Search Results (919)

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

Relapse remains the leading cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in acute myeloid leukemia (AML). Early identification of patients at increased post-transplant relapse risk is essential to enable intensified surveillance and pre-emptive therapeutic strategies. Wilms’ tumor 1 (WT1) is overexpressed in most AML cases and represents a broadly applicable molecular marker; however, its utility as a peripheral blood (PB) measurable residual disease (MRD) marker after allo-HSCT remains incompletely defined. In this prospective multicenter cohort study, 43 adults with AML in complete remission underwent allo-HSCT between 2021 and 2023. WT1 expression in PB was quantified using standardized real-time quantitative PCR before transplantation (WT1_pre) and at day +30 (WT1_30). Receiver operating characteristic analysis identified an optimal threshold for relapse prediction. A WT1 cutoff of ≥3 copies/10⁴ ABL discriminated relapse risk. WT1_30 demonstrated strong prognostic performance (AUC 0.79; p = 0.005), whereas WT1_pre showed more modest predictive value (AUC 0.69; p = 0.037). Patients with WT1_30 ≥ 3 had inferior 12-month progression-free survival compared with those with WT1_30 < 3 (52.9% vs. 90.9%, p = 0.0059) and a higher 12-month cumulative incidence of relapse (31% vs. 9%, p = 0.054). WT1_pre ≥ 3 was also associated with inferior progression-free and overall survival (both p = 0.0008). Relapsed patients had significantly higher WT1_30 levels than non-relapsed patients (median 5.0 vs. 2.0 copies/10⁴ ABL; p = 0.018). Peripheral blood WT1 expression, particularly at day +30, is associated with an increased relapse risk after allo-HSCT in AML and may support early post-transplant risk stratification. The identified cutoff should be considered exploratory and requires validation in larger independent cohorts. Full article

Severe aplastic anemia (SAA) in pregnancy represents a rare but life-threatening clinical challenge. Standard therapies such as hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy are limited during pregnancy due to safety concerns, leaving supportive care as the mainstay. Thrombopoietin receptor agonists (TPO-RAs) such as eltrombopag have emerged as promising agents in refractory SAA, though evidence of their safety in pregnancy remains scarce. We present the case of a 27-year-old woman with SAA post-allogeneic bone marrow transplant who relapsed during subsequent pregnancies. Her disease course was characterized by recurrent pancytopenia, mixed chimerism, and repeated need for stem cell boosts. During pregnancy in 2023, discontinuation of cyclosporine led to worsening cytopenias, prompting reintroduction of cyclosporine and the continuation of eltrombopag. This combined approach, alongside G-CSF and stem cell boosts, contributed to favorable hematologic stabilization. She successfully delivered a healthy infant and achieved hematologic recovery following a third stem cell boost postpartum. This report highlights the potential utility of TPO-RAs during pregnancy when conventional therapy is limited, while emphasizing the need for vigilant monitoring of maternal–fetal outcomes. A review of the literature suggests that although routine use of eltrombopag in pregnancy is not recommended, it may be considered in refractory SAA cases with careful risk–benefit assessment. The case underscores the role of multidisciplinary care, individualized therapeutic planning, and the need for further studies on TPO-RAs in pregnancy-associated bone marrow failure syndromes. Full article

Extramedullary relapse (EMR) of acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) represents a clinically and biologically distinct entity compared with medullary relapse, characterized by marked heterogeneity, compartmental immune escape mechanisms, and generally poor prognosis. EMR arises at the intersection of clonal resistance, evolutionary disease adaptation, and heterogeneous distribution of the graft-versus-leukemia effect, resulting in evolutionary trajectories that are often dissociated between medullary and extramedullary compartments. In the absence of prospectively validated therapeutic algorithms, EMR management requires a structured and adaptive approach based on multidimensional assessment integrating leukemia biology, disease burden and anatomical distribution, bone marrow minimal residual disease (MRD) status, and immune reconstitution. Therapeutic strategies include local treatments, targeted agents, immunotherapies, and immunomodulatory interventions, applied within a dynamic sequence tailored to treatment response. Follow-up plays a central role as an active tool for prognostic stratification and clinical decision-making, enabling early detection of systemic progression and optimization of the timing of consolidative strategies, including second Allo-HSCT in selected patients. An integrated and biologically driven management of post-Allo-HSCT EMR is essential to improve outcomes in this high-risk clinical setting. Full article

