and cytarabine. Treatment responses varied, with several patients achieving remission or stable disease, while others had progressive or end-stage disease. This study highlights the clinical heterogeneity of ECD and the value of integrating histopathology, molecular profiling, and imaging to guide management and improve outcomes.
