43 results on '"Marta Sonia Gonzalez"'
Search Results
2. P967: A MACHINE LEARNING MODEL FOR RISK PREDICTION IN MULTIPLE MYELOMA PROGRESSING AFTER THE FIRST LINE OF THERAPY
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Adrian Mosquera-Orgueira, Marta Sonia Gonzalez Perez, Jose Angel Diaz Arias, and Maria-Victoria Mateos
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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3. P1234: A PROGNOSTIC MODEL BASED ON GENE EXPRESSION PARAMETERS PREDICTS A BETTER RESPONSE TO BORTEZOMIB-CONTAINING IMMUNOCHEMOTHERAPY IN DIFFUSE LARGE B-CELL LYMPHOMA
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Adrian Mosquera-Orgueira, Jose Angel Diaz Arias, Rocio Serrano Martin, Victor Portela Piñeiro, Miguel Cid Lopez, Andres Peleteiro Raindo, Laura Bao Perez, Marta Sonia Gonzalez Perez, Manuel Mateo Perez Encinas, Maximo Francisco Fraga Rodriguez, Juan Carlos Vallejo Llamas, and Jose Luis Bello Lopez
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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- View/download PDF
4. PB2384: EVALUATION OF NEW MACHINE LEARNING SYSTEMS FOR PROGNOSTICATION BASED ON GENE EXPRESSION SIGNATURES IN MANTLE CELL AND PERIPHERAL T CELL LYMPHOMAS
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Adrian Mosquera-Orgueira, Jose Angel Diaz Arias, Rocio Serrano Martin, Victor Portela Piñeiro, Andres Peleteiro Raindo, Miguel Cid Lopez, Laura Bao Perez, Marta Sonia Gonzalez Perez, Manuel Mateo Perez Encinas, Maximo Francisco Fraga Rodriguez, Juan Carlos Vallejo Llamas, and Jose Luis Bello Lopez
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
- Full Text
- View/download PDF
5. Refining risk prediction in pediatric acute lymphoblastic leukemia through DNA methylation profiling
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Orgueira, Adrian Mosquera, Krali, Olga, Miguez, Carlos Perez, Raindo, Andres Peleteiro, Arias, Jose Angel Diaz, Perez, Marta Sonia Gonzalez, Encinas, Manuel Mateo Perez, Sanmartin, Manuel Fernandez, Sinnet, Daniel, Heyman, Mats, Lönnerholm, Gudmar, Noren-Nyström, Ulrika, Schmiegelow, Kjeld, Nordlund, Jessica, Orgueira, Adrian Mosquera, Krali, Olga, Miguez, Carlos Perez, Raindo, Andres Peleteiro, Arias, Jose Angel Diaz, Perez, Marta Sonia Gonzalez, Encinas, Manuel Mateo Perez, Sanmartin, Manuel Fernandez, Sinnet, Daniel, Heyman, Mats, Lönnerholm, Gudmar, Noren-Nyström, Ulrika, Schmiegelow, Kjeld, and Nordlund, Jessica
- Abstract
Acute lymphoblastic leukemia (ALL) is the most prevalent cancer in children, and despite considerable progress in treatment outcomes, relapses still pose significant risks of mortality and long-term complications. To address this challenge, we employed a supervised machine learning technique, specifically random survival forests, to predict the risk of relapse and mortality using array-based DNA methylation data from a cohort of 763 pediatric ALL patients treated in Nordic countries. The relapse risk predictor (RRP) was constructed based on 16 CpG sites, demonstrating c-indexes of 0.667 and 0.677 in the training and test sets, respectively. The mortality risk predictor (MRP), comprising 53 CpG sites, exhibited c-indexes of 0.751 and 0.754 in the training and test sets, respectively. To validate the prognostic value of the predictors, we further analyzed two independent cohorts of Canadian (n = 42) and Nordic (n = 384) ALL patients. The external validation confirmed our findings, with the RRP achieving a c-index of 0.667 in the Canadian cohort, and the RRP and MRP achieving c-indexes of 0.529 and 0.621, respectively, in an independent Nordic cohort. The precision of the RRP and MRP models improved when incorporating traditional risk group data, underscoring the potential for synergistic integration of clinical prognostic factors. The MRP model also enabled the definition of a risk group with high rates of relapse and mortality. Our results demonstrate the potential of DNA methylation as a prognostic factor and a tool to refine risk stratification in pediatric ALL. This may lead to personalized treatment strategies based on epigenetic profiling., Adrián Mosquera Orgueira and Olga Krali contributed equally to this work.
