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61 Molecular International Prognosis Scoring System for Myelodysplastic Syndromes

Program: Oral and Poster Abstracts
Type: Oral
Session: 637. Myelodysplastic Syndromes – Clinical and Epidemiological: Low Risk Myelodysplastic Syndrome Prognosis and Treatment
Hematology Disease Topics & Pathways:
Adults, Genomics, Translational Research, Clinically Relevant, Diseases, Genomic Profiling, Biological Processes, Myeloid Malignancies, Technology and Procedures, Study Population, Molecular Testing, Clinical Practice (e.g. Guidelines, Health Outcomes and Services, and Survivorship, Value; etc.)
Saturday, December 11, 2021: 9:30 AM

Elsa Bernard, PhD1, Heinz Tuechler2*, Peter L. Greenberg, MD3, Robert P. Hasserjian, MD4, Juan Arango Ossa5*, Yasuhito Nannya, MD, PhD6, Sean M Devlin, PhD7*, Maria Creignou, MD8*, Philippe Pinel9*, Lily Monnier9*, Juan S Medina-Martinez10*, Yesenia Werner11*, Martin Jädersten, MD, PhD12*, Ulrich Germing, MD13*, Guillermo Sanz, MD, PhD14, Arjan A. Van de Loosdrecht, MD, PhD15, Olivier Kosmider, PharmD, PhD16*, Matilde Y Follo, PhD17*, Felicitas R Thol, MD18, Lurdes Zamora, PhD19*, Ronald Feitosa Pinheiro, MD, PhD20*, Andrea Pellagatti, PhD21*, Harold Elias, MD10*, Detlef Haase, MD22*, Christina Ganster22, Lionel Ades, MD, PhD23, Magnus Tobiasson, MD24*, Matteo G. Della Porta, MD25*, Akifumi Takaori-Kondo, MD, PhD26, Takayuki Ishikawa, MD, PhD27, Shigeru Chiba, MD, PhD28*, Senji Kasahara, MD, PhD29, Yasushi Miyazaki, MD, PhD30, Pierre Fenaux, MD, PhD31, Monika Belickova32*, Michael R. Savona, MD33, Virginia M. Klimek, MD34, Fabio Pires de Souza Santos, MD35, Jacqueline Boultwood, PhD36, Ioannis Kotsianidis, PhD37, Valeria Santini, MD38, Francesc Solé, PhD39, Uwe Platzbecker, MD40, Michael Heuser, MD41, Peter Valent, MD42, Kazuma Ohyashiki, MD, PhD43, Carlo Finelli, MD44*, Maria Teresa Teresa Voso, MD45, Lee-Yung Shih, MD46, Michaela Fontenay47, Joop H. Jansen, PhD48, José Cervera, MD, PhD49*, Norbert Gattermann, MD50, Benjamin L. Ebert, MD, PhD51, Rafael Bejar, MD, PhD52, Luca Malcovati, MD53, Mario Cazzola, MD, PhD54, Seishi Ogawa55,56,57, Eva Hellström-Lindberg, MD, PhD8 and Elli Papaemmanuil, PhD5,58

