Search Results (1,598)

Radiometabolic therapy is a mechanistically plausible but clinically underused strategy in lymphoma. Its rationale is based on the selective delivery of cytotoxic radiation to malignant lymphoid cells through antibodies, peptides, or small molecules directed against tumor-associated targets. Radioimmunotherapy with anti-CD20 agents, including 90Y-ibritumomab tiuxetan and 131I-tositumomab, demonstrated meaningful efficacy in B-cell non-Hodgkin lymphoma, particularly in indolent and relapsed/refractory settings. However, despite encouraging clinical results, its use progressively declined because of logistical, regulatory, commercial, and multidisciplinary barriers. More recently, renewed interest has emerged with the development of novel antibody–radionuclide conjugates and radioligand-based theranostic strategies targeting CD22, CD37, CD45, and CXCR4. Among these, CXCR4-directed imaging and therapy with 68Ga-pentixafor and 177Lu/90Y-pentixather illustrate image-guided patient selection and targeted radionuclide treatment in advanced hematologic malignancies. This narrative review summarizes evidence retrieved from Scopus and PubMed on radiometabolic therapy in lymphoma, with particular attention paid to established radioimmunotherapy, emerging targets, radioligand therapy, dosimetry, toxicity, and combination strategies with chemotherapy, immunotherapy, and hematopoietic stem cell transplantation. Available evidence supports the plausibility and possible clinical utility of these approaches, but remains heterogeneous and, for several newer targets, preliminary. Future development will require prospective trials, standardized imaging-based selection, individualized dosimetry, and integration within multidisciplinary lymphoma treatment pathways. Full article

Sickle Cell Disease (SCD) is a pervasive monogenic disorder characterized by chronic hemolytic anemia, unpredictable vaso-occlusive crises, and progressive multi-organ damage, representing a significant global health burden. Driven by a point mutation in the β-globin gene, the resulting abnormal Hemoglobin S (HbS) polymerizes under deoxygenated conditions, leading to erythrocyte sickling and systemic endothelial dysfunction. While supportive therapies such as hydroxyurea and transfusions manage symptoms, the mandate for definitive curative therapies is urgent. Historically, allogeneic hematopoietic stem cell transplantation (HSCT) utilizing matched sibling donors (MSD) has been the sole curative option, offering high survival rates but constrained by limited donor availability and the risk of graft-versus-host disease (GVHD). Consequently, alternative donor sources, including matched unrelated donors, umbilical cord blood, and haploidentical donors, have expanded patient access, particularly with the integration of post-transplant cyclophosphamide (PTCy) to mitigate alloreactivity. Concurrently, the advent of autologous gene therapy, encompassing lentiviral gene addition (Lyfgenia) and CRISPR-Cas9 gene editing (Casgevy) offers a revolutionary donor-independent approach that eliminates GVHD risk. Lyfgenia employs a lentiviral vector to introduce an anti-sickling βT87Q hemoglobin variant into autologous hematopoietic stem cells, while Casgevy employs CRISPR-Cas9 to disrupt the erythroid-specific enhancer of the BCL11A transcription factor, derepressing γ-globin expression and elevating fetal hemoglobin. This review synthesizes the pathophysiological mechanisms of SCD, evaluates the clinical outcomes and limitations of both allogeneic HSCT and autologous gene therapies, and outlines the clinical decision-making paradigms and future innovations required to achieve equitable global access to these transformative treatments. Full article

Acute myeloid leukemia (AML) is a genetically and clinically heterogeneous hematologic malignancy in which intensive induction chemotherapy remains the standard therapeutic platform for medically fit adults. In recent years, however, the frontline treatment paradigm has progressively evolved from a purely cytotoxic approach toward a biologically informed strategy. This shift has been driven by the identification of recurrent molecular alterations—particularly FLT3 and IDH1/2 mutations—as well as renewed interest in antibody-based therapies and the growing recognition that relapse, resistance, and measurable residual disease (MRD) are shaped by clonal architecture rather than blast burden alone. This review examines the development of targeted therapies combined with intensive chemotherapy in AML. We discuss the biological rationale for combination approaches and summarize the key clinical studies that have defined current practice, including trials evaluating FLT3 inhibitors, gemtuzumab ozogamicin, IDH inhibitors, and venetoclax-based strategies. We also address the role of targeted therapy across different treatment phases, including induction, consolidation, and post-remission settings, and analyze emerging data regarding MRD-guided treatment strategies, mechanisms of resistance, and integration with allogeneic hematopoietic stem cell transplantation. The integration of targeted agents with intensive chemotherapy is reshaping frontline AML therapy and represents a critical step toward precision medicine. While genotype-directed strategies—such as FLT3 inhibition—have already demonstrated survival benefit, optimal patient selection, treatment sequencing, and duration remain areas of active investigation. Future progress will likely depend on MRD-driven treatment adaptation, improved understanding of clonal evolution, and the development of rational multi-agent combinations capable of achieving deeper and more durable remissions. Full article

