Search Results (279)

Background: Relapsed/refractory acute myeloid leukemia (R/R AML) remains a therapeutic challenge due to disease heterogeneity, resistance mechanisms, and poor tolerability to intensive regimens. Venetoclax (VEN), a BCL-2 inhibitor, has shown promise in combination with hypomethylating agents (HMAs), but data on response timing in the R/R setting are limited. The aim of this study was to assess the efficacy, safety, and kinetics of response to HMA-VEN therapy in a real-world cohort of R/R AML patients, with particular focus on early versus late responders. Methods: This prospective single-center study included 33 adult patients with R/R AML treated with VEN plus either azacitidine (AZA) or decitabine (DEC) from 2018 to 2021. The primary endpoint was the composite complete remission (cCR) rate and the rate of early and late response, respectively, occurring within two cycles of therapy or later; secondary endpoints included overall survival (OS), relapse-free survival (RFS), time to relapse (TTR), and safety. Results: The cCR was 58%, with complete remission (CR) or CR with incomplete recovery (CRi) achieved in 52% of patients. Median OS was 9 months. No significant differences in OS or TTR were observed between early (≤2 cycles) and late (>2 cycles) responders. Eight responders (42%) underwent allogeneic hematopoietic stem cell transplantation (HSCT), with comparable transplant rates in both groups of responders. Toxicity was manageable. Grade 3–4 neutropenia occurred in all patients, and febrile neutropenia occurred in 44% of patients. An Eastern Cooperative Oncology Group (ECOG) score >2 was associated with inferior response and shorter treatment duration. Conclusions: HMA-VEN therapy is effective and safe in R/R AML, including for patients with delayed responses. The absence of a prognostic disadvantage for late responders supports flexible treatment schedules and suggests that the continuation of therapy may be beneficial even without early blast clearance. Tailored approaches based on performance status and comorbidities are warranted, and future studies should incorporate minimal residual disease (MRD)-based monitoring to refine response assessment. Full article

Background/Objectives: The advent of tyrosine kinase inhibitors (TKIs) revolutionized the management of chronic myeloid leukemia (CML), achieving survival rates near those of the general population. Despite this success, prolonged therapy presents challenges, including physical, emotional, and financial burdens. Treatment-free remission (TFR), defined as sustained deep molecular response (DMR) after discontinuing TKIs, has emerged as a viable clinical goal. This study evaluates real-world data from the Canary Islands Registry of CML (RCLMC) to explore outcomes, predictors, and the feasibility of TFR. Methods: This retrospective observational study included 393 patients diagnosed with CML-CP between 2007 and 2023. Molecular response was monitored according to international guidelines. Survival probabilities were estimated using the Kaplan–Meier method. Logistic regression analysis was performed to identify predictors of molecular relapses after TKI discontinuation. Results: Of the 383 patients who received TKI treatment, 58.3% achieved molecular response grade 2 (MR2) (BCR-ABL1 ≤ 1%), 95.05% achieved MR2, and 50.5% reached MR4 within the first year. Of the 107 patients attempting TFR, 73.2% maintained remission at 36 months. Relapses occurred in 24 patients, all regaining molecular response upon reintroduction of TKIs. No cases of disease progression were observed. Conclusions: Our findings support the feasibility and safety of TFR in a real-world clinical setting for well-selected patients, with outcomes consistent with international studies. The study underscores the importance of molecular monitoring and patient-specific strategies to optimize outcomes. Full article

