Arcuri LJ, Natal VHG, Américo AD
… +12 more, Perini G, Kerbauy MN, Kerbauy LN, Lima ACM, De León AG, Ribeiro AAF, de Souza Santos FP, Panzarella T, Walker I, Hamerschlak N, Rocha V, de Oliveira Ribeiro C
Regimens combining calcineurin inhibitors with methotrexate or mycophenolate have been the backbone for graft-versus-host disease (GVHD) prophylaxis. Early studies highlighted a delicate dose-response balance. The inclus...Regimens combining calcineurin inhibitors with methotrexate or mycophenolate have been the backbone for graft-versus-host disease (GVHD) prophylaxis. Early studies highlighted a delicate dose-response balance. The inclusion criteria comprised randomized clinical trials of patients with hematologic malignancies undergoing sibling- or unrelated-donor transplants, adding a pharmacologic immunosuppressive agent to standard GVHD prophylaxis. This meta-analysis examined the impact of intensified GVHD prophylaxis strategies on relapse risk and included 16 randomized controlled trials among 26 eligible studies, with 1344 patients in the intervention group and 1260 in the control group. Few mismatched donors or children were included. The studies evaluated additions such as anti-thymocyte/lymphocyte globulin (ATG, ATLG), posttransplant cyclophosphamide (PTCy), sirolimus, abatacept, and alemtuzumab. Results showed no significant effect on relapse risk or progression-free survival overall, with HR = 1.12 (p = 0.16) for relapse and HR = 0.92 (p = 0.16) for progression-free survival. Sensitivity analysis identified one outlier study using alemtuzumab that reported higher relapse and indicated a modest increased risk with ATLG. The findings suggest that adding agents like ATG, sirolimus, abatacept, or PTCy does not increase relapse risk in matched sibling or unrelated transplants. While caution is advised with ATLG and alemtuzumab, the overall evidence supports the safety of modern prophylactic strategies, potentially improving transplant outcomes without compromising relapse risk.
This Phase I/II clinical trial (NCT04471064) evaluated the preliminary efficacy, safety, and pharmacokinetics of XY0206, a novel oral FMS-like tyrosine kinase 3 (FLT3) inhibitor, in patients with relapsed or refractory a...This Phase I/II clinical trial (NCT04471064) evaluated the preliminary efficacy, safety, and pharmacokinetics of XY0206, a novel oral FMS-like tyrosine kinase 3 (FLT3) inhibitor, in patients with relapsed or refractory acute myeloid leukemia (R/R AML). From September 2020 to December 2022, this open-label, multicenter study enrolled patients aged ≥ 18 years with R/R AML. The trial included dose-escalation and dose-expansion phases, with six cohorts receiving XY0206 at doses ranging from 12.5 to 62.5 mg once daily or 25 mg twice daily. Of the 61 enrolled participants, 37 had FLT3 mutation-positive (FLT3) AML. The overall response rate (ORR) was 34.4% in the entire cohort and 48.6% in FLT3 patients. Among FLT3 patients, the composite complete remission rate (CRc) was 45.9%, including a complete remission (CR) rate of 5.4% and a CR with partial hematologic recovery (CRh) rate of 13.5% and a CR with incomplete hematologic recovery (CRi) rate of 27.0%. In patients with FLT3 internal tandem duplication (FLT3-ITD) mutations, the ORR was 56.7%, with a CRc of 53.3% (CR: 6.7%; CRh: 16.7% ; CRi: 30.0%). The 37.5 mg dose cohort, identified as the target dose, was expanded exclusively for FLT3 patients. XY0206 exhibited a favorable safety profile and demonstrated potent antileukemic activity, particularly in FLT3 R/R AML patients, supporting its further clinical development. Trial Registration: CTR20201214 (CDE); ClinicalTrials.gov ID: NCT04471064.
