Search Results (40)

Background/Objectives: BK virus-associated haemorrhagic cystitis (BKV-HC) is a severe complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT) for which no standard treatment exists. Intravesical platelet-rich plasma has been proposed, but recipients are profoundly thrombocytopenic, and an autologous product cannot be obtained. We report the outcome of an intravesical allogeneic platelet concentrate (allo-PC) prepared from irradiated single-donor apheresis platelets in patients refractory to all available treatment. Methods: Single-centre retrospective series of 14 consecutive patients with Grade 3–4 BKV-HC treated between January 2018 and June 2021, selected from 84 patients who developed haemorrhagic cystitis during this period. All had failed hyperhydration, forced diuresis, continuous bladder irrigation and cidofovir; 10 had undergone previous cystoscopic cauterisation, 10 had immunosuppression reduction, and 4 had hyperbaric oxygen, all without resolution. The median duration of haematuria before allo-PC was 45.5 days. The primary outcome was resolution of macroscopic haematuria; transfusion requirement, catheter removal and readmission were reported separately. Results: Macroscopic haematuria resolved in 12 of 14 patients (85.7%, 95% CI 60.1–96.0) after a median of 5.5 days (IQR 4.0–12.5). Seven patients (50.0%, 95% CI 26.8–73.2) met all secondary criteria. Product platelet concentration correlated inversely with time to resolution (r_s = −0.917, 95% CI −0.977 to −0.725). Because a fixed 50 mL volume was given, the delivered dose varied 18-fold (0.30–5.62 × 10⁹ platelets/kg). Body weight also correlated with time to resolution (r_s = +0.791), but in partial correlation the association with platelet concentration persisted after adjustment for weight (r_s = −0.783, p = 0.004) and for age (r_s = −0.827, p = 0.002), whereas the association with weight did not persist after adjustment for platelet concentration (r_s = +0.292, p = 0.38). No procedure-related complication exceeded Clavien–Dindo Grade I. Conclusions: In patients who had exhausted all available treatment, intravesical allo-PC was followed by resolution of haematuria in most cases. The association between product platelet content and time to resolution was not explained by body weight or age. These uncontrolled findings are hypothesis-generating. Full article

Extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae causes difficult-to-treat bloodstream infections in patients with haematological malignancies, particularly after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Carbapenems remain reliable, but their anti-anaerobic activity may aggravate intestinal dysbiosis and increase selection pressure for carbapenem resistance. Cefepime–enmetazobactam is a novel fourth-generation cephalosporin/β-lactamase inhibitor combination active against many class A ESBL-producing Enterobacterales. We describe a profoundly immunocompromised patient with acute myeloid leukaemia after allo-HSCT, grade III steroid-refractory gastrointestinal graft-versus-host disease, and intestinal colonization by an ESBL-producing K. pneumoniae isolate resistant to ceftolozane–tazobactam. The patient developed persistent bacteraemia and right pyelonephritis with small renal abscess-like lesions. Meropenem was rapidly de-escalated to cefepime–enmetazobactam, with temporary adjunctive fosfomycin and subsequently tigecycline. Blood-culture time to positivity progressively lengthened from 1.18 h to 16 h before cultures became negative. Serial cefepime therapeutic drug monitoring permitted repeated assessment of exposure and neurological toxicity risk. Whole-genome sequencing identified K. pneumoniae ST307 carrying bla_CTX-M-15, bla_TEM-1, bla_SHV-28, and bla_OXA-1, together with multiple resistance determinants and a large conjugative plasmid. This case describes the use of cefepime–enmetazobactam as part of a targeted carbapenem-sparing strategy for invasive ESBL-producing K. pneumoniae infection in a highly immunocompromised allo-HSCT recipient. Full article

