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

Program: Oral and Poster Abstracts
Type: Oral
Session: 637. Myelodysplastic Syndromes: Clinical and Epidemiological: Treatment and Prognostication of MDS
Hematology Disease Topics & Pathways:
Research, Translational Research
Sunday, December 8, 2024: 5:30 PM

Elena Riva, PhD1*, Michela Calvi, PhD2,3*, Matteo Zampini, PhD1,4*, Lorenzo Dall'Olio, PhD5*, Alessandra Merlotti, PhD6,7*, Antonio Russo, MD3*, Giulia Maggioni, MD3*, Lara Orlandi2,3*, Alessandro Frigo3*, Francesca Ficara, PhD3,8*, Laura Crisafulli, PhD1,8*, Elisabetta Sauta, PhD3*, Saverio D'Amico, MSc3*, Enrico Lugli, PhD3*, Alessia Campagna, MD3*, Marta Ubezio, MD3*, Cristina Astrid Tentori, MD3*, Gabriele Todisco, MD3,9*, Luca Lanino, MD1, Alessandro Buizza, MD3*, Denise Ventura, MSc1*, Nicole Pinocchio, MSc1*, Elena Saba, PhD1*, Armando Santoro, MD10*, Valeria Santini, MD11, Arjan A. van de Loosdrecht, MD, PhD12*, Rami S. Komrokji, MD13, Guillermo Garcia-Manero, MD14, Pierre Fenaux, MD15, Lionel Ades, MD, PhD16, Uwe Platzbecker, MD17, Torsten Haferlach, MD18, Antonio Medina Almeida, MD, PhD19, Amer M. Zeidan, MBBS, MHS20, Shahram Kordasti, MD, PhD21,22, Daniel Remondini, PhD6*, Gastone Castellani, PhD23*, Clara Di Vito, PhD2,3*, Domenico Mavilio, MD, PhD2,3* and Matteo Giovanni Della Porta, MD3,4*

1IRCCS Humanitas Research Hospital, Rozzano, Milano, Italy
2Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
3IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
4Department of Biomedical Sciences, Humanitas University, Milan, Italy
5Data Science and Bioinformatics Laboratory, IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy
6Department of Physics and Astronomy, DIFA, University of Bologna, Bologna, Italy
7IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
8Institute for Genetic and Biomedical Research, Milan Unit, CNR, Milan, Italy
9Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
10IRCCS Humanitas Research Hospital, Rozzano, Italy
11MDS Unit, Hematology, AOUC, University of Florence, Florence, Italy
12Department of Hematology, Amsterdam University Medical Center, Free University, Amsterdam, Netherlands
13Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL
14Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
15Hopital Saint Louis, Groupe Francophone des Myelodysplasies, Paris, France, PARIS, FRA
16Hopital Saint Louis, Paris, France
17Department for Hematology, Cell Therapy, Hemostaseology and Infectious Diseases, University of Leipzig Medical Center, Leipzig, Germany
18MLL Munich Leukemia Laboratory, Munich, Germany
19Hospital Da Luz Lisboa, Lisbon, Portugal
20Department of Internal Medicine, Section of Hematology, Yale School of Medicine - Yale Cancer Center, New Haven, CT
21Department of Clinical Haematology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
22Hematology Unit, Azienda Ospedaliero Universitaria delle Marche, Ancona, Italy
23Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy

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.

Disclosures: Santoro: Abb-vie: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EISAI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Astrazeneca: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; Lilly: Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Incyte: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Speakers Bureau; Arqule: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau; Beigene: Speakers Bureau; Sandoz: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Santini: Ascentage, AbbVie, Bristol Myers Squibb, CTI BioPharma, Geron, Gilead, Novartis, Servier, Syros Pharmaceuticals: Other: Advisory Board. Komrokji: CTI biopharma: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; BMS: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Taiho: Membership on an entity's Board of Directors or advisory committees; Servio: Honoraria; DSI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Keros: Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servio: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sumitomo Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; DSI: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Garcia-Manero: Janssen: Research Funding; Merck: Research Funding; Amphivena: Research Funding; AbbVie: Research Funding; Astex: Other: Personal fees; Curis: Research Funding; Novartis: Research Funding; Helsinn: Research Funding; Onconova: Research Funding; Astex: Research Funding; Forty Seven: Research Funding; H3 Biomedicine: Research Funding; Aprea: Research Funding; Genentech: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; Helsinn: Other: Personal fees; Genentech: Other: Personal fees. Fenaux: Astex: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Servier: Research Funding; AbbVie: Honoraria, Research Funding; Agios: Research Funding; Janssen: Research Funding; Novartis: Research Funding; BMS: Honoraria, Research Funding. Ades: Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Platzbecker: Amgen: Consultancy, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; MDS Foundation: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Research Funding; Curis: Consultancy, Honoraria, Research Funding; Geron: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Novartis: Consultancy, Research Funding. Almeida: Gilead: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Zeidan: Zentalis: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; ALX Oncology: Consultancy, Honoraria; Schroedinger: Consultancy, Honoraria; Keros: Consultancy, Honoraria; Treadwell: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Kura: Consultancy, Honoraria, Research Funding; Chiesi: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Geron: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Consultancy, Honoraria; Vinerx: Consultancy, Honoraria; Sumitomo: Consultancy, Honoraria; Hikma: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Lava Therapeutics: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria, Research Funding; Glycomimetics: Consultancy, Honoraria; Akeso Pharma: Consultancy, Honoraria; Faron: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Astex: Research Funding; Janssen: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Medus: Consultancy, Honoraria; Notable: Consultancy, Honoraria; Orum: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Rigel: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Syros: Consultancy, Honoraria, Research Funding; Syndax: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Research Funding; BioCryst: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Shattuck Labs: Research Funding; Regeneron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding. Della Porta: Bristol Myers Squibb: Consultancy.

*signifies non-member of ASH