BACKGROUND: Transfusion of one unit of packed red blood cells is traditionally expected to increase hemoglobin concentration by approximately 1 g/dL in adults. However, substantial variability in hemoglobin response is f...BACKGROUND: Transfusion of one unit of packed red blood cells is traditionally expected to increase hemoglobin concentration by approximately 1 g/dL in adults. However, substantial variability in hemoglobin response is frequently observed in clinical practice. Smaller-than-expected increments may raise concerns regarding ongoing bleeding, hemodilution, or altered erythrocyte distribution. Understanding predictors of inadequate hemoglobin response may help clinicians interpret post-transfusion laboratory values and avoid unnecessary repeat transfusion. METHODS: We conducted a prospective observational cohort study of 518 hemodynamically stable hospitalized adults receiving a single unit of red blood cell transfusion. Hemoglobin concentrations were measured at baseline and at 12, 24, and 48 h after transfusion. Inadequate hemoglobin response was defined a priori as a 24-h hemoglobin increment (ΔHb24) < 1 g/dL. Multivariable logistic regression was used to identify predictors of inadequate response. Model discrimination and calibration were evaluated using receiver operating characteristic analysis and calibration plots. A simplified clinical prediction score and nomogram were derived from the regression model. RESULTS: The mean 24-h hemoglobin increment was 1.41 ± 0.37 g/dL. Inadequate hemoglobin response occurred in 106 patients (20.5%). Patients with inadequate response had higher baseline hemoglobin levels and a greater prevalence of splenomegaly. In multivariable analysis, higher baseline hemoglobin (OR 1.35 per 1 g/dL increase, 95% CI 1.18-1.54) and splenomegaly (OR 1.70, 95% CI 1.10-2.65) were independently associated with inadequate hemoglobin response. The prediction model demonstrated moderate discrimination (AUC 0.64; 95% CI 0.58-0.70) and acceptable calibration. A simplified clinical score stratified patients into low-, intermediate-, and high-risk categories for inadequate response. Decision curve analysis demonstrated modest clinical utility across a range of threshold probabilities. CONCLUSIONS: Inadequate hemoglobin response after single-unit red blood cell transfusion occurs in approximately one fifth of patients and appears to be influenced primarily by recipient physiological factors rather than donor unit characteristics. A simple clinical prediction model may assist clinicians in interpreting post-transfusion hemoglobin changes and reduce unnecessary repeat transfusions.
Martino EA, Caserta S, Vigna E
… +11 more, Bruzzese A, Alvaro ME, Amodio N, Lucia E, Olivito V, Labanca C, Mendicino F, Skafi M, Gattei V, Morabito F, Gentile M
Eur J Haematol
· 2026 Aug · PMID 42003055
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The integration of measurable residual disease (MRD) into the management of chronic lymphocytic leukemia (CLL) has emerged as a major advance in risk stratification and trial design, particularly in the context of time-l...The integration of measurable residual disease (MRD) into the management of chronic lymphocytic leukemia (CLL) has emerged as a major advance in risk stratification and trial design, particularly in the context of time-limited, targeted regimens. High-sensitivity MRD assessment, enabled by multicolor flow cytometry, allele-specific oligonucleotide PCR, and next-generation sequencing (NGS), provides a robust, quantifiable measure for depth of remission and long-term outcomes. Landmark trials-including CLL14, MURANO, CAPTIVATE, and GLOW-have consistently demonstrated that achieving undetectable MRD (uMRD) strongly predicts prolonged progression-free survival (PFS) and overall survival (OS), within a range of chemoimmunotherapy and venetoclax-based time-limited regimens. In selected clinical trials, MRD assessment has been prospectively incorporated into strategies exploring time-limited therapy and MRD-adapted discontinuation, although routine MRD-guided decision-making in clinical practice remains investigational. CLL research is increasingly focused on treatment-free observation in select patients achieving deep and sustained remissions, with MRD playing a central prognostic role. Emerging technologies, including circulating tumor DNA (ctDNA) monitoring and artificial intelligence (AI)-driven predictive modeling, promise to further refine risk stratification and personalize therapy. This review summarizes the current evidence supporting MRD as a prognostic biomarker and clinical trial endpoint, discusses investigational MRD-adapted strategies, and outlines future directions-including ctDNA and AI-based tools-that may ultimately support more individualized treatment duration and treatment-free observation in CLL.
