Search Results (1,336)

Background/Objectives: Determination of baseline predictors of longer-term quality of life (QOL) after autologous hematopoietic stem cell transplantation (Auto-HSCT) may identify patients with the greatest supportive care needs. We hypothesized that baseline older age, weight loss, and worse functional performance would negatively predict QOL over two years post-HSCT. Methods: Physical function, body composition, and QOL were assessed before (PRE) and one month (1MO) after Auto-HSCT in U.S. Veterans (N = 23). QOL and survival were also assessed approximately every six months for two years after Auto-HSCT (5MO, 1YR, 1.5YR, and 2YR). Changes over time were tested via Generalized Estimating Equation regression analyses (p < 0.05 = significant). The impact of PRE variables on QOL at each follow-up was tested via Spearman’s correlations (p < 0.01 = significant). Results: Relative to PRE, depression and anxiety significantly improved (p ≤ 0.039) at 1MO while fatigue and vitality significantly worsened (p ≤ 0.024) 1MO to 5MO post-HSCT. Vitality, depression, and anxiety returned to PRE levels thereafter, while fatigue trajectory varied depending on the survey used. Bone-Marrow-Transplant-related QOL significantly improved at 5MO (p = 0.014) while self-reported function (p ≤ 0.021) and physical activity (p ≤ 0.045) significantly improved 1-2YR post-HSCT. Greater PRE 30 s chair stand test performance consistently correlated with better self-reported function 1-2YR (r = 0.76–0.91, p ≤ 0.007) post-HSCT. Greater PRE 6 min walk test performance consistently correlated with better symptom burden 1-2YR (r = 0.71–0.81, p ≤ 0.01) post-HSCT. Conclusions: In support of our hypothesis, baseline functional performance was associated with QOL during two years of recovery after Auto-HSCT; older age and recent weight loss at baseline only predicted worse baseline QOL. Our data indicates that evaluation of the 30 s chair stand and 6 min walk tests as rehabilitation targets and/or predictors of QOL, fitness, or mortality after Auto-HSCT are warranted. Larger, controlled studies are needed to confirm the findings from this exploratory analysis. Full article

Background: Post-remission cytarabine consolidation is a cornerstone of therapy for acute myeloid leukemia (AML), but the optimal dosing strategy in older adults (≥60 years) remains unclear. High-dose cytarabine (HiDAC) is often avoided due to toxicity concerns, and data guiding cumulative dosing are limited. Methods: We conducted a single-center retrospective cohort study of 111 patients aged ≥60 years with AML who achieved complete remission after standard 7 + 3 induction and received at least one cycle of cytarabine consolidation between 2012 and 2024. A 90-day landmark analysis excluded early relapses or deaths. Results: The median age was 65 years; 41% proceeded to allogeneic hematopoietic stem cell transplantation (allo-SCT). Cytarabine consolidation was well tolerated, with no neurotoxicity and only one instance of reversible nephrotoxicity. Patients were stratified by median cumulative cytarabine dose into low-intensity (<18 g/m², LIC) and high-intensity (≥18 g/m², HIC) groups. HIC was associated with improved overall survival compared with LIC (median OS: 31 vs. 13 months, p = 0.02), particularly among non-transplanted patients (25 vs. 7 months, p = 0.01). On multivariable analysis, HIC (HR 0.71, 95% CI 0.51–0.82, p = 0.01) and allo-SCT (HR 0.58, 95% CI 0.44–0.79, p = 0.03) independently predicted superior survival. Conclusions: Higher cumulative cytarabine consolidation is safe, feasible, and associated with improved survival in older AML patients, especially among patients ineligible for transplant. Prospective studies are warranted to define the optimal dosing strategy in this population. Full article