Background: Telomere length and telomerase activity are important determinants of haematopoietic cell proliferative capacity and may influence outcomes after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Genetic variation within the telomerase reverse transcriptase (TERT) gene may further contribute to transplantation success and post-transplant complications. Methods: Telomere length was assessed in 98 paediatric allo-HSCT recipients and their donors using quantitative real-time PCR before allo-HSCT and at one and two years post-transplantation. Selected four TERT polymorphisms (rs2736100, rs2853669, rs2735940, and rs10069690) were genotyped in donors and recipients before allo-HSCT. Associations between telomere length, genetic variants, and clinical outcomes were analysed. Results: Telomere length did not differ between recipients and donors before transplantation; however, donors younger than 18 years exhibited significantly longer telomeres. Telomere length increased at one and two years after allo-HSCT compared with pre-transplant values, with the most pronounced changes observed in patients with acute lymphoblastic leukaemia. No direct associations were found between TERT polymorphisms and telomere length. Nevertheless, the recipient rs2735940 T allele was associated with improved survival, the donor rs2736100 G allele with the achievement of complete chimerism, and the recipient rs2853669 C allele with an increased risk of acute graft-versus-host disease (aGvHD). Haplotype analysis identified associations between TERT variants and cytomegalovirus reactivation as well as aGvHD. Conclusions: Paediatric allo-HSCT is associated with dynamic post-transplant changes in telomere length. Although TERT polymorphisms did not directly affect telomere length, several variants were linked with clinically relevant transplantation outcomes, highlighting the potential role of telomere biology in haematopoietic reconstitution and transplant-related complications. Full article

Background/Objectives: Haematopoietic stem cell transplantation (HSCT) causes substantial morbidity in children and young people (CYP). Although prehabilitation benefits adults with cancer, its role in paediatric HSCT remains underexplored. This study aimed to describe current pre-transplant assessment and supportive care practices across paediatric HSCT centres, explore healthcare professional perspectives on prehabilitation implementation, and integrate patient and public involvement (PPI) to inform future intervention design. Methods: A cross-sectional survey was administered to healthcare professionals across 16 paediatric HSCT centres in the UK and the Republic of Ireland, alongside semi-structured PPI discussions conducted with eight children, young people, and caregivers with direct experience of paediatric HSCT. Survey data were analysed descriptively, free-text responses by qualitative content analysis, and PPI by reflexive thematic analysis. Results: Forty-nine eligible responses were received from healthcare professionals. Formal prehabilitation services were reported by 27 (55.1%) respondents, with substantial within-centre variation. Nutritional advice was the most consistently delivered component, 36 (72%), whilst physical activity interventions were the least consistently provided, 13 (26%). Workforce limitations were identified as the dominant barrier by 37 (95%) respondents. PPI findings described provision as reactive and inconsistent, with families expressing preference for flexible, hybrid, and family-centred delivery models. Conclusions: Prehabilitation provision in paediatric HSCT is variable, often informal, and limited by workforce capacity. CYP and caregivers expressed a desire for prehabilitation, particularly through flexible, hybrid (face-to-face and online), and family-centred approaches. Future research should prioritise co-design and feasibility testing of safe, individually tailored programmes that can be integrated into paediatric HSCT pathways. Full article

Cutaneous graft-versus-host disease (GVHD) is a common complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT). Despite established guidelines, discrepancies persist between clinical trial evidence and real-world practice, particularly for newer agents such as ruxolitinib. To characterize the phenotypic spectrum of cutaneous GVHD, evaluate real-world treatment strategies—with a specific focus on systemic and topical ruxolitinib—and assess adherence to national and international guidelines, we conducted a retrospective observational study of patients undergoing allo-HSCT between 2015 and 2025 who were referred to a dedicated dermato-haematology clinic. Clinical, histological, and therapeutic data were collected. Cutaneous manifestations were classified according to National Institutes of Health (NIH) and Italian Group for Blood and Marrow Transplantation (GITMO) criteria. Of 62 transplanted patients, 44 (71%) developed GVHD, with the skin as the most frequently involved organ. Acute GVHD predominantly presented with maculopapular eruptions, whereas chronic GVHD showed heterogeneous phenotypes, including sclerotic variants. First-line management was largely guideline-concordant. Systemic ruxolitinib was administered to 3% of patients in the aGVHD group and 3% in the cGVHD group. Steroid-refractory and steroid-dependent status was not systematically recorded; therefore, treatment eligibility could not be reliably determined, and the observed frequencies should not be interpreted as evidence of underuse. Topical ruxolitinib was not used and remains investigational for cutaneous GVHD. Interpretation should also consider that the study period encompassed changes in regulatory approval, reimbursement, and access to targeted therapies. Structured multidisciplinary assessment may support the management of complex cutaneous GVHD, although its effects on treatment decisions and patient outcomes require prospective evaluation. Full article