The prognosis of mucormycosis after hematopoietic stem cell transplantation (HSCT) is generally poor but data on post-HSCT outcomes in patients with pre-HSCT mucormycosis are limited. We reviewed patients with documented mucormycosis at MD Anderson Cancer Center (2008–2024) and identified five patients who subsequently underwent HSCT. A literature review identified 24 additional such cases. Most patients had acute myeloid leukemia (69%). The most common site of mucormycosis was pulmonary (59%), while 31% had disseminated mucormycosis. All patients received antifungals and 76% had surgery prior to HSCT. At the time of HSCT, 67% had mucormycosis responding to treatment. No patient went to transplant with progressing mucormycosis. Eighty percent of patients with ≥12 months of follow-up after HSCT were alive. Five of the twenty-nine patients (17%) had documented or suspected mucormycosis recurrence post-HSCT. Relapsed malignancy pre-HSCT was associated with increased 12-month post-HSCT mortality (p = 0.031). Furthermore, post-transplant mortality was higher in cord blood recipients (p = 0.019) and tended to be higher in patients not undergoing surgery pre-HSCT (p = 0.062). Despite publication bias, our data suggest that HSCT can be conducted safely in selected patients with pre-HSCT mucormycosis, particularly when underlying hematologic malignancy is in remission, mucormycosis is stable, and surgical source control is feasible. Full article

Background/Objectives: Inherited variants in IKZF1 and CDKN2A/2B are among the most consistently reported germline susceptibility markers for childhood acute lymphoblastic leukemia (ALL). Nonetheless, effect sizes differ across ancestry groups, age ranges, and immunophenotypic subtypes, making well-characterized population-specific replication studies valuable for refining ancestry-specific evidence. This study examined two sentinel variants with historical relevance, IKZF1 rs4132601 and CDKN2A rs3731217, within a pediatric Greek cohort. Methods: A case–control study with retrospective case ascertainment and control recruitment through routine pediatric visits was conducted, comprising 50 children and adolescents with ALL and 91 healthy controls from Crete, Greece. Constitutional DNA was isolated from peripheral blood samples collected during remission in cases, while controls provided peripheral blood for targeted germline genotyping. Genotyping was performed using PCR-restriction fragment length polymorphism analysis. We evaluated Hardy–Weinberg equilibrium and genotype and allele distributions and analyzed the data using logistic regression models. Results: Control minor allele frequencies were broadly compatible with public European reference data. Neither IKZF1 rs4132601 nor CDKN2A rs3731217 showed a significant association with susceptibility to childhood ALL under either genotype-based or additive models. Results remained consistent after excluding T-cell ALL cases. Exploratory genotype-phenotype analyses did not reveal robust associations with clinical or molecular features. Conclusions: In this first Greek pediatric assessment of IKZF1 rs4132601 and CDKN2A rs3731217, no significant association with ALL susceptibility was observed. Within the constraints of limited statistical power, these negative findings provide population-specific evidence, refine regional allele-frequency and effect-size estimates, highlight the limitations of relying on single historical sentinel single-nucleotide polymorphisms (SNPs), and support future ancestry-informed and polygenic approaches in southeastern European cohorts. Full article

Background/Objectives: Although gingivitis is the most common oral disease in children, periodontitis accompanied by alveolar bone resorption may develop in patients with severe congenital neutropenia. However, no reports to date have focused on changes in the alveolar bone of these patients during long-term follow-up. Case Summary: A girl aged 8 years and 5 months who developed leukemia due to severe neutropenia was admitted to the hospital and referred to the pediatric dentistry department for oral care. Panoramic radiographs at the first visit revealed significant alveolar bone resorption and mobility in the remaining deciduous teeth. We provided oral care, and the patient later underwent a hematopoietic stem cell transplant. No oral mucositis was observed. Measurement of alveolar bone thickness in the anterior and posterior regions revealed that the ratio increased as the patient’s systemic condition improved, showing a relative increase in alveolar bone thickness in the posterior region. Conclusions: Although this report is descriptive and observational, the patient’s alveolar bone loss with severe congenital neutropenia improved as the patient’s systemic condition improved. In addition, improvement of alveolar bone loss was observed along with systemic recovery and tooth eruption. Full article

Background: Cardiovascular complications are increasingly recognized in patients undergoing hematopoietic stem cell transplantation (HSCT). Early detection of subclinical myocardial dysfunction may improve risk stratification, and global longitudinal strain (GLS) is emerging as a sensitive marker of early cardiac impairment. Methods: We conducted a single-center observational cohort study including 518 adult patients undergoing autologous (n = 64) or allogeneic (n = 454) HSCT between 2004 and 2025. Baseline cardiovascular risk factors, transplant characteristics, and echocardiographic parameters—including GLS in a subset—were recorded. Abnormal GLS was defined as less negative than −20%. The primary outcome was the occurrence of cardiovascular events (composite of cardiovascular death, myocardial infarction, stroke, atrial fibrillation/flutter, pericardial effusion, pulmonary embolism, and left ventricular systolic dysfunction). Multivariable logistic regression was used to identify independent predictors. Results: Median age was 53 years; 58% were male. Cardiovascular events were predominantly atrial fibrillation, pericardial effusion, and reduced left ventricular function, whereas ischemic events were rare. Over 90% of events occurred within 100 days post-transplant. Multivariable analysis identified older age (OR 1.28 per 10-year increment; 95% CI 1.10–1.48; p = 0.002), chronic kidney disease (OR 2.44; 95% CI 1.18–5.02; p = 0.01), pre-transplant atrial fibrillation (OR 2.12; 95% CI 1.04–4.31; p = 0.03), and abnormal baseline GLS (OR 1.89; 95% CI 1.02–3.52; p = 0.04) as independent predictors. Importantly, the prognostic value of GLS remained significant after excluding clinically insignificant pericardial effusions from the composite endpoint. GLS deterioration during follow-up occurred more frequently in patients receiving reduced-intensity conditioning compared with myeloablative conditioning (25% vs. 12.7%; p = 0.006). Conclusions: Subclinical myocardial dysfunction detected by GLS identifies HSCT recipients at increased cardiovascular risk. These findings support the incorporation of strain imaging into routine pre- and post-transplant cardiovascular evaluation to enable earlier detection and guide targeted interventions. Full article