Barbieri E, Arletti L, Quaresima M
… +9 more, Rivolti E, Braglia L, Fabiano C, Alfano AMR, Rinaldini M, Bizzarri V, Cattani C, Marinelli M, Gamberi B
Eur J Haematol
· 2026 Aug · PMID 42002885
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Gain/amplification of chromosome arm 1q (+1q) is among the most frequent cytogenetic abnormalities (CAs) in multiple myeloma (MM), and a recognized marker of poor prognosis, now integrated into modern risk stratification...Gain/amplification of chromosome arm 1q (+1q) is among the most frequent cytogenetic abnormalities (CAs) in multiple myeloma (MM), and a recognized marker of poor prognosis, now integrated into modern risk stratification systems. The advent of anti-CD38 monoclonal antibodies, particularly daratumumab, has significantly improved outcomes. However, the prognostic impact of +1q under daratumumab-based treatments (DBTs) remains uncertain, since pivotal trials rarely reported +1q-specific outcomes, and available real-world data are limited and inconsistent. We conducted a single-center retrospective study of 174 MM patients treated with DBTs between 2018 and 2023 to evaluate the prognostic effect of +1q. By FISH cytogenetic assessment we identified standard-risk (SR), isolated +1q, +1q plus additional high-risk CAs (+1q + HiRCAs), and non-1q HiRCAs groups. The primary endpoint was progression-free survival (PFS); secondary endpoints were time to next treatment (TTNT) and overall survival (OS). Median age was 72.0 years, median line of DBT administration was 2, and 125 patients (71.8%) received daratumumab-lenalidomide-dexamethasone (DaraRd). Cytogenetic data were available for 92 patients (52.9%): 43 SR, 11 non-1q HiRCAs, 18 isolated +1q and 20 +1q + HiRCAs. After a median follow-up of 30.7 months, isolated +1q was associated with significantly shorter PFS (HR 4.77, 95% CI: 1.68-13.53) and TTNT (HR 3.83, 95% CI: 1.33-11.09) versus SR, while +1q + HiRCAs had the worst outcomes across all endpoints (PFS HR 7.67; TTNT HR 5.81; OS HR 6.03). Multivariate analysis confirmed isolated +1q as an independent predictor of inferior PFS (HR 4.56, 95% CI: 1.61-12.95) and TTNT (HR 3.64, 95% CI: 1.26-10.55), with +1q + HiRCAs conferring the highest risks on all outcomes (PFS HR 8.36; TTNT HR 6.37; OS HR 6.18). Findings were consistent in the DaraRd subgroup. These findings demonstrate that +1q retains prognostic significance in the era of DBTs. Isolated +1q remains an independent factor of adverse prognosis, further worsened by co-existing HiRCAs.
Eur J Haematol
· 2026 Aug · PMID 41994904
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Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia (AIHA). CAD occurs in the context of a small clonal B-cell lymphoproliferation restricted to blood and/or bone marrow (BM), without overt or ext...Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia (AIHA). CAD occurs in the context of a small clonal B-cell lymphoproliferation restricted to blood and/or bone marrow (BM), without overt or extramedullary lymphoma. The WHO-HAEM5 introduced a description of the CAD-associated lymphoproliferative disorder (CAD-LPD) in the BM as a desirable criterium for CAD. Still, data on BM pathology underlying CAD remain scarce. We assessed the clinical and pathologic characteristics of a large patient cohort with cold-type AIHA. A total of 85 BM biopsies of 56 patients were evaluated. In 10 patients (18%), pathology revision revealed other overt B-cell malignancies leading to a diagnosis of cold agglutinin syndrome. In the remaining 46, evidence for B-cell clonality was found in the vast majority (45; 98%), manifesting as a paraproteinemia and/or clonal B-cells or plasma cells in BM. Most of these 45 had an M-protein (89%), evidence of monoclonal B-cells and/or plasma cells in BM tissue (89%), and were MYD88 wild-type (100%). Surprisingly, while ancillary methods detected clonality in the majority (84%), only 5 (11%) of 45 CAD cases strictly fulfilled the WHO-HAEM5 morphological description for CAD-LPD. These data imply that sensitive techniques should be used in BM evaluation in CAD.
