Impacto de las mutaciones somáticas en pacientes con síndromes mielodisplásticos sometidos a distintas modalidades de tratamiento

[ES] De acuerdo con la clasificación de las neoplasias hematológicas de la Organización Mundial de la Salud (OMS), los Síndromes Mielodisplásicos (SMD) constituyen un conjunto de enfermedades clonales de la célula madre hematopoyética caracterizado por citopenias, displasia en una o más líneas mieloides, hematopoyesis ineficaz y aumento del riesgo de progresión a Leucemia Mieloide Aguda (LMA). Esta definición reúne las principales características clínicas y biológicas de los SMD, pero en el pasado no siempre estuvo clara la línea que los separaba de otras patologías con características en común, como las leucemias agudas, las insuficiencias medulares o las neoplasias mieloproliferativas crónicas. Debido a la ausencia de rasgos patognomónicos, esto es, inequívocamente específicos, el diagnóstico de los SMD continúa basándose, desde hace décadas, en la microscopia óptica, con lo que ésta tiene de subjetividad y de variabilidad entre observadores, y en la exclusión de causas alternativas de citopenia o displasia, de ahí la necesidad de incorporar otras técnicas, como la citogenética, la biología molecular o la citometría de flujo, que contribuyan a confirmar el origen clonal de la enfermedad y a despejar las dudas que con frecuencia arroja la citomorfología. Al mismo tiempo, la gran heterogeneidad en el comportamiento clínico de los SMD, fruto de la implicación de mecanismos fisiopatológicos diversos, ha llevado a priorizar el desarrollo de herramientas pronósticas que ayuden a tomar decisiones individualizadas. Además, la escasa respuesta de los SMD a los tratamientos convencionales obliga a la búsqueda constante de alternativas terapéuticas, especialmente aquellas adaptadas al perfil genético de cada paciente. A lo largo de la presente introducción realizaremos, en primer lugar, un recorrido a través de la historia de los SMD, lo que nos permitirá entender mejor su compleja fisiopatología y las dificultades que entraña su diagnóstico. Luego, exploraremos el papel que ha desempeñado la citogenética en el diagnóstico y el pronóstico de los SMD. Continuaremos con una exposición de los aspectos más relevantes de la epidemiología, el diagnóstico, el pronóstico y el tratamiento de los SMD en la actualidad. Finalmente, trataremos en profundidad el papel que desempeña actualmente la biología molecular y cómo las mutaciones somáticas, objeto de nuestro estudio, nos pueden ayudar a mejorar el diagnóstico, refinar el pronóstico y optimizar el tratamiento de estos pacientes

Real-World Validation of Molecular International Prognostic Scoring System for Myelodysplastic Syndromes

The study was conducted by GenoMed4All consortium and supported by EuroBloodNET, the European Reference Network on rare hematologic diseases. The Humanitas Ethics Committee approved the study. Written informed consent was obtained from each participant. This study was registered at ClinicalTrials.gov (ClinicalTrials.gov identifier: NCT04889729).European Union (GenoMed4All project No. 101017549 to M.G.D.P., C.D.G., T.H., U.P., P.F., M.D.C.; Transcan 7 Horizon 2020-EuroMDS project No. 20180424 to M.G.D.P., F.S., U.P., P.F.; HARMONY project No. 116026 to GC); AIRC Foundation (Associazione Italiana per la Ricerca contro il Cancro, Milan Italy-Project No. 22053 to M.G.D.P. and No. 26216 to G.C.); PRIN 2017 (Ministry of University & Research, Italy-Project 2017WXR7ZT to M.G.D.P.); Ricerca Finalizzata 2016 and 2018 (Italian Ministry of Health, Italy-Project RF2016-02364918 to M.G.D.P. and Project NET-2018-12,365,935 to M.G.D.P., F.P., M.T.V.); Cariplo Foundation (Milan Italy-Project No. 2016-0860 to M.G.D.P.); Beat Leukemia Foundation, Milan Italy (to M.G.D.P.)PURPOSEMyelodysplastic syndromes (MDS) are heterogeneous myeloid neoplasms in which a risk-adapted treatment strategy is needed. Recently, a new clinical-molecular prognostic model, the Molecular International Prognostic Scoring System (IPSS-M) was proposed to improve the prediction of clinical outcome of the currently available tool (Revised International Prognostic Scoring System [IPSS-R]). We aimed to provide an extensive validation of IPSS-M.METHODSA total of 2,876 patients with primary MDS from the GenoMed4All consortium were retrospectively analyzed.RESULTSIPSS-M improved prognostic discrimination across all clinical end points with respect to IPSS-R (concordance was 0.81 v 0.74 for overall survival and 0.89 v 0.76 for leukemia-free survival, respectively). This was true even in those patients without detectable gene mutations. Compared with the IPSS-R based stratification, the IPSS-M risk group changed in 46% of patients (23.6% and 22.4% of subjects were upstaged and downstaged, respectively).In patients treated with hematopoietic stem cell transplantation (HSCT), IPSS-M significantly improved the prediction of the risk of disease relapse and the probability of post-transplantation survival versus IPSS-R (concordance was 0.76 v 0.60 for overall survival and 0.89 v 0.70 for probability of relapse, respectively). In high-risk patients treated with hypomethylating agents (HMA), IPSS-M failed to stratify individual probability of response; response duration and probability of survival were inversely related to IPSS-M risk.Finally, we tested the accuracy in predicting IPSS-M when molecular information was missed and we defined a minimum set of 15 relevant genes associated with high performance of the score.CONCLUSIONIPSS-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

Real-World Validation of Molecular International Prognostic Scoring System for Myelodysplastic Syndromes

Purpose: Myelodysplastic syndromes (MDS) are heterogeneous myeloid neoplasms in which a risk-adapted treatment strategy is needed. Recently, a new clinical-molecular prognostic model, the Molecular International Prognostic Scoring System (IPSS-M) was proposed to improve the prediction of clinical outcome of the currently available tool (Revised International Prognostic Scoring System [IPSS-R]). We aimed to provide an extensive validation of IPSS-M. Methods: A total of 2,876 patients with primary MDS from the GenoMed4All consortium were retrospectively analyzed. Results: IPSS-M improved prognostic discrimination across all clinical end points with respect to IPSS-R (concordance was 0.81 v 0.74 for overall survival and 0.89 v 0.76 for leukemia-free survival, respectively). This was true even in those patients without detectable gene mutations. Compared with the IPSS-R based stratification, the IPSS-M risk group changed in 46% of patients (23.6% and 22.4% of subjects were upstaged and downstaged, respectively).In patients treated with hematopoietic stem cell transplantation (HSCT), IPSS-M significantly improved the prediction of the risk of disease relapse and the probability of post-transplantation survival versus IPSS-R (concordance was 0.76 v 0.60 for overall survival and 0.89 v 0.70 for probability of relapse, respectively). In high-risk patients treated with hypomethylating agents (HMA), IPSS-M failed to stratify individual probability of response; response duration and probability of survival were inversely related to IPSS-M risk.Finally, we tested the accuracy in predicting IPSS-M when molecular information was missed and we defined a minimum set of 15 relevant genes associated with high performance of the score. 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