Background/Objectives: Celiac disease (CD) is an autoimmune disorder characterized by small intestinal enteropathy triggered by gluten ingestion, often associated with gut dysbiosis. The most effective treatment is strict adherence to a gluten-free diet (GFD), which alleviates symptoms. This study uniquely integrates taxonomic, functional, and resistance profiling to evaluate the gut microbiota of women with CD on a GFD. Methods: To evaluate the long-term impact of a GFD, this study analyzed the gut microbiota of 10 women with CD on a GFD for over a year compared to 10 healthy controls with unrestricted diets. Taxonomic diversity (16S rRNA gene sequencing and the analysis of α and β-diversity), metabolic functionality (Biolog EcoPlates^®), and antibiotic resistance profiles (Cenoantibiogram) were assessed. Results: Metagenomic analysis revealed no significant differences in taxonomic diversity but highlighted variations in the abundance of specific bacterial genera. Women with CD showed increased proportions of Bacteroides, Streptococcus, and Clostridium, associated with inflammation, but also elevated levels of beneficial genera such as Roseburia, Oxalobacter, and Paraprevotella. Despite no significant differences in metabolic diversity, higher minimum inhibitory concentrations (MICs) in women in the healthy control group suggest that dietary substrates in unrestricted diets may promote the proliferation of fast-growing bacteria capable of rapidly developing and disseminating antibiotic resistance mechanisms. Conclusions: These findings indicate that prolonged adherence to a GFD in CD supports remission of gut dysbiosis, enhances microbiota functionality, and may reduce the risk of antibiotic resistance, emphasizing the importance of dietary management in CD. Full article

Over the past two decades, the treatment landscape of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has undergone a profound transformation. Once considered the subtype with the worst prognosis, Ph+ ALL is now associated with the possibility of long-term survival in a significant proportion of patients. This dramatic improvement has been driven by the advent of tyrosine kinase inhibitors (TKIs) and, more recently, by the incorporation of blinatumomab, a bispecific T-cell engager antibody, into frontline therapeutic strategies. In this evolving context, two major areas have become the focus of clinical investigation: on the one hand, the identification of high-risk patients who truly benefit from allogeneic hematopoietic stem cell transplantation (allo-HSCT); on the other, the characterization of patients who can achieve durable responses without transplantation and who may be candidates for treatment discontinuation of TKIs. This review aims to summarize the current evidence supporting the concept of treatment-free remission (TFR) in Ph+ ALL. Full article

Background/Objectives: Histological follow-up still lacks consensus in the long-term management of adult patients with celiac disease (CD) adhering to a gluten-free diet (GFD). Despite clinical and serological improvement, a significant proportion of patients continue to have persistent villous atrophy. We aimed to synthesize current evidence regarding histological outcomes after GFD treatment in adult CD, focusing on mucosal healing rates, assessment methods, and remission criteria. Methods: We conducted a literature search with extraction and analysis of published cohort studies that included adult patients with CD on GFD with follow-up biopsy data. Extracted parameters included demographic details, baseline histology, GFD duration and adherence, serologic status, and histologic recovery rates with corresponding remission criteria. Results: Data from 46 studies comprising 15,530 patients were analyzed. The overall mean age was 41 years, and 73.3% were female. Mean histologic remission across cohorts was 58.8%, with considerable interstudy variation. Remission criteria also varied widely, ranging from strict Marsh 0 control histology to more inclusive definitions that considered Marsh 1 or even non-atrophic mucosa (Marsh < 3) as indicative of recovery, while some studies relied on quantitative villous height-to-crypt depth ratio thresholds, substantially influencing reported remission rates. Longer GFD duration and rigorous diet adherence assessment using validated questionnaires and accurate laboratory tools were associated with higher remission rates. Conclusions: Histologic remission in GFD-treated adult patients with CD is highly variable and strongly influenced by remission definitions and adherence assessment methods. Standardized reporting using validated metrics for histologic outcome and dietary compliance is essential for harmonizing follow-up strategies in adult CD. Full article