Caserta S, Martino EA, Lofaro D
… +11 more, Vigna E, Bruzzese A, Mendicino F, Alvaro ME, Labanca C, Lucia E, Olivito V, Amodio N, Morabito F, Gattei V, Gentile M
Eur J Haematol
· 2026 Aug · PMID 41981887
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Immunoglobulin heavy chain variable region-unmutated (IGHV-U) chronic lymphocytic leukemia (CLL) represents a biologically aggressive subgroup with limited responsiveness to chemoimmunotherapy (CIT). To clarify the compa...Immunoglobulin heavy chain variable region-unmutated (IGHV-U) chronic lymphocytic leukemia (CLL) represents a biologically aggressive subgroup with limited responsiveness to chemoimmunotherapy (CIT). To clarify the comparative effectiveness of available frontline options, we conducted a comprehensive Bayesian network meta-analysis of randomized clinical trials including more than 4500 IGHV-U patients. Targeted therapies consistently outperformed CIT backbones, confirming the minimal benefit of cytotoxic approaches in this population. Acalabrutinib-based regimens, either as monotherapy or combined with obinutuzumab, emerged as the most effective strategies for progression-free survival, followed by other BTK inhibitors and venetoclax-based combinations. Chlorambucil- and Fludarabine-containing regimens ranked lowest. The fixed-duration venetoclax-obinutuzumab regimen also demonstrated strong efficacy, though estimates were less precise due to a smaller evidence base. Overall, heterogeneity was low, model fit was robust, and no statistical evidence was detected. These findings support targeted agents as the preferred first-line treatment for IGHV-U CLL and provide a quantitative framework to guide regimen selection while highlighting the need for head-to-head trials and long-term follow-up to optimize treatment sequencing.
Kutsch N, Ligtvoet R, Robrecht S
… +14 more, Linde H, Illmer T, Dörfel S, Lipke J, Aldaoud A, Schlag R, Dengler J, Al-Sawaf O, Langerbeins P, Cramer P, Hallek M, Eichhorst B, Fischer K, Fink A
Eur J Haematol
· 2026 Aug · PMID 41978941
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Within a dataset of the German CLL Study Group (GCLLSG) registry, 274 patients were allocated to a cohort with venetoclax and 888 to a cohort with BTKi (79 acalabrutinib, 809 ibrutinib), each as first administered target...Within a dataset of the German CLL Study Group (GCLLSG) registry, 274 patients were allocated to a cohort with venetoclax and 888 to a cohort with BTKi (79 acalabrutinib, 809 ibrutinib), each as first administered targeted substance class within the documented treatment sequence. Venetoclax was administered as first-line treatment in 152 of 274 patients (55.5%). After a median observation time of 14 months from the start of the first documented venetoclax treatment, the 1-year event-free survival (EFS) was 82.1% and the 1-year overall survival (OS) was 94.2%. The 1-year OS was 96.3% when venetoclax was given as first-line treatment versus 92.1% when given for the first time in a later therapy line (HR 0.38, 95% CI 0.14-1.05). In the BTKi cohort, 351 of 888 patients (39.5%) received a BTKi as first-line treatment. The median observation time was 34 months from the start of the first documented BTKi treatment, with a 3-year EFS of 32.4% and a 3-year OS of 78.5%. The 3-year OS for a BTKi in first-line was 87.9% compared to 73.8% in a later therapy line (HR 0.43, 95% CI 0.30-0.61). Our analysis suggests better survival outcomes when these agents are used as first-line therapy with the caveat that patients treated in later therapy lines typically exhibit more advanced disease and a poorer general condition.