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- 2024
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6. P967: A MACHINE LEARNING MODEL FOR RISK PREDICTION IN MULTIPLE MYELOMA PROGRESSING AFTER THE FIRST LINE OF THERAPY
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Mosquera-Orgueira, Adrian, primary, Perez, Marta Sonia Gonzalez, additional, Diaz Arias, Jose Angel, additional, and Mateos, Maria-Victoria, additional
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- 2023
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7. P1234: A PROGNOSTIC MODEL BASED ON GENE EXPRESSION PARAMETERS PREDICTS A BETTER RESPONSE TO BORTEZOMIB-CONTAINING IMMUNOCHEMOTHERAPY IN DIFFUSE LARGE B-CELL LYMPHOMA
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Mosquera-Orgueira, Adrian, primary, Arias, Jose Angel Diaz, additional, Serrano Martin, Rocio, additional, Portela Piñeiro, Victor, additional, Cid Lopez, Miguel, additional, Peleteiro Raindo, Andres, additional, Bao Perez, Laura, additional, Perez, Marta Sonia Gonzalez, additional, Encinas, Manuel Mateo Perez, additional, Rodriguez, Maximo Francisco Fraga, additional, Llamas, Juan Carlos Vallejo, additional, and Bello Lopez, Jose Luis, additional
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- 2023
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8. P878: SELINEXOR IN COMBINATION WITH DARATUMUMAB-BORTEZOMIB AND DEXAMETHASONE FOR THE TREATMENT OF RELAPSE OR REFRACTORY MULTIPLE MYELOMA: UPDATED RESULTS OF THE PHASE 2, MULTICENTER GEM-SELIBORDARA STUDY
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Gonzalez-Calle, Veronica, primary, Rodríguez-Otero, Paula, additional, Sureda, Anna, additional, de la Fuente, Felipe de Arriba, additional, Reinoso Segura, Marta, additional, Ribas, Paz, additional, Pilar Gonzalez, Ana, additional, Gonzalez Montes, Yolanda, additional, Oriol, Albert, additional, Martinez-Lopez, Joaquín, additional, Perez, Marta Sonia Gonzalez, additional, Garcia, Miguel Teodoro Hernandez, additional, Sirvent Auzmendi, Maialen, additional, Blade, Joan, additional, Palacios, Juan José Lahuerta, additional, San Miguel, Jesús, additional, and Mateos, Maria-Victoria, additional
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- 2023
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9. Immune Biomarkers of Survival and Severe Infection in Newly Diagnosed Multiple Myeloma (NDMM) Patients (pts) Treated with the Backbone Regimen Lenalidomide and Dexamethasone (Rd)
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Catarina Maia, Noemi Puig, Cristina Pérez Ruiz, Maria Teresa Cedena Romero, Camila Guerrero, Marta Larrayoz, Cirino Botta, Norma C. Gutierrez, María José Calasanz, Maria Luisa Martin-Ramos, Miguel Hernández, Laura Rosinol Dachs, Esther González Garcia, Felipe De Arriba, Albert Oriol, Veronica Gonzalez-Calle, Fernando Escalante, Javier de la Rubia, Mercedes Gironella Mesa, Rafael Rios, Ricarda Belen Garcia Sanchez, Jose Maria Arguiñano PEREZ, Adrian Alegre, Jesus Martin, María del Carmen Couto Caro, Maria Casanova, Mario Arnao Herraiz, Ernesto Pérez, Sebastián Garzón López, Marta Sonia Gonzalez Perez, Guillermo Martín-Nuñez, Adriana Rossi, Morton Coleman, Cristina Encinas, Ana M. Vale, Ana Isabel Teruel, María Cortés Rodríguez, Jose A. Martinez-Climent, Juan-José Lahuerta, Joan Bladé Creixenti, Ruben Niesvizky, Jesús San-Miguel, Maria-Victoria Mateos, and Bruno Paiva
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
10. Belantamab Mafodotin in Combination with Vrd for the Treatment of Newly Diagnosed Transplant Eligible Multiple Myeloma Patients: Results from the Phase II, Open Label, Multicenter, GEM-BELA-Vrd Trial
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Veronica Gonzalez-Calle, Paula Rodriguez Otero, Beatriz Rey-Bua, Javier De La Rubia, Felipe De Arriba, Valentin Cabañas, Esther González Garcia, Enrique M. Ocio, Cristina Encinas, Alexia Suarez Cabrera, Joan Bargay, Joaquin Martinez Lopez, Marta Sonia Gonzalez, Jose Angel Hernandez-Rivas, Laura Rosiñol, Miguel-Teodoro Hernández, Bruno Paiva, Maria Teresa Cedena Romero, Noemi Puig, Juan-José Lahuerta, Joan Bladé, Jesús San-Miguel, and Maria-Victoria Mateos