Menin inhibitors are a class of targeted agents that exemplify how a deeper understanding of leukemia pathogenesis can unify seemingly distinct genetic acute leukemia subgroups under a common therapeutic strategy. In particular, acute leukemia with NPM1 mutations (NPM1m) and KMT2A rearrangements (KMT2Ar) represent the primary targets of this emerging drug class. Acute myeloid leukemia (AML) with NPM1m—which accounts for approximately 30% of AML cases and AML or acute lymphoblastic leukemia (ALL) with KMT2Ar—and is present in 5–10% of cases, shares a common pathogenetic mechanism: the aberrant activation of the MEIS1–HOXA axis. These leukemic subsets are associated with poor prognosis, particularly in the relapsed/refractory (R/R) setting. For KMT2Ar AML, the prognosis is especially dismal, with a median overall survival (OS) of 2.4 months and a complete remission (CR) rate of only 5%. In NPM1m AML, intensive chemotherapy achieves remission in approximately 80% of cases, but relapse remains a major challenge, occurring in nearly 50% of patients. Relapsed NPM1m AML is linked to a poor prognosis, with a median OS of 6.1 months (12-month OS: 30%) and a median relapse-free survival (RFS) of 5.5 months (12-month RFS: 34%). Menin inhibitors directly target the leukemogenic transcriptional program driven by HOX and MEIS1, disrupting oncogenic signaling and offering a promising therapeutic approach for these high-risk patients. This class of agents has rapidly progressed through clinical development, showing promising antileukemic activity in both treatment-naïve and R/R AML. Currently, six menin inhibitors are in clinical evaluation as monotherapy or in combination regimens: revumenib, ziftomenib, bleximenib (previously JNJ-75276617), enzomenib (previously DSP-5336), DS-1594, and BMF-219. In this review, we critically analyze the clinical development and therapeutic potential of the four most extensively studied menin inhibitors—revumenib, ziftomenib, bleximenib, and enzomenib. We discuss their efficacy, safety profiles, and potential roles within the current treatment algorithm. The continued clinical evaluation of menin inhibitors may redefine treatment paradigms for NPM1m and KMT2Ar AML and other acute leukemia with the aberrant MEIS1-HOXA axis, offering new hope for patients with limited therapeutic options. Full article

Background/Objectives: Acute myeloid leukemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) mutations carries a poor prognosis. While FLT3 inhibitors like midostaurin show benefits in combination with chemotherapy, the role of allelic ratio (AR), NPM1 mutation status, and hematopoietic stem cell transplantation (HSCT) remains uncertain. Real-world data can help refine prognostic classification and treatment strategies. Methods: We retrospectively analyzed 37 fit patients with FLT3-ITD AML treated with standard “7+3” chemotherapy, with and without midostaurin, between 2013 and 2022. Patients were stratified by FLT3-ITD AR, NPM1 status, and treatment approach. Outcomes assessed included complete remission (CR), disease-free survival (DFS), and overall survival (OS). Results: Overall, 67.6% achieved CR/CRi. Response rates did not differ significantly by AR (low vs. high: 66.7% vs. 69.2%) or midostaurin use (72.6% vs. 60%; p = 0.49). NPM1 mutations were associated with improved DFS (10.3 vs. 3 months, p = 0.036) but not OS. HSCT, performed in 54.1% of patients, mainly in first remission (CR1), significantly prolonged DFS (not reached vs. 5.3 months, p = 0.005) and remained an independent predictor in multivariate analysis (HR: 0.160, p = 0.039). OS (median 15.1 months) did not vary significantly across subgroups. Among patients achieving CR1, OS was significantly longer in those who underwent HSCT after midostaurin-based induction compared to those not transplanted (median OS not reached vs. 12.8 months; 95% CI, 6.9–18.7; p = 0.045), whereas no significant benefit was observed after standard induction. In a landmark analysis restricted to patients transplanted in CR1, those who had received midostaurin-based induction showed a trend toward improved OS compared to those treated with standard induction (median OS not reached vs. 11.5 months; 95% CI, 0.5–25.0; p = 0.086). Conclusions: This real-life study supports the importance of NPM1 mutations and HSCT in CR1, especially in the midostaurin era, for improving DFS in FLT3-ITD AML. These findings support updated guidelines for reducing the prognostic weight of AR and highlight the need for improved post-remission strategies in this setting. Full article