Abdulgayoom M, Alshurafa A, Kaddoura R
… +3 more, Al-Mashdali AF, Mohamed SF, Yassin MA
Eur J Haematol
· 2026 Aug · PMID 41974620
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Anemia of chronic disease (ACD), also referred to as anemia of inflammation, is a prevalent and clinically significant complication of chronic infection, autoimmune disease, malignancy, and chronic kidney disease. It is...Anemia of chronic disease (ACD), also referred to as anemia of inflammation, is a prevalent and clinically significant complication of chronic infection, autoimmune disease, malignancy, and chronic kidney disease. It is characterized by inflammation-driven iron sequestration, impaired erythropoietin (EPO) production and signaling, and suppression of effective erythropoiesis. Current therapies (iron supplementation and erythropoiesis-stimulating agents) often address downstream consequences and may be limited by hepcidin-driven functional iron deficiency, cytokine-mediated EPO resistance, and safety concerns in vulnerable populations. This review re-examines ACD through an integrated framework of hepcidin dysregulation, iron sequestration, and inflammatory inhibition of the EPO axis. We then synthesize emerging evidence that sodium-glucose cotransporter 2 (SGLT2) inhibitors produce sustained increases in hemoglobin/hematocrit beyond transient hemoconcentration across cardiovascular and kidney disease trials, including in non-diabetic populations. Mechanistic studies suggest a coordinated biologic response that may include reduced hepcidin, improved iron mobilization, physiologic augmentation of endogenous EPO, and attenuation of systemic inflammation-pathways directly relevant to ACD. We critically re-appraise current ACD paradigms by contrasting downstream "replacement" strategies (iron and ESAs) with pathway-level approaches (HIF-PHIs and SGLT2 inhibition), and we outline biomarker-guided study designs to test whether SGLT2 inhibition may act as an adjunctive physiologic modulator of iron-erythropoietic crosstalk in well-phenotyped inflammatory anemia cohorts, while emphasizing that current evidence remains hypothesis-generating rather than practice-changing.
BACKGROUND: Optimal patient selection for the most effective BTK inhibitor (BTKi) partner of venetoclax in fixed-duration (FD) BTKi-venetoclax regimens for chronic lymphocytic leukemia (CLL) remains uncertain. This uncer...BACKGROUND: Optimal patient selection for the most effective BTK inhibitor (BTKi) partner of venetoclax in fixed-duration (FD) BTKi-venetoclax regimens for chronic lymphocytic leukemia (CLL) remains uncertain. This uncertainty largely reflects trial populations that are younger and fitter than many real-world patients, which may limit generalizability to older individuals or those with multiple comorbidities. The present study aims to provide harmonized, pragmatic guidance that bridges trial evidence and routine clinical practice for physicians caring for patients within a regional Italian area served by an established CLL network. METHODS: An adapted Delphi process engaged nine hematologists from Campania, a Southern Italian region, to evaluate the impact of BTKi-venetoclax upfront decision making on three key CLL decision domains: (1) specific comorbidities, (2) genomics (TP53/del(17p), IGHV status, complex karyotype), and (3) logistics (caregiver support, distance to center, and venetoclax ramp-up capacity). A preregistered systematic literature review (2014-2025) informed 12 statements, with consensus defined as ≥ 75% agreement. The two-round Delphi included structured discussion and anonymous voting. Additionally, artificial intelligence (AI) benchmarking with ChatGPT-4 assessed concordance with evidence briefs. RESULTS: Consensus was achieved on 83.3% of statements. The panel recommended FD BTKi-venetoclax regimens for fit, younger patients with low- or intermediate-genomic risk. For patients with low-intermediate cardiovascular risk, continuous second-generation BTKi monotherapy or FD therapy combining a second-generation BTKi acalabrutinib with venetoclax is preferable to FD ibrutinib-venetoclax. Adverse genomic features and logistical challenges were key factors favoring continuous second-generation BTKi therapy. AI benchmarking indicated potential for hybrid human-AI decision support, although concordance was fair (58.3%; Cohen's κ = 0.32). CONCLUSION: This study provides a pragmatic, consensus-driven framework for FD BTKi-venetoclax therapy in CLL, emphasizing patient selection and logistical feasibility. The work lays the groundwork for more rigorous evaluation of human-AI collaboration in the still-complex landscape of first-line CLL therapy.