Background: Acute graft-versus-host disease (aGVHD) is a leading cause of morbidity and mortality following pediatric hematopoietic stem cell transplantation (HSCT). Approximately half of children achieve complete response (CR) to corticosteroids, whereas steroid-refractory (SR) disease carries a 1–2-year mortality of 41–44%. Mortality risk is 2.6-fold higher in children > 13.9 years, and respiratory failure accounts for 26% of deaths. Existing second-line agents—ruxolitinib, tocilizumab, or extracorporeal photopheresis—have delayed onset or high toxicity. Begelomab (BEGESAND^®), a monoclonal antibody targeting CD26/dipeptidyl peptidase-4 (DPP4), inhibits CD26-mediated T-cell activation and has demonstrated 75% response in adults with minimal toxicity. However, pediatric data are lacking. Methods: We retrospectively reviewed five consecutive pediatric patients (ages 3–20 years) treated with Begelomab (BEGESAND^®) for SR (n = 4) or steroid-dependent (SD; n = 1) aGVHD between 2017–2021 under emergency IND authorization. Begelomab (BEGESAND^®) was administered intravenously at 2.7 mg/m²/day on days 1–5, 10, 14, 17, 21, 24, and 28. GVHD was graded by MAGIC criteria; flow cytometry and immunohistochemistry (IHC) assessed CD26 expression and immune effects. Results: All patients had grade IV disease after ≥2 prior agents. Two with pre-existing sepsis died early, before treatment response could be assessed. Of three evaluable patients, two (67%) achieved CR within 21 days and one achieved durable control by 6 months. All three remain alive; no Begelomab (BEGESAND^®)-related toxicity, cytopenia, or new infections occurred. Flow cytometry showed preserved T-cell subsets, and IHC demonstrated CD26 localization at sites of epithelial injury. Conclusions: Begelomab (BEGESAND^®) showed promising timely and durable responses with excellent safety in pediatric SR/SD-aGVHD, supporting further evaluation in multicenter pediatric trials. Full article

Background/Objectives: Total body irradiation (TBI) is widely used in conditioning regimens before hematopoietic stem cell transplantation. In conventional opposed-field TBI, monitor unit (MU) calculation and lung shielding definition are often based on manual procedures that may introduce operator-dependent variability. This study aimed to develop machine learning (ML) models to support the prediction of these treatment parameters using routinely available clinical and imaging data. Methods: A retrospective analysis was performed on 80 patients treated with conventional opposed-field TBI. Clinical, geometric, and CT-derived variables were used to train regression models for MU prediction. Feature selection was performed using LASSO regression, followed by Ridge regression for final modeling. Lung shielding thickness prediction was developed using planning CT data from 66 patients through recursive feature elimination and Random Forest regression. Model performance was assessed using nested 5-fold cross-validation and mean absolute error (MAE). Results: The final Ridge model achieved an MAE of 74.0 ± 6.9 MU, improving compared with the full-feature model 115.6 ± 44.0 MU. The Random Forest benchmark achieved an MAE of 81.1 ± 10.3 MU. For lung shielding thickness prediction (6–9 mm), the Random Forest model achieved an MAE of 0.60 mm. Prediction uncertainties were consistent with clinically accepted in vivo dosimetric tolerances. Conclusions: ML-based models can support the estimation of key TBI treatment parameters, potentially improving workflow efficiency and reducing operator-dependent variability while complementing standard treatment planning and verification procedures. Full article

RUNX1 alterations contribute to pediatric myeloid malignancies through both germline predisposition syndromes and somatic leukemogenic events, but their clinical and biological significance in children remains incompletely defined. This retrospective single-center study evaluated six pediatric patients with myelodysplastic syndromes or acute leukemias harboring RUNX1 variants, integrating clinical, cytogenetic, and targeted next-generation sequencing data, with germline status confirmed using non-hematopoietic tissues. Three patients carried germline RUNX1 variants, characterized by antecedent cytopenias, dysplastic features, and increased treatment-related toxicity, including severe infections, persistent cytopenias, and transplant-related mortality. In contrast, somatic RUNX1 alterations were associated with overt high-risk disease, frequently accompanied by complex cytogenetics or monosomy 7, and demonstrated heterogeneous outcomes ranging from sustained remission to post-transplant relapse. Mixed-phenotype acute leukemia was observed in both groups. These findings support a model of RUNX1-driven leukemogenesis, in which germline and somatic alterations represent distinct yet interconnected trajectories, while highlighting the importance of distinguishing variant origin for risk stratification, donor selection, and therapeutic decision-making in pediatric myeloid malignancies. Given the small cohort size, the findings remain descriptive and require validation in larger prospective studies. Full article