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
11. Curative Strategy (GEM-CESAR) for High-Risk Smoldering Myeloma (SMM): Post-Hoc Analysis of Sustained Undetectable Measurable Residual Disease (MRD)
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Maria-Victoria Mateos, Joaquín Martínez-López, Paula Rodríguez-Otero, Jesús San-Miguel, Veronica Gonzalez-Calle, Marta Sonia Gonzalez, Albert Oriol, Norma C. Gutierrez, Rafael Rios, Laura Rosinol Dachs, Miguel Angel Alvarez, Joan Bargay, Ana Pilar Gonzalez, Fernando Escalante, Adrian Alegre, Belén Iñigo, Javier de la Rubia, Ana Isabel Teruel, Felipe De Arriba, Luis Palomera, Miguel-Teodoro Hernández, Javier Lopez Jimenez, Marta Reinoso Segura, Aránzazu García Mateo, Enrique M. Ocio, Joan Bladé, Juan-José Lahuerta, María Teresa Cedena, Noemi Puig, and Bruno Paiva
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
12. Multiomics Profiling of Measurable Residual Disease (MRD) for Understanding the Biology of Ultra-Drug Resistance in Multiple Myeloma (MM)
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Camila Guerrero, Noemi Puig, Maria Teresa Cedena Romero, Ibai Goicoechea, Leire Burgos, Diego Alignani, Aitziber Lopez, Sarai Sarvide, María José Calasanz, Ramon Garcia-Sanz, Joaquin Martinez-Lopez, Laura Rosiñol, Esther González Garcia, Albert Oriol, Rafael Rios, Estrella Carrillo-Cruz, Marta Sonia Gonzalez Perez, Carmen Montes Gaisan, Felipe De Arriba, Jose Maria Arguiñano, Josep M Marti, Yolanda Gonzalez-Montes, Antonio Garcia-Guiñon, Juan-José Lahuerta, Joan Bladé Creixenti, Maria-Victoria Mateos, Jesús San-Miguel, and Bruno Paiva
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
13. Supplementary Figure from A Machine Learning Model Based on Tumor and Immune Biomarkers to Predict Undetectable MRD and Survival Outcomes in Multiple Myeloma
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Bruno Paiva, Jesus F. San-Miguel, Maria-Victoria Mateos, Joan Blade, Laura Rosiñol, Juan-José Lahuerta, Joaquin Martinez-Lopez, Marta-Sonia Gonzalez-Perez, Adrian Mosquera-Orgueira, Ana Pilar Gonzalez-Rodriguez, Luis Palomera, Felipe de Arriba, Joan Bargay, Rafael Martinez-Martinez, Miguel-Teodoro Hernandez, Rafael Rios, Albert Oriol, Maria-Luisa Martin-Ramos, Norma C. Gutierrez, Maria-Jose Calasanz, Cirino Botta, Juan-José Garcés, Cristina Perez, Ibai Goicoechea, Maria-Teresa Cedena, Noemi Puig, and Camila Guerrero
- Abstract
Supplementary Figure from A Machine Learning Model Based on Tumor and Immune Biomarkers to Predict Undetectable MRD and Survival Outcomes in Multiple Myeloma
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- 2023
14. Data from A Machine Learning Model Based on Tumor and Immune Biomarkers to Predict Undetectable MRD and Survival Outcomes in Multiple Myeloma
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Bruno Paiva, Jesus F. San-Miguel, Maria-Victoria Mateos, Joan Blade, Laura Rosiñol, Juan-José Lahuerta, Joaquin Martinez-Lopez, Marta-Sonia Gonzalez-Perez, Adrian Mosquera-Orgueira, Ana Pilar Gonzalez-Rodriguez, Luis Palomera, Felipe de Arriba, Joan Bargay, Rafael Martinez-Martinez, Miguel-Teodoro Hernandez, Rafael Rios, Albert Oriol, Maria-Luisa Martin-Ramos, Norma C. Gutierrez, Maria-Jose Calasanz, Cirino Botta, Juan-José Garcés, Cristina Perez, Ibai Goicoechea, Maria-Teresa Cedena, Noemi Puig, and Camila Guerrero
- Abstract