Karhu A, Aronen S, Rönkä A
… +20 more, Sunela K, Klaavuniemi T, Aromaa-Häyhä A, Kuusisto M, Jokelainen O, Böhm J, Vuolukka K, Arkko UM, Vaittinen S, Harmanen M, Väyrynen JP, Kuitunen H, Nousiainen S, Kuitunen J, Kangas J, Pellonperä E, Kurttila H, Pietilä M, Tirkkonen J, Kuittinen O
Eur J Haematol
· 2026 Aug · PMID 41974450
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T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare subtype of large B-cell lymphoma (LBCL) for which central nervous system (CNS) relapse remains a devastating complication. The CNS International Prognostic...T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare subtype of large B-cell lymphoma (LBCL) for which central nervous system (CNS) relapse remains a devastating complication. The CNS International Prognostic Index (IPI) is usually used to predict the risk of CNS relapse. However, the overall risk of CNS relapse among patients with THRLBCL remains poorly known. To clarify the risk of CNS relapse in THRLBCL, data for 106 patients with THRLBCL diagnosed between 2000 and 2020 were collected from seven hospitals throughout Finland. The control data consisted of 660 patients with diffuse LBCL (DLBCL) diagnosed and treated in Oulu University Hospital. Most of the patients with THRLBCL and DLBCL presented with advanced stage disease and were classified as high-intermediate or high-risk groups based on their IPI score. 368 patients received R-CHOP as first line therapy. Our data included patients who had received CNS prophylaxis. For the entire patient population, we found a 5-year CNS relapse risk of 1.04% and 5.29% among patients with THRLBCL and DLBCL, respectively (p < 0.001). In conclusion, THRLBCL has lowered CNS relapse risk compared to DLBCL.
INTRODUCTION: Plasma cell myeloma is a heterogeneous hematologic malignancy characterized by clonal expansion of plasma cells. While RAS-MAPK pathway mutations are known high-risk features, the clinical relevance of STAT...INTRODUCTION: Plasma cell myeloma is a heterogeneous hematologic malignancy characterized by clonal expansion of plasma cells. While RAS-MAPK pathway mutations are known high-risk features, the clinical relevance of STAT3/STAT5 mutations remains unclear. METHOD: We analyzed 16 myeloma patients with STAT3/STAT5 mutations identified by next-generation sequencing (9 STAT3, 5 STAT5A, 2 STAT5B) and compared them with 32 mutation-negative controls. RESULTS: STAT3/STAT5 mutations were present at initial diagnosis in all eight patients with available initial sequencing data, suggesting these are early events in pathogenesis. STAT3/STAT5 mutations were the sole mutations in five patients, while 10 had co-mutations, most frequently in KRAS/NRAS (n = 5) and TP53 (n = 3). In co-mutated cases, STAT3/STAT5 represented the dominant clone in 4 and co-dominant in 6. All mutations were missense, with 63% involving the SH2 domain. Compared with controls, STAT3/STAT5-mutated patients had higher serum lactate dehydrogenase levels, higher incidence of IgA paraprotein, higher R-ISS stage, more complex karyotype, and frequent CKS1B gain/amplification. Overall survival was significantly shorter in patients with STAT3/STAT5 mutations (median 42 vs. 72 months, p < 0.0001). CONCLUSION: STAT3/STAT5 mutations are early, dominant, and potentially pathogenic events in plasma cell myeloma. Their association with adverse clinical features and inferior survival supports their routine assessment and potential therapeutic targeting.
Choi YB, Mathew R, Li H
… +15 more, Cada M, Klaassen RJ, Villeneuve S, Abish S, Corriveau-Bourque C, Robitaille N, Steele M, Sinha R, Rayar M, Wheaton L, Breakey V, Goodyear L, Crooks B, Tole S, Dror Y
Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome characterized by erythroid aplasia, congenital anomalies, and cancer predisposition. Although corticosteroids are the standard first-line the...Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome characterized by erythroid aplasia, congenital anomalies, and cancer predisposition. Although corticosteroids are the standard first-line therapy for transfusion-dependent patients, treatment response varies, and reliable predictors remain undefined. We retrospectively analyzed data from the Canadian Inherited Marrow Failure Registry to identify clinical and genetic factors associated with steroid responsiveness. Among 80 patients with evaluable steroid response, 30 were classified as the responder group and 50 as the non-responder group (non-response or loss of response after initial improvement). The median age at diagnosis was significantly higher in the responder group than in the non-responder group (20 months vs. 3 months, p = 0.004). ROC curve analysis showed that age at diagnosis had predictive value for steroid responsiveness, with an optimal cutoff of 9.5 months. DBA-associated genetic mutations were identified in 58 patients. Notably, RPL5 mutations were significantly more frequent in the non-responder group than in the responder group (22.0% vs. 0%, p = 0.004). No significant difference in overall survival was observed between the responder and non-responder groups. Differences in corticosteroid response were associated with diagnostic age and specific genetic variants, offering potential guidance for individualized treatment decisions.
