Phase I Study with Dose-escalation and Expansion Evaluating the Safety and Efficacy of Oral Arsenic (ATO) in Low-risk Myelodysplastic Syndromes Failing Erythropoiesis Stimulating Agents and Luspatercept (or Ineligible for the Latter)

Phase I study with dose-escalation and expansion evaluating the safety and efficacy of oral Arsenic (ATO) in low-risk Myelodysplastic Syndromes having failed to Erythropoiesis Stimulating Agents and Luspatercept (or ineligible for the latter).

开始日期2025-02-01

申办/合作机构

Groupe Francophone des Myélodysplasies

NCT05782127

/ Recruiting临床1/2期IIT

A Phase I/II, Open-label, Single Arm, Multicenter Dose-finding Study Assess the Safety and Preliminary Efficacy of Oral Azacitidine CC-486 (ONUREG) in Combination with Venetoclax (VENCLYXTO) in Previously Untreated Higher-risk Myelodysplastic Syndromes Ineligible for Allogenic Transplantation

This phase I/II open-label, dose-finding, multi-center study will assess safety and primary efficacy of Onureg and Venetoclax combination, to define the optimal biological dose and optimal treatment duration of Onureg to be used along with Venetoclax for further studies in previously untreated patients with higher-risk myelodysplastic syndromes (HR-MDS) not eligible to transplant.

开始日期2023-12-06

申办/合作机构

Groupe Francophone des Myélodysplasies

[+2]

NCT05768711

/ Recruiting临床2期IIT

Phase II Study With Safety run-in of Azacitidine (AZA) Combined With Venetoclax (VEN) in Patients With Higher-risk Chronic Myelomonocytic Leukemia (CMML)

Open-label phase II, single arm, multicenter study with safety run-in to evaluate the efficacy and safety of Azacitidine combined with Venetoclax in patients with higher-risk chronic myelomonocytic leukemia

开始日期2023-10-04

申办/合作机构

Groupe Francophone des Myélodysplasies

[+1]

100 项与 Groupe Francophone des Myélodysplasies 相关的临床结果

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0 项与 Groupe Francophone des Myélodysplasies 相关的专利（医药）

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166

项与 Groupe Francophone des Myélodysplasies 相关的文献（医药）

2024-11-05·Blood

Landscape of Immune Cell States and Ecosystems in Patients with Myelodysplastic Syndrome to Refine Prognostic Assessment and Predict Treatment Response. a Study By i4MDS Consortium

作者: Santini, Valeria ; Buizza, Alessandro ; Santoro, Armando ; Zeidan, Amer M. ; Mavilio, Domenico ; Sauta, Elisabetta ; Merlotti, Alessandra ; Remondini, Daniel ; Maggioni, Giulia ; Garcia-Manero, Guillermo ; Fenaux, Pierre ; Komrokji, Rami S. ; Riva, Elena ; Saba, Elena ; Ficara, Francesca ; Calvi, Michela ; Ubezio, Marta ; Platzbecker, Uwe ; Frigo, Alessandro ; Ventura, Denise ; Tentori, Cristina Astrid ; Ades, Lionel ; Lugli, Enrico ; Lanino, Luca ; van de Loosdrecht, Arjan A. ; Crisafulli, Laura ; Campagna, Alessia ; Zampini, Matteo ; Almeida, Antonio Medina ; Della Porta, Matteo Giovanni ; Di Vito, Clara ; Pinocchio, Nicole ; Castellani, Gastone ; D'Amico, Saverio ; Haferlach, Torsten ; Kordasti, Shahram ; Orlandi, Lara ; Todisco, Gabriele ; Dall'Olio, Lorenzo ; Russo, Antonio