Background/Objectives: The combination of venetoclax (VEN) and hypomethylating agents (HMA), such as azacitidine (AZA) or decitabine (DEC), has transformed the treatment landscape for acute myeloid leukemia (AML) in patients unfit for intensive chemotherapy. However, optimal management of neutropenia and the impact of post-remission treatment interruptions (washouts) remain unclear. This study aimed to evaluate the safety and efficacy of post-remission washouts and their effect on clinical outcomes. Methods: We conducted a retrospective single-center study of 44 AML patients treated with HMA/VEN between 2020 and 2021. Clinical, molecular, and treatment-related data were collected, including treatment duration, post-remission washout duration, response rates, disease-free survival (DFS), and overall survival (OS). Statistical analyses included Fisher’s exact test and univariate and multivariate Cox models. Results: Overall, 61% of patients responded to therapy, with significantly higher response rates among those potentially eligible for the VIALE-A trial (86% vs. 39%, p = 0.002). Neither treatment duration nor post-remission washout length was associated with DFS or OS. DFS was significantly longer in patients treated with AZA compared to DEC (p = 0.006). Median OS was 7.7 months, with longer OS observed in patients who did not meet VIALE-A trial eligibility criteria (p = 0.021). Achieving complete remission (CR) was associated with improved OS (14.5 months). Conclusions: Post-remission treatment interruptions (washouts) did not negatively impact DFS or OS, suggesting they may be a safe strategy to support hematologic recovery. However, the choice of HMA appears to influence response duration, with AZA outperforming DEC in maintaining disease control. Full article

Background: Despite the remarkable efficacy of tyrosine kinase inhibitors (TKIs), patients with chronic myeloid leukemia (CML) often face adverse effects, prompting investigations into treatment-free remission (TFR) for patients with sustained deep responses. Methods: Our objective was to assess real-world outcomes of TFR in a single-center cohort of patients in the southeastern U.S., as well as to compare different TKI management strategies (abrupt cessation of a TKI at a standard dose, TKI dose tapering prior to cessation, or upfront TKI dose reduction followed by abrupt cessation before TFR). Results: We queried our CML database of 233 patients and identified 39 patients that aimed for TFR. The median TFR duration was 14.6 months, with 63% actively remaining in TFR with a median follow-up of 21 m. TFR was lost by 54%, 16%, 8%, and 21% of patients in 0–6 m, 6–12 m, 1–2 y, and >2 y, respectively. Among the three TKI management strategies, the safety outcomes were comparable, with no instances of disease progression or CML-related mortality. All patients who lost TFR successfully regained a major molecular response (MMR) upon the resumption of TKIs. In terms of efficacy, 61%, 59%, and 59% of patients who underwent abrupt cessation of standard-dose TKIs, standard-dose tapering, or upfront dose reduction maintained TFR, respectively. Conclusions: Our study highlights the relative safety of pursuing TFR via different TKI treatment strategies in a real-world setting. Full article

Background and Objectives: Due to the progress made in all areas of research, pediatric patients diagnosed with acute lymphoblastic leukemia (ALL) now have an average overall survival rate of 90%. There are still discrepancies between high-income countries and limited-resource centers. The aim of this study was to analyze prognostic factors and outcome parameters in a 223-patient cohort from a single center in Romania, treated with two adapted BFM protocols. Materials and Methods: The patients diagnosed with ALL in our center were enrolled in this study from January 2016 to December 2022 and subsequently followed up until December 2024. The patients were treated first according to the ALL IC BFM 2009 protocol until June 2019 and afterwards with the ALL AIEOP BFM 2017 protocol starting with July 2019. The prognostic factors were analyzed in both subgroups and the outcomes were measured: event-free survival (EFS), overall survival (OS), cumulative incidence of relapse (CIR), relapse-free survival (RFS) and non-relapse mortality (NRM). Results: The comparison between the two subgroups revealed that every parameter improved over time: complete remission after induction (87.75% vs. 80.7%), early deaths (3.92% vs. 5.78%), deaths in remission (4.08% vs. 5.26%), 5-year EFS (73.79% vs. 70.22%), 5-year CIR (18.36% vs. 19.04%), 5-year RFS (81.76% vs. 80.97%), 5-year NRM (7.85% vs. 10.77%), and 5-year OS (88.18% vs. 82.54%). Whereas for the standard-risk group, events such as relapse or death were isolated, for intermediate-risk patients, the events were limited to a small number and did not significantly influence the overall results, and for high-risk children, the results improved significantly between the two subgroups. The worst outcomes were observed in patients with the BCR::ABL1 fusion gene, T-cell phenotype, and in teenagers, compared to the ETV6::RUNX1 fusion gene, B precursor ALL, and in smaller children, respectively. Conclusions: The 5-year OS increased in our center from 82.54% to almost 90%, with the most substantial finding being the survival rate for high-risk patients, now reaching up to 80%. The prognostic factors were age at diagnosis, genetic characteristics, and response to treatment, especially prednisone sensibility. Full article