BACKGROUND: Platelet transfusion is commonly used to reduce bleeding risk in platelet consumptive disorders. However, platelets may also promote thromboinflammatory pathways, and contemporary data evaluating the associat...BACKGROUND: Platelet transfusion is commonly used to reduce bleeding risk in platelet consumptive disorders. However, platelets may also promote thromboinflammatory pathways, and contemporary data evaluating the association between platelet transfusion, thrombosis, and mortality in this population are limited. METHODS: We performed a retrospective cohort study using the National Inpatient Sample from 2018 to 2021. Non-elective hospitalizations with immune thrombocytopenic purpura, thrombotic thrombocytopenic purpura, heparin-induced thrombocytopenia, or other primary thrombocytopenias were included. The exposure was receipt of any platelet transfusion during hospitalization. Primary outcomes were in-hospital mortality and in-hospital thrombotic events, defined as venous thromboembolism or arterial thrombosis using ICD-10-CM codes. Inverse probability of treatment weighting and survey-weighted logistic regression were used to adjust for demographics, comorbidities, illness severity, major bleeding, and disease-specific therapies. RESULTS: Among 67 405 hospitalizations (337 705 weighted national estimates), 10.5% received platelet transfusion. Mortality was higher in transfused versus nontransfused hospitalizations (9.5% vs. 6.1%; p < 0.001). After adjustment, platelet transfusion was associated with increased odds of in-hospital mortality (adjusted odds ratio [aOR], 1.42; 95% CI: 1.28-1.60) and thrombosis (any thrombosis: aOR, 1.28; 95% CI: 1.18-1.39). Associations were observed for venous (aOR, 1.39) and arterial thrombosis (aOR, 1.15). Thrombotic risk persisted among hospitalizations without major bleeding but was attenuated with major bleeding. Intravenous immunoglobulin was associated with higher odds of thrombosis, while plasma exchange was associated with lower odds. CONCLUSION: In patients hospitalized with platelet consumptive disorders, platelet transfusion was associated with higher odds of in-hospital thrombosis and mortality, supporting judicious, indication-driven transfusion practices.
Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who progress to the third-line setting face a lack of standardized treatment, despite the presence of multiple available therapies. In this co...Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who progress to the third-line setting face a lack of standardized treatment, despite the presence of multiple available therapies. In this context, antibody-drug conjugates represent a relatively new class of anticancer agents; among them, loncastuximab tesirine is a second-in-class agent approved for the treatment of patients with R/R DLBCL after ≥ 2 lines of systemic therapy. Because many patients with R/R DLBCL are ineligible for intensive therapies due to advanced age and comorbidities, the availability of any new agent is particularly important. We present an overview of the clinical evidence for loncastuximab tesirine and offer practical guidance on its use in R/R DLBCL. Additionally, three clinical cases are described to illustrate its efficacy in transformed DLBCL, the management of treatment and safety when used as a bridge to allogeneic stem cell transplantation, and its role in the sequencing of therapies for R/R DLBCL. Findings from our Italian experience may be informative on the clinical application of loncastuximab tesirine in other countries where it is approved and available.
Martino EA, Caserta S, Skafi M
… +13 more, Vigna E, Bruzzese A, Amodio N, Fiorillo M, Lucia E, D'Arrigo G, Olivito V, Labanca C, Mendicino F, Alvaro ME, Tripepi G, Morabito F, Gentile M
OBJECTIVES: Pediatric myelodysplastic syndromes (MDS) differ from adult MDS, and their genetic basis is poorly understood. This study characterizes the genomic features and clinical outcomes of advanced pediatric MDS. ME...OBJECTIVES: Pediatric myelodysplastic syndromes (MDS) differ from adult MDS, and their genetic basis is poorly understood. This study characterizes the genomic features and clinical outcomes of advanced pediatric MDS. METHODS: In this retrospective study, next-generation sequencing was performed on 63 pediatric patients with advanced MDS, including 46 with MDS with excess blasts (MDS-EB) and 17 with MDS-EB in transformation (MDS-EB-T, 2016 WHO classification), to detect somatic and potential germline variants. RESULTS: Mutations in 53 genes were detected in 49 patients (77.8%), with a median of 2 variants per patient (range, 0-8). Alterations in the RAS/MAPK pathway were most common, occurring in 28 patients (44.4%). Monosomy 7 significantly co-occurred with SETBP1, ETV6, and GATA2 mutations (p < 0.01). Time-dependent analyses showed HSCT improved 2-year overall survival (OS, 42.6% vs. 84.5%, p = 0.003) and event-free survival (EFS, 37.3% vs. 58.2%, p = 0.011). In multivariate analyses, HSCT was strongly associated with improved OS and EFS (p < 0.01). PTPN11 mutation remained an independent predictor of poorer OS and EFS (p < 0.05), and MDS-EB-T subtype independently predicted inferior EFS (p < 0.05). CONCLUSION: In advanced pediatric MDS, HSCT was associated with improved survival, whereas PTPN11 mutations emerged as an adverse prognostic factor.
