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464 Real-World Validation of Molecular International Prognostic Scoring System (IPSS-M) for Myelodysplastic Syndromes

Program: Oral and Poster Abstracts
Type: Oral
Session: 637. Myelodysplastic Syndromes – Clinical and Epidemiological III
Hematology Disease Topics & Pathways:
Research, MDS, adult, Translational Research, elderly, Clinical Research, Chronic Myeloid Malignancies, Diseases, survivorship, Myeloid Malignancies, Technology and Procedures, Study Population, Human, molecular testing
Sunday, December 11, 2022: 9:45 AM

Elisabetta Sauta, PhD1*, Marie Robin, MD, PhD2, Matteo Bersanelli, PhD3*, Erica Travaglino, BsC4*, Manja Meggendorfer, PhD5, Lin-Pierre Zhao, MD2*, Juan Carlos Caballero Berrocal, MD6*, Giulia Maggioni, MD7*, Cristina Astrid Tentori, MD7*, Massimo Bernardi, MD8*, Carmen Di Grazia, MD9*, Luca Vago, MD, PhD8, Giulia Rivoli, MD10*, Lorenza Borin, MD11*, Saverio D'Amico, MSc1*, Marta Ubezio, MD7*, Alessia Campagna7*, Antonio Russo, MD7*, Daniele Mannina, MD7*, Luca Lanino12*, Patrizia Chiusolo, MD13*, Luisa Giaccone, MD, PhD14*, Maria Teresa Voso, MD15, Marta Riva, MD16*, Esther Natalie Oliva, MD17, Matteo Zampini, PhD7*, Elena Riva7*, Olivier Nibourel, PhD18*, Claudia Sala, PhD19*, Marilena Bicchieri, PhD3*, Niccolo Bolli, MD20*, Alessandro Rambaldi, MD21, Francesco Passamonti, MD22*, Victor Savevski, MEng1*, Armando Santoro, MD23*, Ulrich Germing24*, Shahram Kordasti, MD, PhD25, Valeria Santini, MD26, Maria Diez-Campelo, MD6,27*, Guillermo Sanz, MD, PhD28, Francesc Solé, PhD29, Wolfgang Kern, MD30, Uwe Platzbecker, MD31, Lionel Ades2, Pierre Fenaux32, Torsten Haferlach, MD30, Castellani Gastone, PhD19* and Matteo G. Della Porta, MD33*

1Artificial Intelligence Center, Humanitas Research Hospital, Rozzano (Milan), Italy
2Department of Hematology and Bone Marrow Transplantation, Hôpital Saint-Louis, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France
3IRCCS Humanitas Research Hospital, Rozzano, Italy
4Cancer Center, IRCCS Humanitas Research Hospital, Rozzano - Milan, Italy
5MLL Munich Leukemia Laboratory, Munich, Bavaria, Germany
6Hematology Department, Hospital Universitario de Salamanca, Salamanca, Spain
7Cancer Center, IRCCS Humanitas Research Hospital & Humanitas University, Rozzano, Italy
8Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milano, Italy
9Ematologia e Centro Trapianti, IRCCS Ospedale Policlinico San Martino, Genova, Italy
10Ospedale Policlinico San Martino, UO Ematologia e Terapie Cellulari, Genova, Italy
11Ospedale San Gerardo, Monza, Italy
12Cancer Center, IRCCS Humanitas Research Hospital & Humanitas University, Rozzano - Milan, Italy
13Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy
14Department of Oncology and Hematology, SSD Stem Cell Transplant Center, A.O.U. Città della Salute e della Scienza di Torino, Turin, Italy
15Policlinico Tor Vergata & Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy
16Department of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Milano, MI, Italy
17Division of Hematology, Azienda Ospedaliena (B-M-M), Reggio Calabria, Italy
18CHRU Lille, Lille, France
19University of Bologna & National Institute of Nuclear Physics (INFN), Bologna, Italy
20Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico & University of Milan, Milan, Italy
21Hematology, ASST Papa Giovanni XXIII, Bergamo, Italy
22Division of Hematology, University Hospital Ospedale di Circolo e Fondazione Macchi - ASST Sette Laghi, University of Insubria, Varese, Italy
23Humanitas University and IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Milan, Italy
24Department of Hematology, Oncology and Clinical Immunology, Universitätsklinik Düsseldorf, Düsseldorf, Germany
25Systems Cancer Immunology, Comprehensive Cancer Centre, King's College London, London, United Kingdom
26AOU Careggi-University of Florence, Florence, Italy
27Institute of Biomedical Research of Salamanca, Hospital Universitario de Salamanca, Salamanca, Spain
28Hematology Deparment, Health Research Institute La Fe, Valencia, Spain
29Institut De Recerca Josep Carreras, Badalona, ESP
30MLL Munich Leukemia Laboratory, Munich, Germany
31Medical Clinical and Policlinic 1, Hematology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany
32Service d'Hématologie Séniors, Hôpital Saint-Louis, Université Paris 7, Paris, France
33Cancer Center, Humanitas Research Hospital and Center for Accelerating Leukemia Research (CALR), Humanitas University, Artificial Intelligence Center, Milan, Italy