Purpose:Undetectable measurable residual disease (MRD) is a surrogate of prolonged survival in multiple myeloma. Thus, treatment individualization based on the probability of a patient achieving undetectable MRD with a singular regimen could represent a new concept toward personalized treatment, with fast assessment of its success. This has never been investigated; therefore, we sought to define a machine learning model to predict undetectable MRD at the onset of multiple myeloma.Experimental Design:This study included 487 newly diagnosed patients with multiple myeloma. The training (n = 152) and internal validation cohorts (n = 149) consisted of 301 transplant-eligible patients with active multiple myeloma enrolled in the GEM2012MENOS65 trial. Two external validation cohorts were defined by 76 high-risk transplant-eligible patients with smoldering multiple myeloma enrolled in the Grupo Español de Mieloma(GEM)-CESAR trial, and 110 transplant-ineligible elderly patients enrolled in the GEM-CLARIDEX trial.Results:The most effective model to predict MRD status resulted from integrating cytogenetic [t(4;14) and/or del(17p13)], tumor burden (bone marrow plasma cell clonality and circulating tumor cells), and immune-related biomarkers. Accurate predictions of MRD outcomes were achieved in 71% of cases in the GEM2012MENOS65 trial (n = 214/301) and 72% in the external validation cohorts (n = 134/186). The model also predicted sustained MRD negativity from consolidation onto 2 years maintenance (GEM2014MAIN). High-confidence prediction of undetectable MRD at diagnosis identified a subgroup of patients with active multiple myeloma with 80% and 93% progression-free and overall survival rates at 5 years.Conclusions:It is possible to accurately predict MRD outcomes using an integrative, weighted model defined by machine learning algorithms. This is a new concept toward individualized treatment in multiple myeloma.See related commentary by Pawlyn and Davies, p. 2482
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- 2023
15. Supplementary Data from A Machine Learning Model Based on Tumor and Immune Biomarkers to Predict Undetectable MRD and Survival Outcomes in Multiple Myeloma
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Bruno Paiva, Jesus F. San-Miguel, Maria-Victoria Mateos, Joan Blade, Laura Rosiñol, Juan-José Lahuerta, Joaquin Martinez-Lopez, Marta-Sonia Gonzalez-Perez, Adrian Mosquera-Orgueira, Ana Pilar Gonzalez-Rodriguez, Luis Palomera, Felipe de Arriba, Joan Bargay, Rafael Martinez-Martinez, Miguel-Teodoro Hernandez, Rafael Rios, Albert Oriol, Maria-Luisa Martin-Ramos, Norma C. Gutierrez, Maria-Jose Calasanz, Cirino Botta, Juan-José Garcés, Cristina Perez, Ibai Goicoechea, Maria-Teresa Cedena, Noemi Puig, and Camila Guerrero
- Abstract
Supplementary Data from A Machine Learning Model Based on Tumor and Immune Biomarkers to Predict Undetectable MRD and Survival Outcomes in Multiple Myeloma
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- 2023
16. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis
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Kastritis E., Palladini G., Minnema M. C., Wechalekar A. D., Jaccard A., Lee H. C., Sanchorawala V., Gibbs S., Mollee P., Venner C. P., Lu J., Schonland S., Gatt M. E., Suzuki K., Kim K., Cibeira M. T., Beksac M., Libby E., Valent J., Hungria V., Wong S. W., Rosenzweig M., Bumma N., Huart A., Dimopoulos M. A., Bhutani D., Waxman A. J., Goodman S. A., Zonder J. A., Lam S., Song K., Hansen T., Manier S., Roeloffzen W., Jamroziak K., Kwok F., Shimazaki C., Kim J. -S., Crusoe E., Ahmadi T., Tran N., Qin X., Vasey S. Y., Tromp B., Schecter J. M., Weiss B. M., Zhuang S. H., Vermeulen J., Merlini G., Comenzo R. L., Bradley Augustson, Fiona Kwok, Peter Mollee, Simon Gibbs, Chantal Doyen, Greet Bries, Isabelle Vande Broek, Ka Lung Wu, Koen Theunissen, Koen Van Eygen, Michel Delforge, Nathalie Meuleman, Philip Vlummens, Angelo Maiolino, Breno Moreno de Gusmão, Carlos Eduardo Miguel, Edvan Crusoe, Fernanda Moura, Fernanda Seguro, Jandey Bigonha, Juliane Musacchio, Karla Zanella, Laura Garcia, Marcelo Eduardo Zanella Capra, Reijane Alves de Assis, Rosane Bittencourt, Vania Hungria, Walter Braga, Wolney Barreto, Christopher Venner, Donna Reece, Emilie Lemieux-Blanchard, Kevin Song, Michael Sebag, Selay Lam, Victor Zepeda, Haitao Zhang, Jianda Hu, Jin Lu, Juan Li, Songfu Jiang, Ting Niu, Wenming Chen, Xiaonong Chen, Zhen Cai, Zhou Fude, Maja Oelholm Vase, Morten Salomo, Niels Abildgaard, Alain Fuzibet, Anne-Marie Stoppa, Arnaud Jaccard, Bertrand Arnulf, Bruno Moulin, Bruno Royer, David Ghez, Denis Caillot, Dominique