Gut microbiota plays a crucial role in regulating immune system function and shaping immunological responses to pathogens capable of causing infections. Alterations in the composition of the intestinal microbiome are associated with immune system dysfunction and increased susceptibility to infections. Patients with acute myeloid leukemia (AML) are highly susceptible to infections due to immune system deregulation caused by the disease itself, as well as chemotherapy-induced bone marrow aplasia. In these patients, gut microbiota dysbiosis and reduced microbial diversity (i.e., imbalances in the composition and function of intestinal microbes) result from multiple factors, including the underlying disease, neutropenia, dietary factors, use of antibiotics, chemotherapy regimens and prolonged hospitalization. Chemotherapy, for instance, induces damage to the intestinal mucosa and disrupts the epithelial barrier, resulting in deregulation of the intestinal microbiome. Previous studies have reported alterations in the human intestinal microbiome in patients with AML undergoing chemotherapy. Of particular interest is the capacity of some commensal bacteria to modulate the tumor microenvironment and response to chemotherapy. Moreover, increased mortality and reduced overall survival have been reported in patients who have undergone allogeneic stem cell transplantation and exhibit decreased gut microbiome diversity at the time of transplantation. These findings indicate that the composition of gut microbiota may play an important role in the prognosis of AML, especially in relation to therapeutic response. This narrative review summarizes new research into the role of the intestinal microbiome and the underlying alterations observed in patients with AML, resulting from the disease and therapeutic interventions and outlines strategies to improve its function and outcomes. Full article

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by clonal hematopoietic dysregulation, amplification of chronic inflammation, and progressive remodeling of the bone marrow fibrotic niche, clinically manifesting as bone marrow failure, splenomegaly, and systemic inflammatory symptoms. Although Janus kinase (JAK) inhibitors can alleviate symptom burden and reduce spleen size, they have limited capacity to eradicate malignant clones or reverse fibrosis. Allogeneic hematopoietic stem cell transplantation remains the only potentially curative option; however, its application is constrained by advanced age, comorbidities, unavailable donor, and transplant-related risks. Therefore, the development of disease-modifying therapeutic strategies has become a central focus in MF research. Chimeric antigen receptor T (CAR-T)-cell therapy has demonstrated robust efficacy across various hematologic malignancies. Its application in MF holds the potential not only to selectively eliminate malignant hematopoietic clones but also to modulate the immunosuppressive and profibrotic microenvironment through advanced cellular engineering, thereby enabling a dual therapeutic paradigm involving both clonal control and microenvironmental reprogramming. In this context, potential targets and pathways include CD123, myeloproliferative leukemia protein (MPL), fibroblast activation protein (FAP), the TGF-β signaling axis, the CXCR4–CXCL12 niche-regulatory axis, and molecules associated with myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Future strategies may optimize both efficacy and safety through combinatorial approaches, including integration with JAK inhibitors, development of armored CAR-T constructs, and bridging to hematopoietic stem cell transplantation. Collectively, CAR-T-cell therapy offers a promising avenue for shifting MF management from symptomatic control toward true disease modification. Full article