BACKGROUND. Biological heterogeneity in Myelodysplastic Syndromes (MDS) is partly driven by tumor-associated genomic lesions, but increasing evidence suggests that immune tumor microenvironment plays a significant role. However, dissecting these cell states and understanding their clinical relevance on a large scale remains challenging.AIMS. In this study, conducted by i4MDS consortium, we characterized the immune ecosystems in a prospective cohort of MDS patients. Specific objectives were: 1) to analyze the contribution of immune ecosystems in refining patients' prognosis; 2) to define specific immune profiles to predict probability of response to hypomethylating agents (HMA); and 3) to develop a panel for immune monitoring in clinical practice.METHODS. We prospectively studied 286 MDS patients at Humanitas Cancer Center Milan, Italy (evaluated at diagnosis and at multiple time points throughout the disease's natural history). T lymphocytes, Natural Killer (NK) and myeloid cells were evaluated in bone marrow (BM) and peripheral blood (PB) by extensive multi-color flow cytometry (PMID:38756352). Phenograph was used to analyze immune cell subset distribution and phenotype, while HDBSCAN identified clusters of patients with homogeneous immune features (defined as ecosystems). Each ecosystem was further characterized by integrating RNA-seq data from CD34+ progenitors. A DURAClone dry pre-formulated antibody panel was designed for implementation in the clinical work-up of patients.RESULTS. We identified five immune ecosystems in the BM, each characterized by varying functionality and maturation stages of immune cells. Two clusters exhibited features of a healthy-like immune system: one with an expanded pool of immature and plastic Naïve T cells and CD56bright NK cells (referred to as “Naïve” ecosystem); and another enriched with memory T cells and functionally activated T and NK cells, termed “Memory, activated”. The other three clusters showed progressive levels of immune dysfunction: one was characterized by overall immune inactivity, labeled as “Not activated” ecosystem; another one displayed a skewing of immune cell maturation towards advanced stages accompanied by immune suppression, and was named as “Terminally differentiated, immunosuppressed”, while the final group was marked by T and NK cell exhaustion and suppression, identified as “Exhausted, immunosuppressed”. Transcriptome analysis of CD34+ MDS progenitors revealed distinct inflammatory signatures and immunosuppressive pathways associated with immune dysfunction.The immune ecosystems exhibited distinct probabilities of survival (P<0.001) and risk of leukemic transformation (P<0.001). Moreover, they were able to further refine the prognosis of patients stratified according to ICC/WHO 2022 categories (P<0.001) and IPSS-M risk groups (P=0.001). In a multivariable model adjusted for age, sex and IPSS-M score, the immune ecosystems retained an independent prognostic impact (P<0.001, HR 1.46). Furthermore, integrating immune cell profiles with molecular profiles improved the accuracy of predicting patient outcomes, the concordance index increasing from 0.76 (IPSS-M alone) to 0.84 (IPSS-M and immune ecosystems).In patients treated with HMA, baseline immune ecosystems identified groups with different probabilities of achieving a complete response, ranging from >75% to <10% (P<0.001). Correcting immune dysfunction in responding patients is a long-term process; those who recovered from immune dysfunction had a significantly higher likelihood of achieving a long-term response (>24 months) compared to MDS with persistent immune dysfunction (P<0.01). At relapse, most patients exhibited severe immune dysregulation.We observed that BM immune ecosystems can be easily detected by the analysis of PB cells, providing a proof of concept for a non-invasive immune monitoring approach. We therefore assessed the reliability of the designed dry pre-formulated antibody panel for clinical work-up in 75 MDS prospectively evaluated.CONCLUSION. Immune ecosystems capture the clinical heterogeneity of MDS within existing subtypes and extend beyond genotypic classifications. These findings provide a systems-level resolution of the MDS microenvironment and identify opportunities for patient immune monitoring in clinical practice, thereby improving the clinical decision-making process.

2024-11-05·Blood

Renew Trial in Progress: A Phase 3, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Elritercept (KER-050) for the Treatment of Transfusion-Dependent Anemia in Adult Participants with Very Low-, Low-, or Intermediate-Risk Myelodysplastic Neoplasms (MDS)

作者: Materna, Chris ; Grayson, Dena ; Bobba, Suresh ; Fenaux, Pierre ; Cluzeau, Thomas ; Giagounidis, Aristoteles ; Santini, Valeria ; Graham, Christine ; Salstrom, Jen L. ; Ross, Miranda ; Zeidan, Amer M. ; Della Porta, Matteo Giovanni ; Komrokji, Rami S. ; Platzbecker, Uwe ; Rovaldi, Christopher ; DeZern, Amy E. ; Hankin, Montagu ; Jiang, Ying ; Garcia-Manero, Guillermo ; Diez-Campelo, Maria ; Chee, Lynette C.Y. ; Sekeres, Mikkael A. ; Thamake, Sanjay ; Buckstein, Rena