Background/Objectives: Multiple sclerosis (MS) constitutes a chronic autoimmune, inflammatory, and neurodegenerative disease, with dissemination in space and time, warranting diagnosis. Epstein–Barr virus (EBV) is increasingly recognized as a key contributor to MS pathogenesis. This review summarizes evidence on EBV-related mechanisms of currently approved disease-modifying therapies (DMTs) and emerging EBV-directed therapeutic strategies in MS. Methods: A systematic search of PubMed, Embase, Cochrane, and Web of Science was performed. Original English-language studies addressing EBV-related therapeutic mechanisms or EBV-targeted interventions in MS were included; 23 studies met the inclusion criteria. Results: Current DMTs may influence EBV-related immunity through diverse mechanisms, including modulation of B-cell subsets, altered lymphocyte trafficking, reduction in EBV-specific humoral responses, and restoration of T-cell surveillance. Monoclonal antibody-based therapies, particularly anti-CD20 agents and natalizumab, appear to affect the EBV–B-cell–immune axis through distinct but complementary mechanisms. Other interventions, including interferons, glatiramer acetate, dimethyl fumarate, autologous hematopoietic stem cell transplantation, and vitamin D supplementation, may also modulate EBV-specific cellular or humoral responses, although the magnitude and durability of these effects vary. Emerging EBV-directed approaches, including EBV-specific T-cell therapy, inhibition of specific proteins, modulation of autophagy, and cholesterol-dependent viral latency, provide additional support for targeting EBV-related pathways in MS. Conclusions: The therapeutic efficacy of DMTs in MS may extend beyond nonspecific immunomodulation and involve partial disruption of EBV-driven immune persistence. Further controlled studies are required to validate EBV-related biomarkers and determine whether direct EBV-targeted therapies can provide sustained clinical benefit. Full article

Background Cytomegalovirus (CMV) infection is a major contributor to morbidity and mortality in recipients of hematopoietic stem cell transplant (HSCT), solid organ transplant (SOT), and chimeric antigen receptor T-cell (CAR-T) therapy. While antiviral agents remain the cornerstone of treatment, CMV-specific immunoglobulins (CMVIG) have been utilized as adjunct therapy with variable outcomes. This study aims to evaluate the virological response and tolerability of CMVIG in cases of severe or refractory CMV viremia, with or without CMV disease. Methods: We conducted a single-center retrospective case series of adult recipients of SOT, allogeneic HSCT, and/or CAR-T cell therapy who developed CMV viremia or disease and received at least one dose of CMVIG between May 2017 and May 2023 at our center. Virological improvement within 14 days of starting CMVIG and tolerability of CMVIG are the primary outcome of this study. Results: A total of 33 patients were included. Of these, 29 underwent transplantation [SOT: 48.2%, HSCT: 51.7%], and five underwent CAR-T cell therapy (one post-HSCT). High-risk CMV serostatus was present in 12%. CMV viremia was documented in 32 patients (97%), and tissue-invasive disease was present in 11 patients (33.3%). Virological response, was observed in 65.6% of the cohort. The median time to undetectable CMV viral load following CMVIG initiation was 28 days. CMVIG was well-tolerated. All-cause mortality at 90 days remained high (57%). Conclusion: In this case series, CMVIG demonstrated a virological response rate of 65.6% in patients with severe or refractory CMV infection. While CMVIG was well-tolerated with minimal adverse events, the high mortality rate despite virological response suggests that CMVIG may be insufficient for this critically ill population. Our findings should be interpreted as observational data from a small case series, and prospective controlled trials are needed to establish the true benefit of CMVIG in combination with standard antiviral therapy. Full article

TP53 mutation is known to be a poor prognostic factor in many hematologic malignancies, but it is not included in any Myelofibrosis-specific prognostic score. Recently, studies have shown that TP53 mutation may negatively impact the outcomes of patients with Myelofibrosis, including those undergoing hematopoietic stem cell transplantation. In this study, we aimed to analyze the impact of TP53 mutation on the overall survival and leukemia-free survival of patients with chronic-phase Myelofibrosis, regardless of whether they had undergone transplantation. A total of 250 patients were included in the study, of whom 9 (3.2%) harbored a TP53 mutation, including six (3.2%) among non-HSCT patients and three (3.1%) among HSCT patients. In both groups, the presence of TP53 mutation correlated with shorter overall survival, while in non-HSCT patients, it also correlated with lower leukemia-free survival. Moreover, we provide a meta-analysis on the role of TP53 mutation in patients with chronic-phase Myelofibrosis, confirming its negative prognostic impact on overall survival. Full article

Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only curative therapy for myelofibrosis (MF), but its use is limited by substantial transplant related morbidity and mortality, particularly in older or comorbid patients. Treosulfan has emerged as a less toxic alternative to busulfan, with potential advantages in myeloablative and reduced intensity conditioning. Methods: We conducted a comprehensive, multi-database literature search (PubMed, Scopus/EMBASE, Cochrane Library, Web of Science, and grey literature) for studies published between 2000 and 2025 evaluating treosulfan-based conditioning in MF patients undergoing allo-HCT. Data on patient characteristics, conditioning regimens, engraftment, graft-versus-host disease (GVHD), and survival outcomes were synthesized. Results: Eight studies including more than 800 patients were analyzed. Treosulfan was most commonly combined with fludarabine, with or without additional agents. Engraftment rates were consistently high at 94 to 100%, with low non-relapse mortality (NRM) and favorable progression-free survival (PFS). An EBMT registry study demonstrated superior survival and significantly lower NRM compared with busulfan based regimens. Benefits were observed across older patients, alternative donors, and second transplants. Higher treosulfan doses were associated with increased toxicity in some cohorts. Conclusions: Treosulfan based conditioning offers an effective and better tolerated option for MF transplantation. Prospective trials are needed to refine dosing and patient selection. Full article