Background: Acute Graft versus Host Disease (aGvHD) is a serious complication of allogeneic stem cell transplantation (Allo-SCT) associated with substantial morbidity and mortality. Enteral nutrition (EN) has been associated with improved transplant outcomes, yet standardized early EN practices remain inconsistently adopted across centers. Methods: This retrospective cohort study evaluated the adoption and clinical outcomes of a standardized Day +1 EN protocol in patients undergoing Allo-SCT. The protocol included feeding tube (FT) placement on Day +1 with EN initiated at 25 mL/h. Demographic and clinical data were extracted from electronic health records for patients treated after protocol adoption (post-protocol) and retrospective controls from one year prior (pre-protocol group). Outcomes included successful Day +1 EN initiation, gastrointestinal (GI) complications, FT removal reason, and occurrence and severity of lower GI and overall aGvHD by Day +100 (Modified Glucksberg Criteria). Group comparisons used Welch’s t-test and Fisher’s Exact test (p < 0.05). Results: The final cohort included 108 patients (67 pre-protocol and 41 post-protocol). Successful Day +1 EN initiation occurred in 95.1% (n = 39) of patients post-protocol versus 4.5% (n = 3) pre-protocol (p < 0.001). GI complications and FT removal reason did not differ significantly between groups, and no FTs were removed due to adverse events. The occurrence of lower GI aGvHD was significantly lower post-protocol (12.2% vs. 28.4%, p = 0.05). Conclusions: Adoption of a standardized Day +1 EN protocol in Allo-SCT patients was successfully implemented and well-tolerated without adverse FT-related events. The significant difference in lower GI GvHD occurrence in the post-protocol group warrants confirmation of Day+1 EN in patients receiving an Allo-SCT in a future randomized trial. Full article

Background: Graft-versus-host disease (GVHD) is a common severe complication of allogeneic hematopoietic stem cell transplant. The current treatments are limited by steroid toxicity, broad immunosuppression, and the potential suppression of the graft-versus-tumor (GVT) effect. Developing less toxic therapies is an unmet need. We previously showed that systemically infused negatively charged immune-modifying microparticles (IMPs) composed of carboxylated poly-lactic-co-glycolic acid are taken up by inflammatory monocytes via the MARCO receptor, reducing symptoms and improving survival in inflammatory conditions. We hypothesized that IMPs could reduce acute GVHD manifestations. Methods: Acute GVHD was induced in an MHC-mismatched murine transplant model with radiation conditioning. IMPs were infused for five days; outcomes were compared to saline controls. We assessed organ histopathology, immune cell populations in the spleen and intestine, serum cytokine levels, and the GVT effect. Results: IMP-treated mice showed significant improvements in terms of clinical GVHD scores, histopathology, and survival. They had increased regulatory T-cells in the spleen and intestine and decreased colonic inflammatory monocytes and cytokines such as IL-6 and IFN-γ. IMPs were ineffective in MARCO knockout mice, confirming receptor dependence. Importantly, GVT activity was preserved, as evidenced by improved survival in mice with A20 lymphoma treated with IMPs. Conclusions: Systemic IMPs reduce clinical GVHD signs and improve survival, likely by decreasing inflammatory monocytes via MARCO and expanded regulatory T-cells numbers, while maintaining GVT activity. These findings support further investigation of IMPs as a targeted GVHD therapy. Full article

Background: The Endothelial Activation and Stress Index (EASIX) is a biomarker initially developed to predict survival in patients with acute graft-versus-host disease after allogeneic haemato-poietic stem cell transplantation and is regarded as a surrogate of endothelial dysfunction. This study aimed to evaluate whether EASIX reflects early hemodynamic instability and vasopressor requirement in critically ill patients. Methods: We retrospectively analysed 447 patients admitted to the intensive care unit (ICU) at the University Clinical Centre in Gdańsk. Illness severity scores—including the Simplified Acute Physiology Score II (SAPS II), Acute Physiology and Chronic Health Evaluation II (APACHE II), and Sequential Organ Failure Assessment (SOFA)—and laboratory parameters, were collected at admission. EASIX, simplified EASIX (sEASIX), and modified EASIX (mEASIX) were calculated using established formulas. Vasopressor requirements, ex-pressed as norepinephrine equivalents (NEE), were recorded during the first 72 h. Statistical analyses included Spearman’s correlation, logistic regression, and receiver operating characteristic curve analysis. Results: In univariate analysis, EASIX was associated with ICU mortality (OR 1.333; 95% CI 1.135–1.576), but this association was not significant after adjustment. EASIX positively correlated with vasopressor requirements, severity scores (SOFA, SAPS II, APACHE II), and inflammatory and metabolic markers (PCT, CRP, lactate). It correlated with norepinephrine-equivalent doses within the first 48 h and moderately discriminated high-dose vaso-pressor use (>0.1 µg/kg/min). A weak negative correlation with ICU length of stay was observed. No association with age was found. Conclusions: EASIX is an age-independent marker associated with disease severity and early vaso-pressor burden in ICU patients. Rather than providing a direct measurement of endothelial function, it reflects a global signal of systemic stress and microvascular derangement and should be interpreted accordingly. Full article