Chauveau, Franck Bridoux, Lauriane Clement-Filliatre, Lionel Karlin, Lotfi Benboubker, Mamoun Dib, Margaret Macro, Mohamad Mohty, Olivier Decaux, Olivier Hermine, Olivier Tournilhac, Philippe Moreau, Salomon Manier, Sylvain Choquet, Véronique Dorvaux, Alexander Carpinteiro, Axel Nogai, Britta Besemer, Christoph Roellig, Roland Fenk, Stefan Knop, Stefan Schönland, Timon Hansen, Argiris Symeonidis, Efstathios Kastritis, Gabor Mikala, Tamás Masszi, Zsolt Nagy, Celia Suriu, Hila Magen, Iuliana Vaxman, Lev Shvidel, Meir Preis, Moshe Gatt, Noa Lavi, Osnat Jarchowsky, Tamar Tadmor, Yael Cohen, Angelo Vacca, Giovanni Palladini, Mario Boccadoro, Maurizio Martelli, Maurizio Musso, Michele Cavo, Chihiro Shimazaki, Hiroyuki Takamatsu, Kazutaka Sunami, Kenshi Suzuki, Nagaaki Katoh, Shinsuke Iida, Takayuki Ikezoe, Tomoaki Fujisaki, Yuta Katayama, Chang Ki Min, Ho-Jin Shin, Jin Seok Kim, Jung Yong Hong, Ki Hyun Kim, Sung-Soo Yoon, Aline Ramirez, Alvaro Cabrera, Christian Ramos, David Gomez Almaguer, Deborah Martinez, Guillermo Ruiz, Helen Dayani Caballero, Juan Antonio Flores Jimenez, Annemiek Broijl, Laurens Nieuwenhuizen, Monique Minnema, Paula Ypma, Wilfried Roeloffzen, Dominik Dytfeld, Grzegorz Charlinski, Grzegorz Helbig, Krzysztof Jamroziak, Sebastian Grosicki, Wieslaw Jedrzejczak, Albert Oriol Rocafiguera, Elham Askari, Fernando Escalante Barrigon, Isabel Krsnik Castello, Javier De la Rubia Comos, Jesus Martin Sanchez, Joaquin Martinez Lopez, Jose Angel Hernandez Rivas, Luis Felipe Casado Montero, Maria Jesus Blanchard Rodriguez, Maria Teresa Cibeira Lopez, Maria Victoria Mateos Manteca, Marta Sonia Gonzalez Perez, Mercedes Gironella Mesa, Rafael Rios Tamayo, Ramon Lecumberri Villamediana, Ricarda Garcia Sanchez, Sunil Lakhwani, Yolanda Gonzalez, Hareth Nahi, Kristina Carlsson, Markus Hansson, Ulf-Henrik Mellqvist, Ali Unal, Burhan Ferhanoglu, Hayri Ozsan, Levent Undar, Mehmet Turgut, Mehmet Yilmaz, Meral Beksac, Muhlis Cem Ar, Muzaffer Demir, Sevgi Besisik, Ashutosh Wechalekar, Jamie Cavenagh, Jim Cavet, Mark Cook, Rachel Hall, Adam Waxman, Anuj Mahindra, Cesar Rodriguez Valdes, Christine Ye, Craig Reeder, Daphne Friedman, David Siegel, Divaya Bhutani, Edward Libby, Eva Medvedova, Frank Passero, Giada Bianchi, Giampaolo Talamo, Guido Tricot, Hans Lee, Heather Landau, Jan Moreb, Jason Valent, Jeffrey Matous, Jeffrey A Zonder, Jesus Berdeja, Jonathan Kaufman, Keith Stockerl-Goldstein, Keren Osman, Ketan Doshi, Kevin Barton, Larry Anderson, Manisha Bhutani, Mehmet Kocoglu, Michael Rosenzweig, Michael Schuster, Michaela Liedtke, Morie Gertz, Naresh Bumma, Natalie Callander, Raymond Comenzo, Robert Vescio, Roger Pearse, Sandy W Wong, Stacey A Goodman, Stefano Tarantolo, Taimur Sher, Tibor Kovacsovics, Tomer Mark, Vaishali Sanchorawala, William Bensinger, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne (UCA), Kastritis E., Palladini G., Minnema M.C., Wechalekar A.D., Jaccard A., Lee H.C., Sanchorawala V., Gibbs S., Mollee P., Venner C.P., Lu J., Schonland S., Gatt M.E., Suzuki K., Kim K., Cibeira M.T., Beksac M., Libby E., Valent J., Hungria V., Wong S.W., Rosenzweig M., Bumma N., Huart A., Dimopoulos M.A., Bhutani D., Waxman A.J., Goodman S.A., Zonder J.A., Lam S., Song K., Hansen T., Manier S., Roeloffzen W., Jamroziak K., Kwok F., Shimazaki C., Kim J.-S., Crusoe E., Ahmadi T., Tran N., Qin X., Vasey S.Y., Tromp B., Schecter J.M., Weiss B.M., Zhuang S.H., Vermeulen J., Merlini G., and Comenzo R.L., Bradley Augustson, Fiona Kwok, Peter Mollee, Simon Gibbs, Chantal Doyen, Greet Bries, Isabelle Vande Broek, Ka Lung Wu, Koen Theunissen, Koen Van Eygen, Michel Delforge, Nathalie Meuleman, Philip Vlummens, Angelo Maiolino, Breno Moreno de Gusmão, Carlos Eduardo Miguel, Edvan Crusoe, Fernanda Moura, Fernanda Seguro, Jandey Bigonha, Juliane Musacchio, Karla Zanella, Laura Garcia, Marcelo Eduardo Zanella Capra, Reijane Alves de Assis, Rosane Bittencourt, Vania Hungria, Walter Braga, Wolney Barreto, Christopher Venner, Donna Reece, Emilie Lemieux-Blanchard, Kevin Song, Michael Sebag, Selay Lam, Victor Zepeda, Haitao