IPSS-M risk and specific sex-associated somatic mutations predict response to ESA therapy in LR-MDS: building a new score
Abstract
Abstract Acquired somatic mutations are incorporated in the classification and prognosis of myelodysplastic syndromes/neoplasms (MDSs). However, the predictive role of molecular features in MDS needs to be elucidated, especially in the lower-risk subtypes (LR-MDS), where treatment has become heterogeneous and predictive biomarkers are lacking. In this study, we investigated genetic markers associated with erythropoiesis-stimulating agents (ESAs) response in LR-MDS. A European cohort of 535 patients with LR-MDS was analyzed using targeted next-generation sequencing (t-NGS) to calculate molecular prognostic scores (International Prognostic Scoring System, molecular [IPSS-M]). The integration of IPSS-M score among the 2 known variables, serum erythropoietin (sEPO) and transfusion dependence (TD), refined the capability to predict response (area under the curve [AUC], 0.71 vs 0.63, P = .0004). Based on these 3 variables, a molecular predictive score, which we named ESA-PSS-M (–0.05 × [sEPO U/L] –4.5 × [IPSS-M score] –5 × [TD (yes = 1; no = 0)]; specificity 76%; sensitivity 57%), was generated and validated in an external cohort (n = 223 patients with LR-MDS). Despite the impact of IPSS-M score, no single mutated gene was linked to ESA response; however, when we stratified cases by sex at birth, the X-linked STAG2 gene mutations were significantly associated with ESA resistance in males with LR-MDS (odds ratio, 0.13; P = .003). To our knowledge, this is the first study based on a large multicenter cohort of patients suggesting that the integration of IPSS-M score and sex-specific mutations can characterize ESA resistance and guide first-line (1L) therapeutic choices for anemic LR-MDS (ie, ESAs vs luspatercept).
Article Details
Authors (27)
Marco G. Raddi
1Myelodysplastic Syndromes Unit, Department of Experimental and Clinical Medicine, Hematology, University of Florence, Azienda Ospedaliero Universitaria Careggi, Florence, Italy
Sophie Park
16CHU Grenoble Alpes - Hopital Michallon, La Tronche, France
Michaela Fontenay
7Université Paris Cité and Assistance Publique-Hôpitaux de Paris Centre, Hôpital Cochin, Paris, France
Olivier Kosmider
11Centre National de la Recherche Scientifique UMR8104, INSERM U1016, Institut Cochin, Université de Paris Cité, Paris, France
Maria Diez Campelo
5Department of Hematology, Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain
Juan C. Berrocal
6Department of Hematology, Hospital Clínico de Valladolid, Valladolid, Spain
Marie Sebert
1Hôpital Saint-Louis, Paris, France
Lionel Adès
Uwe Platzbecker
Matteo G. Della Porta
Giorgio Mattiuz
1MDS Unit, Hematology, AOU Careggi, University of Florence, Department of Experimental and Clinical Medicine, Florence, Italy
Sven De Pourcq
1MDS Unit, Hematology, AOU Careggi, University of Florence, Department of Experimental and Clinical Medicine, Florence, Italy
Lorenzo Tofani
7University of Florence, Department of Statistics, Informatics, Applications (L.T,B.B.), Firenze, Italy
Giulia Maggioni
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Elena Tofacchi
1MDS Unit, Hematology, AOU Careggi, University of Florence, Department of Experimental and Clinical Medicine, Florence, Italy
Angela Consagra
30University of Florence, MDS Unit, Hematology, AOU Careggi - Department of Experimental and Clinical Medicine, Florence, Italy
Luca Rigodanza
1MDS Unit, Hematology, AOU Careggi, University of Florence, Department of Experimental and Clinical Medicine, Florence, Italy
Gloria Andreossi
11University of Florence, Florence, Italy
Cristina Amato
1MDS Unit, Hematology, AOU Careggi, University of Florence, Department of Experimental and Clinical Medicine, Florence, Italy
Mathieu Meunier
2Fi LMC, Lyon, France
Celia Orlando
3Department of Hematology, University Hospital of Grenoble Alpes, Grenoble, France
Emmanuelle Clappier
2Institut de Recherche Saint-Louis, Université Paris Cité, Paris, France
Nicolas Chapuis
4Laboratory of Hematology, Hôpital Cochin, Université Paris Cité and Assistance Publique-Hôpitaux de Paris Centre, Paris, France
Pierre Walczak
7Department of Hematology, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, and Université Paris Cité and Leukemia Institute Paris Saint-Louis, Paris, France
Katharina Zoldan
8Department for Hematology, Cell Therapy and Hemostaseology, University of Leipzig Medical Center, Leipzig, Germany
Anne Sophie Kubasch
16University Hospital of Leipzig, Department of Hematology, Dresden, Germany
Valeria Santini
7DMSC University of Florence, AOUC, MDS Unit, Hematology, Florence, Italy