Background: Acute myeloid leukemia (AML) is characterized by reduced antileukemic effector cells and increased immunosuppressive cell populations. Leukemia-derived dendritic cells (DC_leu), generated from 18 leukemic whole blood (WB) ex vivo using ‘Kit-M’ (clinically approved: GM-CSF + PGE1), lead to improved cytotoxicity against autologous blasts after mixed lymphocyte culture (MLC) with patients’ T-cells. Methods: We studied Kit-M-mediated effects on frequencies of tolerogenic, immunosuppressive DC (DC_tol) and correlated findings with ex vivo-achieved antileukemic effects (increased intracellular IFNγ production/degranulation, blast lysis) and patients’ clinical characteristics. Results: We show significantly decreased frequencies of DC_tol (and increased frequencies of mature DC_leu) without induced blast proliferation in Kit-M treated vs. untreated WB samples. After T-cell-enriched MLC with Kit-M pretreated vs. not pretreated, WB frequencies of regulatory (CD152+ T-cells) were significantly decreased, while ‘activated’ (IFNγ+, degranulating) non-naive, proliferating, memory, CD154+) T-cells, as well as NK and CIK-cells were (significantly) increased. We found a (significant) positive correlation of achieved improved blast lysis, frequencies of DC_leu and ‘activated’ (IFNγ+/degranulating) T- or NK/CIK cells, and a (significant) negative correlation with frequencies of DC_tol and regulatory (CD152+ T-cells). Kit-M treatment of leukemic WB increases DC_leu and decreases DC_tol, correlating with improved immune reactions/improved cytotoxicity against autologous blasts, and downregulated suppressive T-cells in samples before or after MLC. Conclusions: These findings demonstrate the potential of Kit-M (using clinically approved drug compositions) to treat AML patients to potentially overcome the immunosuppressive tumor microenvironment, leading to improved antileukemic responses—thereby stabilizing remission of the disease in AML patients. Full article

Relapse remains the leading cause of treatment failure following hematopoietic cell transplantation (HCT) for hematologic malignancies. Circulating tumor DNA (ctDNA) has emerged as a promising minimally invasive biomarker for measurable residual disease (MRD) assessment and early relapse detection; however, the prognostic significance of ctDNA in the post-transplant setting has not been comprehensively synthesized. We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines and registered the protocol in PROSPERO (CRD420261392100). PubMed, Embase, Web of Science, EBSCO, Cochrane CENTRAL, and supplementary sources were searched through November 2025. Eligible studies evaluated tumor-specific ctDNA or tumor-informed/tumor-associated cfDNA in patients undergoing allogeneic or autologous HCT for hematologic malignancies. Random-effects meta-analyses were performed for relapse/progression, overall survival (OS), and relapse-free/progression-free survival (RFS/PFS). Studies evaluating total cfDNA quantity, methylation-based cfDNA profiling, cfRNA, or chimerism-only monitoring were synthesized narratively. Ten observational cohort studies comprising 883 patients met inclusion criteria. Across acute leukemias, lymphomas, multiple myeloma, and myelodysplastic syndromes, ctDNA/cfDNA positivity was consistently associated with adverse outcomes. The pooled hazard ratio (HR) for relapse or disease progression was 12.57 (95% CI: 4.59–34.46; p < 0.001), while pooled HRs were 7.45 (95% CI: 4.11–13.48; p < 0.001) for OS and 4.46 (95% CI: 2.22–8.97; p < 0.001) for RFS/PFS. Although statistical heterogeneity was low, interpretation was limited by the relatively small number of studies contributing to each pooled endpoint. Narrative evidence additionally suggested that broader circulating nucleic acid approaches may provide complementary information regarding graft-versus-host disease, infection, and other post-transplant complications. Tumor-specific ctDNA positivity is consistently associated with increased relapse risk and inferior survival outcomes following HCT. These findings support further investigation of ctDNA-based MRD monitoring as a promising non-invasive biomarker for post-transplant molecular surveillance and risk stratification. However, prospective multicenter validation studies, assay standardization, and ctDNA-guided interventional trials remain necessary before routine clinical implementation can be recommended. Full article

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