Background and Significance: In MDS, defects occur at multiple stages of hematopoiesis. Available Erythropoiesis Stimulating or Erythroid Maturation Agents (ES/EMAs) target early or late stages of erythropoiesis, respectively, and are only effective in subsets of patients. For patients with high transfusion burden (HTB) who have diminished erythropoietic capacity and a worse prognosis, ES/EMAs show limited efficacy and durability of response (DOR). Elritercept is an investigational, modified activin receptor type IIA ligand trap designed to inhibit activin A and other select TGF-β superfamily ligands (activin B, GDFs 8, & 11) that is being evaluated in diseases with ineffective hematopoiesis (IH), including MDS (NCT04419649) and myelofibrosis (NCT05037760). In preclinical studies, elritercept increased erythropoiesis and thrombopoiesis and acted on early- and late-stage erythropoietic and megakaryocyte progenitors, indicating a differentiated mechanism of action, potentially due to inhibition of activin A. By eliciting effects on hematopoiesis across multiple differentiation stages and cell lineages, elritercept has the potential to address the complex nature of IH and to provide robust and sustained hematological improvement in patients with MDS who have limited treatment options, including those with HTB and/or non-ring sideroblast (RS) MDS.Study Design and Methods: RENEW (NCT06499285) is a global, multicenter, randomized, double-blind, placebo-controlled Phase 3 study to evaluate the efficacy and safety of elritercept in adults with transfusion-dependent, very low-, low-, and intermediate-risk MDS per IPSS-R (lower-risk [LR] MDS). Eligible participants are aged ≥18 years and have MDS with or without RS and low transfusion burden (LTB, 4 to 7 RBC units per 16 weeks) or HTB (≥8 RBC units per 16 weeks). Approximately 225 participants will be randomized 2:1 to receive either elritercept, administered SC Q4W starting at 3.75mg/kg with up-titration to 5mg/kg after at least 8 weeks of treatment, or placebo. Participants will be stratified by RS status (RS-positive vs non-RS) and baseline transfusion burden (LTB vs HTB). Participants will be enrolled into a double-blind treatment period consisting of a primary phase (24 weeks), secondary phase (24 weeks), and extension phase (until the end of treatment [EOT]). Following EOT, participants will undergo an 8-week safety follow-up period and a long-term follow-up period as per protocol. Every quarter during the long-term follow-up, data will be collected on survival, first dose of the next MDS treatment line, and progression to AML, if applicable. The primary endpoint is the proportion of participants with achievement of transfusion independence (TI) ≥8 weeks from baseline through week 24. Secondary endpoints are the proportion of participants with achievement of TI ≥24 weeks from baseline through week 48, the proportion of participants with HTB achieving TI for ≥8 weeks from baseline through week 24, and the incidence and severity of adverse events (AEs) and serious AEs. The RENEW trial is expected to support the registration of elritercept for the treatment of anemia in adults with LR-MDS.

2024-11-05·Blood

Artificial-Intelligence, Data-Driven, Comprehensive Classification of Myeloid Neoplasms Based on Genomic, Morphological and Histological Features

作者: Kubasch, Anne Sophie ; Santini, Valeria ; Buizza, Alessandro ; Jerez, Andres ; Fenaux, Pierre ; Bewersdorf, Jan Philipp ; Travaglino, Erica ; Todisco, Gabriele ; Ball, Somedeb ; Roldan, Veronica ; Pleyer, Lisa ; Kröger, Nicolaus ; Avendaño Pita, Alejandro ; Ubezio, Marta ; Cerezo Velasco, Estefania ; Fiallo Suarez, Dolly Viviana ; Lanino, Luca ; Meggendorfer, Manja ; Haferlach, Torsten ; Quintela, David ; Chou, Wen-Chien ; Yao, Chi-Yuan ; Campagna, Alessia ; Casetti, Ilaria Carola ; Riva, Elena ; Passamonti, Francesco ; Fontenay, Michaela ; Calabuig, Marisa ; Gagelmann, Nico ; Sallman, David ; Lin, Chien-Chin ; Díaz-Beyá, Marina ; D'Amico, Saverio ; Chiusolo, Patrizia ; Vannucchi, Alessandro M. ; Robin, Marie ; Voso, Maria Teresa ; Padron, Eric ; Dall'Olio, Daniele ; Komrokji, Rami S. ; Borin, Lorenza Maria ; Asti, Gianluca ; Dall'Olio, Lorenzo ; Castellani, Gastone ; Hunter, Anthony M. ; Al Ali, Najla H. ; Garcia-Manero, Guillermo ; Garcia Martin, Paloma ; Della Porta, Matteo Giovanni ; Solary, Eric ; Tien, Hwei-Fang ; Awada, Hussein ; Guglielmelli, Paola ; Sauta, Elisabetta ; Platzbecker, Uwe ; Kewan, Tariq ; Consagra, Angela ; Zeidan, Amer M. ; Ficara, Francesca ; Loghavi, Sanam ; Vucinic, Vladan ; Wang, Yu-Hung ; Palomo, Laura ; Gurnari, Carmelo ; Tentori, Cristina Astrid ; Maciejewski, Jaroslaw ; Diez-Campelo, Maria ; Zampini, Matteo ; Xicoy, Blanca ; Germing, Ulrich ; Kern, Wolfgang ; Cornejo, Elena ; Russo, Antonio ; Maggioni, Giulia ; Bernardi, Massimo ; Sala, Claudia ; Hou, Hsin-An ; Delleani, Mattia ; Santoro, Armando ; Sole, Francesc