Zhang, Jianda Hu, Jin Lu, Juan Li, Songfu Jiang, Ting Niu, Wenming Chen, Xiaonong Chen, Zhen Cai, Zhou Fude, Maja Oelholm Vase, Morten Salomo, Niels Abildgaard, Alain Fuzibet, Anne-Marie Stoppa, Arnaud Jaccard, Bertrand Arnulf, Bruno Moulin, Bruno Royer, David Ghez, Denis Caillot, Dominique Chauveau, Franck Bridoux, Lauriane Clement-Filliatre, Lionel Karlin, Lotfi Benboubker, Mamoun Dib, Margaret Macro, Mohamad Mohty, Olivier Decaux, Olivier Hermine, Olivier Tournilhac, Philippe Moreau, Salomon Manier, Sylvain Choquet, Véronique Dorvaux, Alexander Carpinteiro, Axel Nogai, Britta Besemer, Christoph Roellig, Roland Fenk, Stefan Knop, Stefan Schönland, Timon Hansen, Argiris Symeonidis, Efstathios Kastritis, Gabor Mikala, Tamás Masszi, Zsolt Nagy, Celia Suriu, Hila Magen, Iuliana Vaxman, Lev Shvidel, Meir Preis, Moshe Gatt, Noa Lavi, Osnat Jarchowsky, Tamar Tadmor, Yael Cohen, Angelo Vacca, Giovanni Palladini, Mario Boccadoro, Maurizio Martelli, Maurizio Musso, Michele Cavo, Chihiro Shimazaki, Hiroyuki Takamatsu, Kazutaka Sunami, Kenshi Suzuki, Nagaaki Katoh, Shinsuke Iida, Takayuki Ikezoe, Tomoaki Fujisaki, Yuta Katayama, Chang Ki Min, Ho-Jin Shin, Jin Seok Kim, Jung Yong Hong, Ki Hyun Kim, Sung-Soo Yoon, Aline Ramirez, Alvaro Cabrera, Christian Ramos, David Gomez Almaguer, Deborah Martinez, Guillermo Ruiz, Helen Dayani Caballero, Juan Antonio Flores Jimenez, Annemiek Broijl, Laurens Nieuwenhuizen, Monique Minnema, Paula Ypma, Wilfried Roeloffzen, Dominik Dytfeld, Grzegorz Charlinski, Grzegorz Helbig, Krzysztof Jamroziak, Sebastian Grosicki, Wieslaw Jedrzejczak, Albert Oriol Rocafiguera, Elham Askari, Fernando Escalante Barrigon, Isabel Krsnik Castello, Javier De la Rubia Comos, Jesus Martin Sanchez, Joaquin Martinez Lopez, Jose Angel Hernandez Rivas, Luis Felipe Casado Montero, Maria Jesus Blanchard Rodriguez, Maria Teresa Cibeira Lopez, Maria Victoria Mateos Manteca, Marta Sonia Gonzalez Perez, Mercedes Gironella Mesa, Rafael Rios Tamayo, Ramon Lecumberri Villamediana, Ricarda Garcia Sanchez, Sunil Lakhwani, Yolanda Gonzalez, Hareth Nahi, Kristina Carlsson, Markus Hansson, Ulf-Henrik Mellqvist, Ali Unal, Burhan Ferhanoglu, Hayri Ozsan, Levent Undar, Mehmet Turgut, Mehmet Yilmaz, Meral Beksac, Muhlis Cem Ar, Muzaffer Demir, Sevgi Besisik, Ashutosh Wechalekar, Jamie Cavenagh, Jim Cavet, Mark Cook, Rachel Hall, Adam Waxman, Anuj Mahindra, Cesar Rodriguez Valdes, Christine Ye, Craig Reeder, Daphne Friedman, David Siegel, Divaya Bhutani, Edward Libby, Eva Medvedova, Frank Passero, Giada Bianchi, Giampaolo Talamo, Guido Tricot, Hans Lee, Heather Landau, Jan Moreb, Jason Valent, Jeffrey Matous, Jeffrey A Zonder, Jesus Berdeja, Jonathan Kaufman, Keith Stockerl-Goldstein, Keren Osman, Ketan Doshi, Kevin Barton, Larry Anderson, Manisha Bhutani, Mehmet Kocoglu, Michael Rosenzweig, Michael Schuster, Michaela Liedtke, Morie Gertz, Naresh Bumma, Natalie Callander, Raymond Comenzo, Robert Vescio, Roger Pearse, Sandy W Wong, Stacey A Goodman, Stefano Tarantolo, Taimur Sher, Tibor Kovacsovics, Tomer Mark, Vaishali Sanchorawala, William Bensinger
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Male ,Treatment outcome ,Immunoglobulin Light-chain Amyloidosis/drug therapy ,CD38 ,Dexamethasone ,Cyclophosphamide/administration & dosage ,Bortezomib ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,CRITERIA ,Immunoglobulin Light-chain Amyloidosis ,ComputingMilieux_MISCELLANEOUS ,Aged, 80 and over ,biology ,Amyloidosis ,Antibodies, Monoclonal ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,General Medicine ,Middle Aged ,3. Good health ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,Antibody ,Human ,Adult ,Dexamethasone/administration & dosage ,ANTIBODY DARATUMUMAB ,Immunoglobulin light chain ,DIAGNOSIS ,Antibodies, Monoclonal/administration & dosage ,Disease-Free Survival ,03 medical and health sciences ,Humans ,Cyclophosphamide ,Aged ,Antineoplastic Combined Chemotherapy Protocol ,business.industry ,Antineoplastic Combined Chemotherapy Protocols/adverse effects ,AL AMYLOIDOSIS ,Daratumumab ,Amyloid fibril ,medicine.disease ,Molecular biology ,Immunoglobulin Light-chain Amyloidosi ,biology.protein ,Bortezomib/administration & dosage ,business ,030215 immunology - Abstract
Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease.We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response.A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy.Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).
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- 2021
17. A machine learning model based on tumor and immune biomarkers to predict undetectable MRD and survival outcomes in multiple myeloma
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Camila Guerrero, Noemi Puig, Maria-Teresa Cedena, Ibai Goicoechea, Cristina Perez, Juan-José Garcés, Cirino Botta, Maria-Jose Calasanz, Norma C. Gutierrez, Maria-Luisa Martin-Ramos, Albert Oriol, Rafael Rios, Miguel-Teodoro Hernandez, Rafael Martinez-Martinez, Joan Bargay, Felipe de Arriba, Luis Palomera, Ana Pilar Gonzalez-Rodriguez, Adrian Mosquera-Orgueira, Marta-Sonia Gonzalez-Perez, Joaquin Martinez-Lopez, Juan-José Lahuerta, Laura Rosiñol, Joan Blade, Maria-Victoria Mateos, Jesus F. San-Miguel, Bruno Paiva, Guerrero, Camila, Puig, Noemi, Cedena, Maria-Teresa, Goicoechea, Ibai, Perez, Cristina, Garces, Juan-Jose, Botta, Cirino, Calasanz, Maria-Jose, Gutierrez, Norma C, Martin-Ramos, Maria-Luisa, Oriol, Albert, Rios, Rafael, Hernandez, Miguel-Teodoro, Martinez-Martinez, Rafael, Bargay, Joan, de Arriba, Felipe, Palomera, Lui, Gonzalez-Rodriguez, Ana Pilar, Mosquera-Orgueira, Adrian, Gonzalez-Perez, Marta-Sonia, Martinez-Lopez, Joaquin, Lahuerta, Juan-Jose, Rosiñol, Laura, Blade, Joan, Mateos, Maria-Victoria, San Miguel, Jesus F, and Paiva, Bruno
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Machine Learning ,Survival Rate ,multiple myeloma ,Cancer Research ,Neoplasm, Residual ,MRD ,Oncology ,immunomonitoring ,Humans ,Biomarkers ,Aged ,machine learning - Abstract
Purpose: Undetectable measurable residual disease (MRD) is a surrogate of prolonged survival in multiple myeloma. Thus, treatment individualization based on the probability of a patient achieving undetectable MRD with a singular regimen could represent a new concept toward personalized treatment, with fast assessment of its success. This has never been investigated; therefore, we sought to define a machine learning model to predict undetectable MRD at the onset of multiple myeloma. Experimental Design: This study included 487 newly diagnosed patients with multiple myeloma. The training (n = 152) and internal validation cohorts (n = 149) consisted of 301 transplant-eligible patients with active multiple myeloma enrolled in the GEM2012MENOS65 trial. Two external validation cohorts were defined by 76 high-risk transplant-eligible patients with smoldering multiple myeloma enrolled in the Grupo Español de Mieloma(GEM)-CESAR trial, and 110 transplant-ineligible elderly patients enrolled in the GEM-CLARIDEX trial. Results: The most effective model to predict MRD status resulted from integrating cytogenetic [t(4;14) and/or del(17p13)], tumor burden (bone marrow plasma cell clonality and circulating tumor cells), and immune-related biomarkers. Accurate predictions of MRD outcomes were achieved in 71% of cases in the GEM2012MENOS65 trial (n = 214/301) and 72% in the external validation cohorts (n = 134/186). The model also predicted sustained MRD negativity from consolidation onto 2 years maintenance (GEM2014MAIN). High-confidence prediction of undetectable MRD at diagnosis identified a subgroup of patients with active multiple myeloma with 80% and 93% progression-free and overall survival rates at 5 years. Conclusions: It is possible to accurately predict MRD outcomes using an integrative, weighted model defined by machine learning algorithms. This is a new concept toward individualized treatment in multiple myeloma. See related commentary by Pawlyn and Davies, p. 2482
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- 2022