Introduction

Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic neoplasms characterized by peripheral blood cytopenia and increased risk of evolution into acute myeloid leukemia. Recently, a new clinical-molecular prognostic model (International Prognostic Scoring System-Molecular, IPSS-M) was proposed to improve conventional risk stratification defined by the IPSS-R [Bernard E et al, NEJM Evid 2022]. In this study, we evaluated the clinical implementability of IPSS-M by: i) providing an extensive independent validation in a real-world patient population; ii) investigating the predictive and prognostic power of IPSS-M in patients receiving disease-modifying treatments (hypomethylating agents, HMA and allogeneic stem cell transplantation, HSCT), and iii) testing the accuracy of IPSS-M prediction when molecular information is missing to define a minimum set of relevant genes associated with high performance of the score.

Patients and Methods

Clinical, cytogenetic and molecular data were collected at diagnosis and/or before starting disease modifying treatment in 2,876 MDS patients from GenoMed4All consortium (Genomics and Personalized Medicine for all through Artificial Intelligence in Haematological Diseases - www.genomed4all.eu). Survival curves were estimated with the Kaplan-Meier method. Multivariate analyses were performed by Cox’s proportional hazards regression models. Model discrimination was assessed using Harrell’s concordance index (C-index).

Results

We calculated the IPSS-M score in the study cohort according to clinical and molecular features collected at diagnosis. Accordingly, 9.6% of patients (n=275) were classified as Very-Low risk, 27.7% (n=797) as Low risk, 10.6% (n=306) as Moderate-Low risk, 11.1% (n=319) as Moderate-High, 19.3% (n=555) as High risk and 21.7% (n=624) as Very-High risk, resulting in the re-stratification of 46% of patients with respect to IPSS-R. Compared to the IPSS-R, the IPSS-M led to an improved discrimination across all endpoints (C-index was 0.81 vs. 0.74 for overall survival, OS and 0.89 vs. 0.76 for leukemia-free survival, LFS, respectively, Figure 1 and 2).

We then analyzed the predictive/prognostic value of IPSS-M in patients receiving HSCT (n=964) and HMA (n=268), respectively, in which clinical and molecular data were available before starting treatment. In patients treated with HSCT, IPSS-M significantly improved the prediction of the risk of disease relapse and the probability of post-transplantation survival with respect to IPSS-R (C-index was 0.76 vs. 0.60 for OS and 0.89 vs. 0.70 for probability of relapse, respectively). The prognostic effect of the IPSS-M was maintained in a multivariate analysis including recipient age and sex, time from diagnosis to transplantation, source of hematopoietic stem cells, type of donor, disease status at transplant and conditioning regimen as covariates (HR was 1.18 for OS and 1.38 for probability of relapse, P<.001). In patients treated with HMA, the probability of overall response evaluated according to 2006 IWG Criteria was 42%, without significant difference among IPSS-M categories (P= 0.19). Median OS in the whole population treated by HMA was 13.9 months. The median probability of OS was 20.7 months in Moderate-High, 17.9 months in High, and 12.7 months in Very-High risk patients (P<.001).