This study aimed to investigate the spatial heterogeneity of molecular signature in the muscle of juvenile dermatomyositis (JDM) patients before and after treatment. Unsupervised reference-free deconvolution of spatial transcriptomics and standardized morphometry were performed in two JDM muscle biopsies with different clinical severity at disease onset and compared to healthy muscle. Identified signatures were scored in two additional JDM muscle biopsies from the same patient before and after remission. Disappearance of the normal muscle signature mostly corresponding to mitochondrial biology was observed in JDM. Three pathological transcriptomic signatures were isolated, related to “myofibrillar stress”, “muscle remodeling” and “interferon signaling” signatures. The “myofibrillar stress signature” was prominent in the most severe biopsy while the “muscle remodeling” signature was mostly present in the biopsy from the patient with good outcome. These signatures unveiled genes not previously associated with JDM including ANKRD1 and FSLT1 for “myofibrillar stress” and “muscle remodeling” signatures, respectively. Post-treatment analysis of muscle after two years remission showed a persistence of pathological signatures. This pilot study of JDM muscle identified spatially distributed pathological signatures that persist after remission. This work paves the way for a better understanding of the pathophysiology in affected muscle and the identification of biomarkers that predict relapse. Full article

Objectives: To analyze variations in patient characteristics, treatment patterns, clinical manifestations, clinical outcomes (i.e., response, flares and flare-free survival in HES; remission, relapses and relapse-free survival in EGPA; and overall survival), and healthcare resource utilization (HCRU) in patients with hypereosinophilic syndrome (HES) and eosinophilic granulomatosis with polyangiitis (EGPA) across five European countries. Methods: In two parallel, retrospective, non-interventional, longitudinal chart review studies (GSK ID: 214661 [EGPA] and 214657 [HES]), physicians collected data of patients they treated in France, Germany, Italy, Spain, and the UK from January 2015 to December 2019, with follow-up until August 2021. Country-level results are presented for each study; HES and EGPA data were pooled in a post hoc exploratory analysis. Results: Per-country, 22–26 HES- and 38–45 EGPA-treating physicians collected data from 52–62 (total 280) patients with HES and 80–85 (total 407) with EGPA. Patient sex and age at diagnosis differed across countries. Pooled HES/EGPA data revealed high oral corticosteroid (OCS) use in all countries (94.9% of patients; median [IQR] duration 20.7 [9.0, 33.8] months); immunosuppressive treatments and biologics use varied between countries (43.7–61.5% and 25.6–59.8%, respectively). The most frequent clinical manifestations were constitutional (51.6–78.8%) and lung (43.5–55.8%) in HES, and lung (41.3–67.9) and ENT (43.8–61.2) in EGPA. Pooled HCRU data showed country-level variation; 70.7–91.2% of patients had disease-related outpatient visits and 36.1–52.6% had ER visits or hospitalizations. Conclusions: Results demonstrate substantial disease burden, including high HCRU and extensive OCS use among patients with HES and EGPA in five European countries. The findings highlight the need for improved treatment strategies such as optimizing use of biologics to mitigate the reliance on corticosteroids. Full article