1Computational Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
2LBI For Leukemia Research, Vienna, AUT
3Stanford Cancer Institute, Division of Hematology, Stanford University School of Medicine, Stanford, CA
4Department of Pathology, Massachusetts General Hospital, Boston, MA
5Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY
6Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Kyoto City, Japan
7Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
8Center for Hematology and Regenerative Medicine, Department of Medicine (MedH), Karolinska Institutet, Huddinge, Sweden
9Memorial Sloan Kettering Cancer Center, New Yrok
10Memorial Sloan Kettering Cancer Center, New York, NY
11Memorial Sloan-Kettering Cancer Center, New York, NY
12Hematology, Karolinska Instituet, Stockholm, Sweden
13Dept. of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
14Hematology Deparment, Hospital Universitario La Fe, Valencia, Spain
15Department of Hematology, VUMC, Kamerik, Netherlands
16Laboratoire d'hématologie, Assistance Publique Hôpitaux de Paris / Hôpital Cochin, Paris, France
17University of Bologna, Bologna, Italy
18Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hanover, Germany
19Hematology Department, ICO - Hospital Germans Trias i Pujol, Badalona, Spain
20; Department of Clinical Medicine; Center for Research and Drug Development (NPDM), Universidade Federal do Ceará, Fortaleza, Brazil
21University of Oxford, Oxford, GBR
22Clinics of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany
23Institut Univeristaire d'Hematologie, Hopital Saint Louis, Paris, France
24Karolinska University Hospital, Stockholm, Sweden
25Humanitas Clinical and Research Center -IRCCS Rozzano, and Department of Biomedical Sciences, Humanitas University, Rozzano Milan, Italy, Italy
26Department of Hematology and Oncology, Kyoto University, Kyoto, Japan
27Department of Hematology, Kobe City Hospital Organization Kobe City Medical Center General Hospital, Kobe, Japan
28Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
29Hematology, Gifu Municipal Hospital, Gifu, Japan
30Atomic Bomb Disease Institute, Nagasaki University Hospital, Nagasaki, Japan
31Hôpital Saint-Louis, Paris, France
32Institute of Hematology and Blood Transfusion, Prague, Czech Republic
33Department of Internal Medicine, Division of Hematology, Vanderbilt University School of Medicine; Ingram Cancer Center, Nashville, TN
34Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
35Hospital Israelita Albert Einstein, Sao Paulo, SP, AC, Brazil
36Blood Cancer UK, University of Oxford, Oxford, United Kingdom
37Department of Haematology, School of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
38DMSC, MDS Unit, AOU Careggi, University of Florence, Firenze, Italy
39MDS Research Group, Institut de Recerca Contra la Leucèmia Josep Carreras, Institut Català d’Oncologia-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
40University Hospital Leipzig, Leipzig, Germany
41Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
42Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
43Department of Advanced Cellular Therapy, Tokyo Medical University, Tokyo, Japan
44Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, "S. Orsola-Malpighi" Hospital, Bologna, (bo), Italy
45University of Rome Tor Vergata, Rome, Italy
46Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
47AP-HP HôPital Cochin, Paris, FRA
48Radboud Institute Molecular Studies, Radboud University Medical Center, Nijmegen, Netherlands
49Servicio de Hematología. Hospital La Fe, Valencia, Spain, Valencia, Spain
50Dept. of Hematology, Oncology and Clinical Immunology, Heinrich Heine University Düsseldorf, Dusseldorf, Germany
51Division of Hematology, Harvard Medical School, Boston, MA
52Moores Cancer Center, University of California San Diego Health, La Jolla, CA
53Department of Molecular Medicine, University of Pavia, Pavia, Italy
54University of Pavia, University of Pavia, Pavia, Italy
55Department of Medicine, Center for Haematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
56Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
57Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto, Japan
58Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY

Background

Despite significant advances in our understanding of the genes recurrently mutated in myelodysplastic syndromes (MDS) and their clinical associations, current guidelines for risk stratification and treatment decisions do not consider gene mutations. Developed and validated in 3,675 representative MDS patients, we propose the Molecular International Prognosis Scoring System (IPSS-M) that considers clinical, cytogenetic and genetic parameters.

Methods

Diagnostic MDS samples from 2,957 patients with less than 20% blasts and white blood cell count below 13x109/L were profiled for mutations in 156 driver genes (discovery cohort). Overall survival (OS) information was available in 95% of patients and leukemia-free survival (LFS) in 88%. Median follow-up was 3.8 years.

Correlative analysis between genetic alterations and outcomes was performed on LFS, OS and leukemic transformation. LFS was selected as the primary endpoint for IPSS-M model development. Candidate target risk variables consisted of blood counts, blasts, cytogenetics and gene mutations, while patient age, sex and MDS type (de novo or not) were treated as confounders. Feature selection was performed using complementary pair stability selection from L1-penalized Cox multivariable models. The relative weights of the selected variables were estimated using a robust Cox model adjusted for confounders. The model was validated in an independent cohort of 718 patients.

Results

We characterized 9,339 driver point mutations or short indels involving 124 genes across the 2,957 patients. We identified at least one gene mutation in 90% of patients, and 2 or more in 71%. We detected copy-number alterations and copy-neutral loss of heterozygosity in 40% and 10% of patients. Only 3% (n=101) of patients had chromosomal alterations without gene mutations.

The IPSS-M risk score was built as a continuous index, defined as a weighted sum of prognostic variables. The model consisted of i) hemoglobin, platelets and bone marrow blasts ii) IPSS-R cytogenetic category iii) 22 binary features derived from the presence of mutations in 21 predictive genes and iv) one feature representing the number of mutations from a group of 17 additional genes. To ease interpretation, a scaling was applied so that a score value of zero represented an average patient (i.e. a theoretical patient with mean values for all variables), while values of minus one, one or two corresponded to half, double or four-fold risk compared to the average patient, respectively (Fig 1A). The IPSS-M score resulted in improved discrimination compared to the IPSS-R score, across LFS, OS and leukemic transformation. We observed a 5 point increase in C-index for each endpoint in the discovery cohort and an increase of 3.4, 1.5 and 4.9 points in the validation cohort (Fig 1B).

A six risk category schema was defined based on score cutoffs: Very Low (14%, n=387), Low (32%, n=876), Moderate Low (11%, n=299), Moderate High (11%, n=284), High (14%, n=382) and Very High (18%, n=473). The IPSS-M risk categories demonstrated strong prognostic separation across all endpoints. Median LFS was 9.7, 6.0, 4.1, 2.3, 1.7 and 0.75 years from Very Low to Very High categories (Fig 1C).