The role of zonulin as a biomarker of intestinal permeability in the allogeneic hematopoietic stem cell transplantation (allo-HSCT) setting remains poorly understood. In this study, we aimed to evaluate serum zonulin dynamics, identify its predictors, and assess its prognostic significance in patients undergoing allo-HSCT. This multicenter, prospective cohort study was conducted across four Brazilian hospitals. Eligible participants were patients aged ≥12 years who provided at least one blood sample during the allo-HSCT course. A control group of 15 healthy adult individuals was also included. Serum zonulin levels were quantified using enzyme-linked immunosorbent assay multiple times over the allo-HSCT course. Outcomes included acute graft-versus-host disease, overall survival, and bloodstream infections. A total of 477 blood samples were collected from 140 patients. Compared with the control group, zonulin levels were persistently elevated at all evaluated time points throughout the allo-HSCT course. However, no significant differences were observed among the different time points assessed during transplantation. No clinical or transplantation-related characteristics were identified as significant predictors of elevated zonulin levels. Finally, zonulin did not demonstrate prognostic value for allo-HSCT-related outcomes. Future studies should investigate whether other intestinal permeability biomarkers have prognostic relevance in the allo-HSCT setting. Full article

Background: Relapse is the leading cause of treatment failure in patients with myeloid hematologic malignancies undergoing allogeneic hematopoietic cell transplantation. Clonal genomic evolution may contribute to post-transplant relapse, yet its determinants and prognostic impact remain incompletely characterized. Methods: In this retrospective study, we analyzed 63 patients with myeloid neoplasms who underwent cytogenetic evaluation both at diagnosis and at relapse after allogeneic hematopoietic stem cell transplantation. Cytogenetic changes (CGE), including evolution, devolution, or combined patterns, were assessed and correlated with clinical characteristics, prior treatment exposure, and survival outcomes. Results: Cytogenetic changes were observed in 46.1% of patients. The presence of cytogenetic changes (CGE) was strongly associated with the presence and complexity of cytogenetic abnormalities at initial diagnosis, whereas prior chemotherapy exposure, conditioning intensity, and donor type showed no significant association. Patients with cytogenetic changes had a lower complete remission rate at day 30 after transplantation; however, relapse-free survival and post-relapse survival did not differ significantly between groups. Conclusions: These findings suggest a potential association between post-transplant cytogenetic changes and intrinsic genomic instability, although treatment-related effects cannot be excluded. Larger, disease-stratified studies integrating cytogenetic and molecular analyses are warranted to further clarify the biological and prognostic relevance of clonal evolution following transplantation. Full article

Sickle cell disease (SCD) is a monogenic disorder responsible for recurrent vaso-occlusive crises, progressive organ damage, and shortened life expectancy. For decades, allogeneic hematopoietic stem cell transplantation from a matched sibling donor has been the only established cure, but its reach remains limited by donor availability and transplant-related toxicity. The approval of two autologous gene therapy products in 2023, exagamglogene autotemcel (exa-cel) and lovotibeglogene autotemcel (lovo-cel), marked a turning point for the SCD population and the gene therapy field in general. This review proposes a molecular rationale for fetal hemoglobin reactivation and β-globin gene addition, describes the engineering of lentiviral and CRISPR-based platforms, and highlights the clinical evidence accumulated to date that demonstrated durable disease modification with acceptable short-term toxicity. We then assess the clinical positioning of gene therapy within the broader spectrum of curative options compared to current available treatments and address the financial, ethical and psychosocial barriers that limit access to gene therapy both within high-income countries and globally. Critical research priorities include long-term safety surveillance, comparative effectiveness studies, pediatric trials below 12 years, and validated patient-reported outcome instruments. Base editing, non-genotoxic conditioning, and in vivo delivery represent the most promising avenues to broaden access and reduce treatment burden. Full article

Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive myeloproliferative neoplasm of early childhood characterized by constitutive activation of the RAS-MAPK signaling pathway. RASopathies are a heterogeneous group of complex genetic disorders arising from germline mutations that dysregulate RAS-MAPK signaling. Noonan syndrome, CBL syndrome, and neurofibromatosis type 1 (NF1) are the three major RASopathies predisposing to JMML. More than 90% of JMML cases harbor germline or somatic mutations in one of five canonical driver genes—PTPN11, NRAS, KRAS, NF1, or CBL—establishing JMML as the prototypical malignant manifestation of RASopathy biology. The fifth edition of the World Health Organization Classification of Tumours reclassified JMML as a myeloproliferative neoplasm while the International Consensus Classification adopted JMML under pediatric and/or germline mutation-associated disorders, introducing a JMML-like category for cases lacking five canonical mutations but harboring emerging drivers such as SH2B3::LNK alterations and ALK::ROS1 fusions. The distinction between germline and somatic mutations profoundly influences prognosis: e.g., germline PTPN11-associated myeloproliferations and many germline CBL cases undergo spontaneous resolution, whereas somatic PTPN11- and NF1-mutated JMML is more aggressive and requires prompt allogeneic hematopoietic stem cell transplantation. DNA methylation profiling has emerged as the most robust prognostic framework, with consensus defining high-, intermediate-, and low-methylation subgroups that independently predict outcome. Both genotype and DNA methylation subclassification have been integrated into clinical decision-making, incorporating pretransplant azacitidine, watch-and-wait approaches for favorable-risk patients, and emerging targeted therapies including MEK inhibitors. This review synthesizes recent advances in understanding JMML as a bona fide RASopathy; provides a diagnostic algorithm, molecular landscapes, and prognostic models; and highlights opportunities for molecularly targeted therapeutic intervention. Full article

Background: Hematopoietic stem cell transplantation (HSCT) is a procedure used in different malignant and non-malignant diseases. Although post-transplant lymphoproliferative disorder (PTLD) is infrequently observed in patients with HSCT, no study on the overall global incidence rate is available to date. Methodology: In this study, we selected 39 studies from 941 studies from three databases (i.e., PubMed, ScienceDirect, and Google Scholar) to identify the global incidence rate of PTLD in HSCT. Results: The pooled incidence was determined to be 5.6% (95% CI: 5.0 to 6.3) and rose further to 12.4% (95% CI: 10.2 to 14.7) after excluding outlier studies. The quality of the studies was high as well. PTLD was prevalent the most in allogenic HSCT (i.e., 5.6% (95% CI: 4.9 to 6.3)) and within the European region (i.e., 27.1% (95% CI: 21.4 to 32.8)). Among risk factors, human leukocyte antigen (HLA) mismatch was reported in most of the studies. Conclusions: This study assessed and discussed the overall global incidence of PTLD in HSCT patients, continent-based incidence, and risk factors that can be helpful in finding the possible prevention mechanism of PTLD and implementing individualized treatment approaches based on the treatment availability during HSCT. Full article

Background: Cytomegalovirus (CMV) viral load monitoring forms the basis of preemptive treatment strategies in patients undergoing solid organ and hematopoietic stem cell transplantation. This study aimed to evaluate the analytical performance and inter-method agreement of a laboratory-developed CMV real-time PCR (qPCR) test compared to a commercial reference method using plasma samples. Methods: A total of 100 EDTA plasma samples were analyzed in parallel using a laboratory-developed CMV qPCR test and the reference method (Roche Cobas^® CMV). Analytical sensitivity was determined us-ing synthetic DNA cloned into the pUC57 plasmid backbone containing the US17 region of the CMV genome, and the limit of detection (LoD₉₅) was calculated using probit regression analysis. The relationship between the quantitative results obtained from clinical samples was evaluated using the Spearman rank correlation coefficient, while inter-method clinical agreement was assessed using the Bland–Altman method. Results: The limit of detection (LoD₉₅) of the laboratory-developed CMV qPCR test, as determined by probit regression analysis, was 63.8 copies/µL. A weak and statistically non-significant correlation was ob-served between the laboratory-developed CMV qPCR test and the reference method in Spearman rank correlation analysis of samples for which numerical quantitative results were available from both methods (ρ = 0.32; p = 0.22; n = 16). Bland–Altman analysis showed a mean difference of −0.48 log₁₀ units, with the vast majority of measurements falling within the 95% limits of agreement. Conclusions: The assay demonstrated measurable analytical performance and inter-method agreement; however, its use for quantitative viral load monitoring, particularly at low CMV DNA levels, should be interpreted with caution. Full article