Background/Objectives: Children and adolescents undergoing Haematopoietic Stem Cell Transplantation (HSCT) experience complex symptoms, often under-reported by patients and undetected by clinicians, which cause distress. Patient-Reported Outcome Measures (PROMs) offer a way to capture symptom experiences directly from patients, with the potential of supporting effective symptom assessment and management, yet their routine use in paediatric HSCT remains unclear. This systematic review synthesises evidence on PROMs used during inpatient paediatric HSCT care, examining their role in symptom monitoring and clinical decision-making, and identifying gaps to strengthen person-centred, developmentally appropriate care. Methods: We searched the MEDLINE, CINAHL, Embase, APA PsychINFO, and Cochrane Library in October 2024 for studies published in English between 2014 and 2025 describing the use of PROMs during inpatient paediatric (0–18 years) HSCT admission (up to Day +100 post HSCT). In March 2025, prior to data extraction, we added additional studies published by authors of included studies. Two-stage independent screening and data extraction were conducted, and the Quality Assessment with Diverse Studies (QuADS) tool was used to appraise each study. Narrative syntheses informed by Symptom Management Theory were used to compare PROM use, clinical integration, and reported impacts. Results: Seventeen studies met inclusion criteria, describing 20 PROMs used during paediatric HSCT hospitalisation. PROMs captured a wide range of physical and psychological symptoms, with pain and nausea most frequently reported. While PROMs reportedly improve symptom detection and communication, integration into routine paediatric HSCT clinical care was rare; and only two studies systematically used PROMs data to guide symptom management. Evidence of PROMs-driven improvements in HSCT clinical outcomes was scarce, and longitudinal data on symptom trajectories were limited. Conclusions: PROMs are not routinely used to inform clinical practice in paediatric HSCT, and current evidence provides only a partial understanding of symptom trajectories and lived symptom experiences during the paediatric acute transplant admission. To realise the full potential of PROMs in enhancing symptom assessment and management, systematic PROMs integration into clinical workflows is required, supported by electronic health record integration, clinician training, and longitudinal research designs that capture symptom evolution across the transplant continuum. Full article

Multiple sclerosis (MS) is a heterogeneous autoimmune disease driven by peripheral immune dysregulation and compartmentalized central nervous system (CNS) inflammation. Despite more than 20 approved disease-modifying therapies, disability accrual remains common, particularly in patients with highly active relapsing disease and progressive phenotypes characterized by silent progression and smoldering neuroinflammation. Two emerging therapeutic strategies address these unmet needs: Bruton’s tyrosine kinase (BTK) inhibitors and autologous haematopoietic stem cell transplantation (HSCT). Although mechanistically distinct, both aim to overcome limitations of conventional immunosuppression by intervening more deeply in the autoimmune cascade. This narrative review synthesized mechanistic, clinical, and translational evidence identified through a comprehensive search of PubMed, Scopus, Web of Science, and ClinicalTrials.gov from January 2010 to August 2025. BTK inhibitors are oral, CNS-penetrant therapies that selectively modulate B-cell signaling and CNS-resident myeloid cells without broad lymphocyte depletion, enabling continuous immunomodulation. Phase II–III trials of evobrutinib, tolebrutinib, and fenebrutinib show consistent MRI activity suppression but variable effects on relapses and disability, suggesting relevance in microglial-driven, relapse-independent disease. HSCT is a one-time immune reconstitution therapy that eradicates autoreactive immune clones and restores immune tolerance. Randomized and real-world studies demonstrate profound suppression of inflammatory activity, stabilization or improvement of disability, and durable treatment-free remission in selected patients with highly active relapsing–remitting MS, although procedure-related risks require strict eligibility criteria and experienced centers. Together with BTK inhibitors, HSCT represents a complementary strategy within an increasingly personalized MS treatment paradigm, emphasizing biomarker-guided patient selection and optimized therapeutic sequencing. Full article