Compared to the IPSS-R, IPSS-M categories (by merging Moderate Low and Moderate High as Moderate) resulted in re-stratification of 46% (n=1246) of patients (Fig 1D). Of these, 74% (n=926) were upstaged and 26% (n=320) were downstaged. All IPSS-R strata were affected by recategorization. More than half of patients from the IPSS-R Intermediate category shifted, among which 18% (n=56/310) were upstaged to IPSS-M Very High. Remarkably, 6% (n=98) of patients from IPSS-R Very Low / Low shifted to IPSS-M Very High / High. Highlighting the clinical relevance of this restratification, we found marked differences in outcomes between patients from different IPSS-M categories within each IPSS-R strata. Strikingly, the median LFS of IPSS-R Intermediate patients classified as IPSS-M Very High was 0.75 years (95% CI 0.63-1.1) while it was 6.5 years (95% CI 5.3-NR) for those classified as IPSS-M Low. Last, we showed that the IPSS-M clearly stratified patients with secondary or therapy-related disease (n=234).

Conclusions

The IPSS-M risk score is continuous, interpretable and reproducible. By including information from 38 gene mutations, it leads to improved discrimination compared to the IPSS-R score and restratifies nearly half of MDS patients.

Disclosures: Greenberg: Notable Labs: Research Funding. Nannya: Otsuka Pharmaceutical Co., Ltd.: Consultancy, Speakers Bureau; Astellas: Speakers Bureau. Medina-Martinez: Isabl Technologies: Divested equity in a private or publicly-traded company in the past 24 months. Germing: Novartis: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding. Sanz: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Helsinn Healthcare: 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; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Van de Loosdrecht: Celgene: Consultancy, Research Funding; Roche: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Alexion: Consultancy. Thol: Novartis: Honoraria; Pfizer: Honoraria; Astellas: Honoraria; BMS/Celgene: Honoraria, Research Funding; Abbvie: Honoraria; Jazz: Honoraria. Ades: Abbvie: Consultancy; Astex: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy. Takaori-Kondo: Bristol-Myers K.K.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Research Funding; Celgene: Research Funding. Chiba: Chugai Pharmaceutical: Research Funding; Kyowa Kirin: Research Funding; Sanofi KK: Research Funding; Takeda Pharmaceutica: Research Funding; Astellas Pharmaceutical: Research Funding. Miyazaki: Eisai: Honoraria; Takeda: Honoraria; Daiichi-Sankyo: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Nippon-Shinyaku: Honoraria; Novartis: Honoraria; Abbvie: Honoraria; Kyowa-Kirin: Honoraria; Chugai: Honoraria; Astellas: Honoraria; Sumitomo-Dainippon: Honoraria, Research Funding. Fenaux: Celgene/BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Savona: Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding. Klimek: Syros Pharmaceuticals: Current Employment. Santos: Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kotsianidis: Novartis Hellas: Consultancy, Other: NONE, Research Funding, Speakers Bureau; Bristol Hellas: Consultancy, Other: NONE, Research Funding, Speakers Bureau; Abbvie: Consultancy, Other: NONE, Research Funding, Speakers Bureau; Janssen Hellas: Consultancy, Other: NONE, Speakers Bureau; Genesis: Consultancy, Other: NONE; Astellas: Other: NONE, Research Funding, Speakers Bureau. Santini: Menarini: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees. Platzbecker: Geron: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Celgene/BMS: Honoraria; AbbVie: Honoraria; Takeda: Honoraria. Heuser: AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; BergenBio: Research Funding; Astellas: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolremo: Membership on an entity's Board of Directors or advisory committees. Valent: Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; OAP Orphan Pharmaceuticals: Honoraria. Ohyashiki: Novartis Pharma: Other: chief clinical trial; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Finelli: Novartis: Consultancy, Speakers Bureau; Takeda: Consultancy; Celgene BMS: Consultancy, Research Funding, Speakers Bureau. Voso: Abbvie: Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; Novartis: Speakers Bureau. Shih: Novartis: Research Funding; Ltd: Research Funding; Celgene Ltd: Research Funding; PharmaEssentia Co: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gattermann: Novartis: Honoraria; Takeda: Research Funding; Celgene: Honoraria. Ebert: Celgene: Research Funding; Skyhawk Therapeutics: Membership on an entity's Board of Directors or advisory committees; Exo Therapeutics: Membership on an entity's Board of Directors or advisory committees; Deerfield: Research Funding; GRAIL: Consultancy. Bejar: BMS: Consultancy, Research Funding; Gilead: Consultancy, Honoraria; Silence Therapeutics: Consultancy; Epizyme: Consultancy, Honoraria; Astex: Consultancy; Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company; Takeda: Research Funding. Ogawa: Eisai Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Kan Research Laboratory, Inc.: Consultancy, Research Funding; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; ChordiaTherapeutics, Inc.: Consultancy, Research Funding; Ashahi Genomics: Current holder of individual stocks in a privately-held company. Hellström-Lindberg: Celgene: Research Funding. Papaemmanuil: Isabl Technologies: Divested equity in a private or publicly-traded company in the past 24 months; Kyowa Hakko Kirin Pharma: Consultancy.

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*signifies non-member of ASH