Finally, we analyzed the loss of accuracy of IPSS-M prediction in the study population when one or more IPSS-M-related molecular features were missing. This analysis is expected to provide useful information for clinicians with respect to the robustness of personalized prognostication when providing IPSS-M calculation with missing values. Information on mutational status of a set of 15 genes (ASXL1, CBL, DNMT3A, ETV6, EZH2, FLT3, IDH2, MLLPTD, NPM1, NRAS, RUNX1, SF3B1, SRSF2, TP53multihit and U2AF1) was required to obtain an accuracy of IPSS-M prediction of 80% (with a C-index of 0.8), while considering a set of 10 and 7 genes the accuracy of IPSS-M prediction decreased to <70% and <60%, respectively.

Conclusion

IPSS-M improves MDS prognostication and might result in a more effective selection of candidates to HSCT. Additional factors other than gene mutations can be involved in determining HMA sensitivity. The definition of a minimum set of relevant genes may facilitate the clinical implementation of the score.

Disclosures: Meggendorfer: MLL Munich Leukemia Laboratory: Current Employment. Giaccone: MSD: Honoraria; MSD: Honoraria; Gilead: Honoraria; Novartis: Honoraria; MSD: Honoraria. Voso: Astellas: Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; jazz: Consultancy, Speakers Bureau. Oliva: Novartis: Patents & Royalties: HM PRO, Speakers Bureau; Daiichi: Consultancy; Sobi: Honoraria; Amgen: Honoraria, Speakers Bureau; Janssen: Consultancy; Apellis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Speakers Bureau. Rambaldi: Celgene-BMS: Honoraria; Roche: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Kite-Gilead: Honoraria; Jazz: Honoraria; ABBVIE: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Omeros: Honoraria; Janssen: Honoraria. Passamonti: Novartis, Bristol-Myers Squibb/ Celgene, Abbvie, Roche, AOP Orphan.: Speakers Bureau; Novartis, Bristol-Myers Squibb/ Celgene, Sierra Oncology, Abbvie, Roche, AOP Orphan, Karyiopharma, Kyowa Kirin and MEI.: Consultancy. Santoro: Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Sandoz: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Eli-Lilly: Speakers Bureau; AstraZeneca: Speakers Bureau; Abb-vie: Speakers Bureau; Roche: Speakers Bureau; Bristol Myers Squibb: 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; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Incyte: Consultancy. Germing: Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria. Kordasti: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Speakers Bureau; BMS: Research Funding; MorphoSys: Research Funding; Beckman Coulter: Speakers Bureau. Santini: Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Diez-Campelo: BluePrint: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sanz: takeda: Honoraria; Janssen Pharmaceuticals, Inc.: Other: Teaching and Speaking; La Hoffman Roche Ltd.: Other: Advisor or review panel participant; Novartis Oncology: Consultancy; Celgene Corporation: Consultancy; Abbvie Pharmaceuticals: Other: Advisor or review panel participant; Helsinn: Honoraria, Other: Advisor or review panel participant; Takeda Pharmaceuticals Ltd: Other: Advisor or review panel participant. Kern: MLL Munich Leukemia Laboratory: Current Employment, Other: Ownership. Platzbecker: Abbvie: Honoraria; BMS/Celgene: Honoraria; Jazz: Honoraria; Janssen: Honoraria; Silence Therapeutics: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Geron: Honoraria. Fenaux: AbbVie, BMS, Janssen, Jazz, Novartis: Consultancy, Honoraria, Research Funding. Haferlach: Munich Leukemia Laboratory: Current Employment, Other: Part ownership.

*signifies non-member of ASH