Haemoglobinopathies, including β-thalassaemia and sickle cell disease (SCD), are among the most common monogenic disorders worldwide and remain major causes of morbidity and early mortality. Historically, management of these life-altering diseases has relied on supportive treatment and symptom management and, although these treatments reduce symptoms and ease disease burden, they do not correct the underlying genetic defect. Allogenic haematopoietic stem cell transplantation (HSCT) has been the only established curative option; however, it comes with substantial risks that significantly restrict its applicability. Over the past two decades, haematopoietic stem cell (HSC) gene therapy for haemoglobinopathies has rapidly progressed from experimental proof-of-concept to approved therapies. Lentiviral gene addition approaches have demonstrated durable expression of functional β-like globin transgenes, achieving transfusion independence in β-thalassaemia patients and significant reductions in vaso-occlusive events in SCD patients. Alternative therapeutic approaches to promote HbF expression have proved to be highly successful. Gene silencing strategies targeting BCL11A have been successful clinically and, more recently, gene editing technologies such as CRISPR/Cas9 have enabled precise disruption of regulatory elements controlling γ-globin repression, leading to the approval of the first CRISPR-based therapy for SCD and β-thalassaemia. Emerging base editing technologies promise even more precise genetic modification and are advancing through clinical evaluation. Despite these advances, access to gene therapy remains restricted due to the need for highly specialised manufacturing, toxic myeloablative conditioning regimens, and high treatment costs. Ongoing improvements and adaptations in these areas are essential to ensure that gene therapies fulfil their potential as accessible, curative treatments for patients suffering from haemoglobinopathies worldwide. Full article

Background/Objectives: In haematology, a wide range of blood disorders are hereditary. The thalassaemias are hereditary anaemias characterised by a high burden of disease at the public health level, challenging the resources of many health systems. This review focuses on thalassaemias for which many countries have developed screening and prevention programmes. To manage this heavy burden, two approaches were introduced over the years. The first one focused on reducing the annual affected births consequent to appropriate non-directive genetic counselling, offering to the parents the chance to make an informed choice concerning their reproductive lives. The second approach was related to the development of curative treatments such as haematopoietic stem cell transplantation (HSCT) in the early years, with continued ongoing efforts for improvements, followed by successful advances in gene-based holistic cures in more recent years. Genetic counselling is a vital component in successful prevention, aiming at informing individuals who are found to be carriers and couples who are both carriers with a 25% risk at every pregnancy of having an affected child in the case of recessive, Mendelian inheritance. The issues are many, and that may have to be discussed, highlighting the level of skills which a genetic counsellor is expected to possess and utilise appropriately in every counselling session. The concern is that such trained and skilled professionals are few in number and not well integrated into the multidisciplinary groups addressing the control of these complex disorders. It is our experience that for blood disorders, counselling is rarely in the hands of qualified scientists. It is our firm belief that it is necessary to incorporate genetic counselling as an integral part of haematology services. Methods: To investigate current practices we have drawn on the experience of existing programmes, as well as published literature. Results: Currently, in almost all haemoglobinopathy prevention programmes, counselling is offered by the clinicians in charge of clinical care or, in some settings, by the nurse of the clinic or the screening laboratory scientist. Conclusions: The Thalassaemia International Federation suggests and is in the process of developing special training in counselling as part of haematology training, as well as professional development modules for those already in practice. Considering the complexity of the issues that must be discussed, a multidisciplinary approach to counselling should be considered where possible. Full article