Acute leukemias characterized by a shared epigenetic dependency on the menin-KMT2A axis rely on aberrant HOX-driven transcriptional programs that sustain leukemic self-renewal and impair differentiation. This dependency...Acute leukemias characterized by a shared epigenetic dependency on the menin-KMT2A axis rely on aberrant HOX-driven transcriptional programs that sustain leukemic self-renewal and impair differentiation. This dependency is most evident in KMT2A-rearranged and NPM1-mutated acute myeloid leukemia (AML), but also extends to other HOX-dependent entities, including leukemias with NUP98 rearrangements and UBTF tandem duplications, broadening the therapeutic relevance of menin inhibition. Menin acts as a central scaffold within chromatin-associated complexes that maintain expression of HOXA cluster genes and MEIS1, integrating signals from epigenetic regulators and lineage-specific transcription factors. Disruption of the menin-KMT2A interaction results in transcriptional reprogramming, induction of differentiation, and loss of leukemic stem cell properties, providing a strong mechanistic rationale for therapeutic targeting. This review synthesizes current knowledge on the molecular basis of menin dependency, with emphasis on structural insights, transcriptional circuitry, and lineage plasticity. We critically evaluate the preclinical and clinical development of menin inhibitors, including revumenib, ziftomenib, bleximinib, and icovamenib, summarizing efficacy signals in relapsed/refractory disease, safety profiles, and emerging resistance mechanisms. Special attention is given to combination strategies with venetoclax, FLT3 inhibitors, chemotherapy, and epigenetic agents, which aim to enhance response durability and mitigate resistance. Finally, we discuss ongoing clinical trials, unresolved challenges in patient selection and sequencing, and future directions for integrating menin inhibition into precision-based treatment paradigms for acute leukemia.
OBJECTIVES: This study investigates the expansion of CAR T-cells and its association to treatment outcome. METHODS: Patients with aggressive B-cell lymphomas treated with anti-CD19 CAR T-cell therapy axicabtagene ciloleu...OBJECTIVES: This study investigates the expansion of CAR T-cells and its association to treatment outcome. METHODS: Patients with aggressive B-cell lymphomas treated with anti-CD19 CAR T-cell therapy axicabtagene ciloleucel (axi-cel) at Skåne and Sahlgrenska University Hospitals from 2019 to October 2024 were included. CAR T-cells in peripheral blood were measured by flow cytometry. Association between maximum levels of CAR T-cells and response, progression-free survival, overall survival, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were investigated. RESULTS: Peak CAR T-cell levels were higher among patients with complete response (CR) at Day 30 (p = 0.013) and at 12 months (p = 0.036). CD8 CAR T-cells were higher in patients with CR (median 135.7, IQR 52.8-433.9) compared to patients not obtaining CR (median 23.2, IQR 11.1-103.3) (p = 0.003). The ratio of CD4:CD8 CAR T-cells was lower in patients obtaining CR (p = 0.046). Patients with CAR T-cells above 52.4 CAR T-cells/μL showed superior progression-free survival (p < 0.001). CONCLUSION: Our study indicates that CAR T-cell levels after axi-cel correlate to durable response, progression-free survival, and that expansion of CD8 CAR T-cells might be of specific importance for efficacy. Potentially, CAR T-cell levels may be used to enable early detection of patients with high risk of CAR T-cell treatment failure.