Background and Methods: Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a severe complication of allogeneic stem cell transplant (allo-SCT). Given the increased use of allo-SCT and variability of SOS/VOD incidence in published reports, cases of allo-SCT from two major transplant centers in Ontario, Canada (2019–2021), were reviewed to identify risk factors prognostic for SOS/VOD onset and to assess outcomes. Results: This study included 536 allo-SCT cases, with a mean age of 53.4 years [min–max: 17–76], including 322 male recipients and 214 female recipients. There were 17 SOS/VOD cases diagnosed during the first 100 days, representing 3% of allo-SCT cases, with a median age of 48 years [18–72] and equally distributed between genders. All cases were classical SOS/VOD, with onset prior to day 21 [1–20]. These cases were graded as one mild, six moderate, six severe, and four very severe cases. The mild case of SOS/VOD recovered after treatment with diuretics. In respect to the 16 cases graded as ≥moderate SOS/VOD, the average inpatient stay was 56 days [24–178], and eight patients were in the ICU for an average of 6 days [0–42], with a median of zero days. Five of the sixteen ≥moderate SOS/VOD patients died within 100 days [9–59]—four from SOS/VOD. After day +100, five remained alive, and six died between days 125 and 419. Treatments for ≥moderate SOS/VOD included diuretics [n = 15], steroids [n = 3], and defibrotide [n = 9]. The nine patients treated with defibrotide were graded as moderate [n = 2], severe [n = 4], and very severe [n = 3]. Three of the nine patients treated with defibrotide died before day 100, and the other six survived beyond day 100. None of the six surviving patients died from SOS/VOD. Univariable regression analysis identified a higher baseline absolute neutrophil count (ANC) of 4.2 × 10⁹/L compared to 2.6 × 10⁹/L [p = 0.035] and lower baseline platelet count of 104 × 10⁹/L compared to 140 × 10⁹/L [p = 0.034] in SOS/VOD and non-SOS/VOD cases, respectively, as independent risks for ≥moderate SOS/VOD. Treatment with inotuzumab ozogamicin was also identified as a risk factor for ≥moderate SOS/VOD (p = 0.016). The absence of late-onset SOS/VOD in the cohort of 536 patients prompted a retrospective analysis of the data to identify potentially missed cases. Seven cases were identified as meeting the diagnostic criteria for SOS/VOD: four classical and three late-onset. One case would have been graded as severe, and the remaining six would have been graded as very severe. Six patients were reported to have died between days 11 and 107, with four deaths before day 100. The clinical diagnoses of patients meeting diagnostic criteria for SOS/VOD included infection (n = 3), graft-versus-host disease (GVHD) (n = 3), and pulmonary hemorrhage (n = 1). The inclusion of potentially missed cases in the analysis again suggested a lower baseline platelet count (p = 0.002) and prior treatment with inotuzumab ozogamicin (p = 0.003) as potential risk factors for SOS/VOD. The baseline ANC was lower in this combined cohort but did not reach statistical significance (p = 0.089) as it did in the confirmed SOS/VOD cohort (p = 0.035). Additional clinical features that were identified as statistically significant for the onset of SOS/VOD (potential and confirmed cases) included a lower Karnofsky Performance Status (p = 0.01), the presence of pulmonary hypertension (p = 0.012), lower baseline hemoglobin (p = 0.017), and higher baseline serum ferritin (p = 0.01). Conclusions: The incidence of classical SOS/VOD in this cohort was consistent with recent published reports and carried a high fatality rate. A higher ANC, lower platelet count at the start of the preparative regimen, and prior treatment with inotuzumab ozogamicin were identified as potential risk factors for diagnosed SOS/VOD. Hospital and intensive care unit stays were longer in SOS/VOD patients. There were no cases of late-onset VOD diagnosed within the first 100 days of allo-SCT transplant, which is inconsistent with recently reported incidence rates. Potentially missed cases of SOS/VOD were identified, suggesting that this disease may be under-diagnosed and underscoring the need for ongoing education and resources to allow for early intervention. Full article