Background and Objectives: Total body irradiation (TBI) remains a cornerstone of conditioning for allogeneic haematopoietic stem-cell transplantation (HSCT). Whereas early research debated the need for irradiation, contemporary investigations focus on optimising dose, fractionation and delivery techniques. Material and Methods: We synthesised six decades of evidence, spanning from single-fraction cobalt treatments to modern helical tomotherapy and intensity-modulated total-marrow/lymphoid irradiation (TMI/TMLI). To complement the literature, we reported our institutional experience on 77 paediatric and adult recipients treated with conventional extended-source-to-skin-distance TBI at the University Hospital Policlinico “G. Rodolico–San Marco” between 2015 and 2025. Results: According to literature data, fractionated myeloablative schedules, typically 12 Gy in 6 fractions, provide superior overall survival and lower rates of severe graft-versus-host disease (GVHD) compared with historical single-dose regimens. Conversely, reduced-intensity protocols of 2–4 Gy broaden HSCT eligibility for older or comorbid patients with acceptable toxicity. Conformal planning reliably decreases mean lung dose without compromising engraftment, and early-phase trials are testing selective escalation to 16–20 Gy or omission of TBI in molecularly favourable cases. With regard to our institutional retrospective series, 92% of patients completed a 12-Gy regimen with only transient grade 1–2 nausea, fatigue or hypotension; all transplanted patients engrafted, and no grade ≥ 3 radiation pneumonitis occurred. Conclusions: Collectively, the published evidence and our experience support TBI as an irreplaceable component of HSCT conditioning and suggest that coupling it with advanced imaging, organ-sparing dosimetry and molecular response monitoring can deliver safer, more personalised therapy in the coming decade. Full article

Invasive fungal disease (IFD) is a recognised and potentially life-threatening complication of chronic graft-versus-host disease (cGVHD) and its treatment. Invasive aspergillosis (IA), most often due to the species Aspergillus fumigatus, is the leading IFD in this setting. IA can occur during the early weeks following allogeneic haematopoietic stem cell transplantation (HSCT) coinciding with profound neutropenia, but increasingly, cases of IA occur after engraftment, coinciding with the occurrence of cGVHD. Immunomodulatory treatments of cGVHD can impair innate immune responses to inhaled Aspergillus conidia, increasing the risk of developing IA. Here, in a pilot study, we present an analysis of the phenotypic characteristics (phagocytic efficiency, fungal killing, and cytokine release) of circulating monocytes derived from patients with cGVHD compared to healthy volunteers. We found that there was no statistically significant difference in their ability to phagocytose A. fumigatus conidia, and while there was a trend in their reduced ability to kill conidia, this was not significant when compared to the ability of volunteers’ monocytes to do so. Although we could not demonstrate in this small cohort of patients with cGVHD that monocytes may be a factor in the increased susceptibility to IA, further investigation of larger numbers of study subjects is warranted so that in vitro biomarkers may be developed for immune responses to Aspergillus in patients with cGVHD. Full article

Background: Haematological malignancies and their treatment regimens often lead to various complications that impair patients’ physical functioning. This study aimed to assess the level of physical activity and exercise capacity in patients with haematological malignancies who were qualified for haematopoietic stem cell transplantation (HSCT). Methods: A prospective, single-centre study was conducted on patients with haematological malignancies qualified for HSCT (study group, n = 103) and a cohort of healthy volunteers (reference group, n = 100). The assessment protocol included the International Physical Activity Questionnaire (IPAQ) and the 6-Minute Walk Test (6MWT). Results: The median age was 57 years in the study group and 56 years in the reference group. In the IPAQ assessment, at least 50% of the study group reported no engagement in moderate or intense physical activity. In the 6MWT, the study group demonstrated a significantly shorter walking distance compared to the reference group (p < 0.0001). Factors such as group membership (study vs. reference group), age, gender, and body mass index (BMI) were found to have a significant impact on 6MWT performance. No significant differences were observed in IPAQ or 6MWT results among subgroups within the study group when categorized by diagnosis. Conclusions: Patients with haematological malignancies who qualified for HSCT often show physical activity levels below recommended standards, which can negatively impact their ability to endure physical exertion. Insufficient activity prior to transplantation may contribute to reduced exercise capacity. Therefore, prehabilitation programmes aimed at improving physical activity and structured exercise should be an integral part of their care. Full article