Background/Objectives: This study aimed to investigate oncologic and obstetrical outcomes of patients conservatively treated for atypical hyperplasia (AH), endometrial intraepithelial neoplasm (EIN), and early endometrial cancer (EC), as well as factors that influence these outcomes. Methods: This study included 87 women conservatively treated due to AH/EIN and well-differentiated endometrioid EC confined only to the endometrium during past 10 years. Therapy type, course, and duration were registered. The response totherapy after 12 months (remission vs. disease persisting or progressing) was considered as the oncologic outcome. All attempted and achieved pregnancies, along with conception method, gestational week, and delivery type, were recorded. The obstetrical outcomes were classified as adverse (miscarriage) or successful (healthy child). Results: All patients received LNG-IUD along with GnRHa and, if indicated, metformin. Complete remission was achieved in 74.7% of patients. The disease was persisting in 17.2% and progressing in 3.5% of patients, while recurrence was registered in 4.6% of patients. Radical surgery during follow-up was indicated in 15% of patients due to condition deterioration. Pregnancy was attempted by 29.9% of patients, out of which nine succeeded (34.6%). There were two early miscarriages, while the remaining seven pregnancies ended in a term delivery of a healthy child, mostly by planned cesarean section. The only predictor of long-term disease remission was malignancy-free control histological findings. Better therapy response and achieving remission in shorter time were predictors of good obstetrical outcome. Conclusions: This study proved the efficacy and safety of current protocols for AH/EIN/EC conservative treatment and indicated that adequate early (6-month) response totherapy has the most importance for long-term remission and pregnancy achievement. Full article

The bone marrow microenvironment is a dynamic and complex niche that plays a central role in the development, progression, and therapeutic resistance of leukemia. Among the various stromal and immune cells that compose this microenvironment, adipocytes are increasingly recognized as active participants rather than passive bystanders. These cells contribute to leukemia pathophysiology by supplying leukemic cells with vital metabolic fuels such as free fatty acids and glutamine, which support cellular bioenergetics and biosynthesis. Furthermore, adipocytes secrete adipokines—including leptin, adiponectin, and others—that influence leukemic cell proliferation, apoptosis, and chemoresistance. Leukemic cells, in turn, are not merely recipients of these signals, but actively remodel the marrow niche to their advantage. They can suppress adipogenesis, inhibit the differentiation of mesenchymal stem cells into adipocytes, or reprogram existing adipocytes to adopt a tumor-supportive phenotype. These transformed adipocytes may enhance leukemic cell survival, dampen immune responses, and create a metabolic sanctuary that enables resistance to standard chemotherapies. This reciprocal and dynamic interaction between leukemic cells and adipocytes contributes significantly to minimal residual disease and relapse, posing a major challenge for durable remission. Recent advances in tissue engineering—such as organ-on-chip and 3D co-culture systems—offer promising platforms to recapitulate and study these leukemia–adipocyte interactions with high fidelity. These models facilitate mechanistic insights and provide a foundation for developing novel therapeutic strategies aimed at disrupting the metabolic and paracrine crosstalk within the leukemic niche. Targeting the adipocyte–leukemia axis represents a compelling and underexplored avenue for improving leukemia treatment by sensitizing malignant cells to existing therapies and overcoming the protective influence of the bone marrow microenvironment. Full article

Approximately 40% of patients with diffuse large B-cell lymphoma (DLBCL) are not cured with first-line chemoimmunotherapy, resulting in poor prognosis. Schmitz et al. classified DLBCL into four prognostic genetic groups using whole-exome sequencing. We applied a simplified approach using a targeted next-generation sequencing assay (Archer FusionPlex Lymphoma Assay) to analyze samples from 105 patients—53 with a progression-free survival (PFS) < 2 years (the “Relapse group”) and 52 with a PFS > 5 years (the “Remission group”) following first-line systemic treatment. Patients were classified according to Schmitz et al. into the following categories: “MCD” (MYD88^L265P and CD79B alteration), “N1” (NOTCH1 alteration), “BN2” (NOTCH2 alteration and BCL6 translocation), and “EZB” (EZH2 alteration and BCL2 translocation). The predictive value of this simplified genetic classification and of relevant clinical features were evaluated. The “Relapse group” included more patients classified as MCD and N1, while fewer were classified as EZB and BN2. Also, cell-of-origin (COO) characteristics and the size of N1 aligned with the classification of Schmitz et al. However, the limited sample size precludes definitive conclusions about the predictive value of our simplified approach. Additionally, male sex, B symptoms, and bone marrow involvement were associated with relapse. Therefore, these clinical features may be useful in predicting outcomes until an effective molecular classification is widely adopted. Full article