Background. Recent advancements in genome characterization have transformed the study of myeloid neoplasms (MN). Accordingly, there is a shift from traditional classification schemes, based on morphological and clinical information, to next-generation systems (2022 WHO/ICC) which incorporate genomic features. However, current classifications do not clearly define the hierarchical importance of genomic vs morphological features in determining disease entities, leading to inconsistencies in clinical practice; moreover, they do not specifically address areas of overlap among different MNMethods. In the TITAN study, we retrospectively studied 20,054 patients with MN in which clinical and morphological data, together with cytogenetics, mutational screening and outcome were available. We included 7104 AML, 8410 MDS, 2986 MDS/MPN and 1554 MF. We used MOSAIC, an AI-based framework to define unsupervised clusters according to homogeneous morphological and genomic features. Shapley Additive exPlanations (SHAP) was applied to investigate features of importance and their effects on cluster assignmentResults. We identified 34 distinct clusters and created a dashboard (https://titan-xkb3corsxq-ew.a.run.app/) where the most relevant features, clinical phenotypes, and outcomes are summarized. SHAP revealed that genomics often outweighs morphology in defining disease entitiesSix clusters had splicing mutations as dominant features, albeit with different hematological phenotypes (mainly including MDS and MDS/MPN pts). The presence of additional high-risk genomic features (RUNX1/ASXL1 mutations, del(7q)/-7, abn(3q26.2) and complex karyotype) identified patients with poor survival within each category. A separate cluster including MN with splicing mutations and increased blasts (mainly including MDS and AML patients) was characterized by poor response to treatments and dismal outcomeMN with TP53 mutations constituted a distinct entity, regardless of clinical phenotype and blast count and had the poorest prognosis. Mutational and CNV analysis showed biallelic inactivation of TP53 in the majority of patients. Most monoallelic TP53 were assigned to a different cluster. Patients that evolved to AML often acquired biallelic inactivation, suggesting that TP53 allelic status may identify different disease phases within the same entityAmong morphological features, marrow fibrosis held significant hierarchical importance in defining clusters, driving patient assignment into three distinct groups characterized by 1) JAK/STAT mutations alone, 2) JAK/STAT mutations with high-risk molecular features, 3) wildtype JAK/STAT. The latter group included both MDS and MF patients who exhibited a higher risk of clonal evolution and shorter survivalOverall, 10 out of 34 clusters included patients from different MN subtypes as defined by ICC/WHO criteria, accounting for 38.1% of the entire population. This suggests that current classifications do not efficiently capture boundaries between different entities. Importantly, among 1482 patients with RNAseq data from BM progenitors available, the newly identified clusters exhibited distinct gene expression profiles, thus providing evidence for the biological consistency of the proposed classificationThe 34 clusters were characterized by different risks of clonal progression and survival. Based on this finding and the observation that, in most cases, heterogeneous phenotypes contributed to each cluster, we developed a pan-MN prognostic score. This score is based on clinical and molecular parameters and is designed to be applicable to all patients, regardless of clinical labels. The performance of the score (c-index 0.75) was comparable to that of currently available disease-specific toolsConclusion. The integrative analysis of genomic profiling and morphological features provides a proof of concept for a novel classification approach for MN, that may refine the overlapping areas among disease entities and more effectively identify patients with a homogeneous biological background. It could serve as a foundation for an innovative prognostic assessment of MN patients, independent of traditional clinical labels. The clinical implementation of pan-MN tools is expected to improve the effectiveness and quality of personalized diagnosis, treatment decisions and clinical trial eligibility

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