Severe haematological diseases and lymphoid malignancies require bone marrow (BM)-suppressive treatments. Knowledge regarding the impact of BM-suppressive treatments on children’s memory T cells is very limited. Memory T cells play a crucial role in defending against herpesviruses, which is particularly relevant in paediatric cancer care. We studied 53 children in total; 34 with cancer and 2 with severe haematological disorders, with some receiving BM-suppressive treatment with or without allogeneic–haematopoietic stem cell transplantation (allo-HSCT), alongside 17 healthy controls. We focused on peripheral blood proportions of memory T-cell subsets using flow cytometry and analysed cytokine-secreting T cells with a four-parameter FluoroSpot assay in response to T-cell mitogen and varicella zoster virus (VZV) peptides. Patients on BM-suppressive treatment showed increased clusters of differentiation (CD)4⁺ and CD8⁺ effector memory (TEM)/terminally differentiated effector (TEFF) T cells compared to the healthy controls. They also exhibited, amongst other things, when compared to the healthy controls, a reduced total number of cytokine-secreting cells, by means of interferon (IFN)-γ, interleukin (IL)-17A, IL-10, and IL-22, following mitogen activation. A diminished IFN-γ response among the children with BM-suppressive treatment was observed upon VZV-peptide stimulation, compared to the healthy children. Collectively, the findings herein indicate that the children who are undergoing or have finished BM-suppressive treatment display qualitative differences in their T-cell memory compartment, potentially increasing their susceptibility to severe viral infections and impacting their immunotherapy, which relies on the functional ability of autologous T cells. Full article

Allogeneic haematopoietic stem cell transplantation (HSCT) leads to the establishment of graft-versus-leukaemia (GVL) immunity, but in many cases also results in the development of graft-versus-host disease (GVHD). This study aimed to determine if P2X7 antagonism using Brilliant Blue G (BBG) could improve the beneficial effects of post-transplant cyclophosphamide (PTCy) in a humanised mouse model of GVHD, without comprising GVL immunity. NOD.Cg-Prkdc^scid Il2rg^tm1Wjl (NSG) mice were injected with human peripheral blood mononuclear cells (PBMCs) (Day 0), then with cyclophosphamide (33 mg/kg) on Days 3 and 4, and with BBG (50 mg/kg) (or saline) on Days 0–10. PTCy with BBG reduced clinical GVHD development like that of PTCy alone. However, histological analysis revealed that the combined treatment reduced liver GVHD to a greater extent than PTCy alone. Flow cytometric analyses revealed that this reduction in liver GVHD by PTCy with BBG corresponded to an increase in human splenic CD39⁺ Tregs and a decrease in human serum interferon-γ concentrations. In additional experiments, humanised NSG mice, following combined treatment, were injected with human THP-1 acute myeloid leukaemia cells on Day 14. Flow cytometric analyses of liver CD33⁺ THP-1 cells showed that PTCy with BBG did not mitigate GVL immunity. In summary, PTCy combined with BBG can reduce GVHD without compromising GVL immunity. Future studies investigating P2X7 antagonism in combination with PTCy may lead to the development of novel treatments that more effectively reduce GVHD in allogeneic HSCT patients without promoting leukaemia relapse. Full article

The use of human leukocyte antigen (HLA)–haploidentical haematopoietic stem cell transplantation (HSCT) with post-transplant cyclophosphamide (PTCY), which markedly reduces the risk of graft-versus-host disease, has rapidly increased worldwide, even in children. It was initially developed for post-transplant relapse or non-remission at transplant for patients with high-risk haematologic malignancies. However, this strategy is currently used more frequently for standard-risk, transplant-eligible paediatric haematological malignancies. It has recently been recognised in adults that the transplant outcomes after PTCY-based HLA–haploidentical HSCT are comparable with those achieved after HLA-matched HSCT. Therefore, even in children, parental donors who are HLA–haploidentical donors and cord blood are currently considered the next donor candidates when an HLA-matched related or unrelated donor is unavailable. This review addresses the current status of the use of haplo-HSCT with PTCY for paediatric haematologic malignancies and future directions for donor selection (sex, age, ABO blood type, and HLA disparity), donor source, the dose of infused CD34⁺ cells, optimal conditioning, the concomitant graft-versus-host disease prophylaxis other than PTCY, and the pharmacokinetic study of CY and CY metabolites. These aspects present key solutions for further improvements in the outcomes of haplo-HSCT with PTCY for paediatric haematological malignancies. Full article