18. Single versus tandem autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma and high-risk cytogenetics. A retrospective, open-label study of the PETHEMA/Spanish Myeloma Group (GEM)
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Ana Villalba, Ana Pilar Gonzalez-Rodriguez, Javier Arzuaga-Mendez, Noemí Puig, Mario Arnao, José María Arguiñano, María Jimenez, Marta Canet, Ana I. Teruel, María Sola, Francisco J. Díaz, Cristina Encinas, Antonio Garcia, Laura Rosiñol, Alexia Suárez, Marta Sonia Gonzalez, Isabel Izquierdo, Miguel Teodoro Hernández, María Stefania Infante, María José Sánchez, Antonia Sampol, and Javier de la Rubia
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Cancer Research ,Tandem transplantation ,autologous stem cell transplantation ,Oncology ,High-risk cytogenetics ,Multiple myeloma ,tandem transplantation ,Hematology ,Autologous stem cell transplantation ,high-risk cytogenetics - Abstract
Tandem ASCT has been suggested as a valid approach to improve the prognosis of patients with MM and HR cytogenetic. In this observational, retrospective study, 213 patients with newly diagnosed MM and HR cytogenetic in 35 hospitals from the Spanish Myeloma Group underwent single or tandem ASCT between January 2015 and December 2019 after induction with VTD/VRD. HR cytogenetic was defined as having =1 of the following: del17p, t(4;14), t(14;16) or gain 1q21. More patients in the tandem group had R-ISS 3 and >1 cytogenetic abnormality at diagnosis. With a median follow-up of 31 months (range, 10-82), PFS after single ASCT was 41 months versus 48 months with tandem ASCT (p = 0.33). PFS in patients with del17p undergoing single ASCT was 41 months, while 52% of patients undergoing tandem ASCT were alive and disease free at 48 months. In conclusion, tandem ASCT partly overcomes the bad prognosis of HR cytogenetic.
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- 2022
19. Refining risk prediction in pediatric acute lymphoblastic leukemia through DNA methylation profiling
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Adrián Mosquera Orgueira, Olga Krali, Carlos Pérez Míguez, Andrés Peleteiro Raíndo, José Ángel Díaz Arias, Marta Sonia González Pérez, Manuel Mateo Pérez Encinas, Manuel Fernández Sanmartín, Daniel Sinnet, Mats Heyman, Gudmar Lönnerholm, Ulrika Norén-Nyström, Kjeld Schmiegelow, and Jessica Nordlund
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Pediatric acute lymphoblastic leukemia ,Epigenetics ,DNA methylation ,Machine learning ,Artificial intelligence ,Relapse risk ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Acute lymphoblastic leukemia (ALL) is the most prevalent cancer in children, and despite considerable progress in treatment outcomes, relapses still pose significant risks of mortality and long-term complications. To address this challenge, we employed a supervised machine learning technique, specifically random survival forests, to predict the risk of relapse and mortality using array-based DNA methylation data from a cohort of 763 pediatric ALL patients treated in Nordic countries. The relapse risk predictor (RRP) was constructed based on 16 CpG sites, demonstrating c-indexes of 0.667 and 0.677 in the training and test sets, respectively. The mortality risk predictor (MRP), comprising 53 CpG sites, exhibited c-indexes of 0.751 and 0.754 in the training and test sets, respectively. To validate the prognostic value of the predictors, we further analyzed two independent cohorts of Canadian (n = 42) and Nordic (n = 384) ALL patients. The external validation confirmed our findings, with the RRP achieving a c-index of 0.667 in the Canadian cohort, and the RRP and MRP achieving c-indexes of 0.529 and 0.621, respectively, in an independent Nordic cohort. The precision of the RRP and MRP models improved when incorporating traditional risk group data, underscoring the potential for synergistic integration of clinical prognostic factors. The MRP model also enabled the definition of a risk group with high rates of relapse and mortality. Our results demonstrate the potential of DNA methylation as a prognostic factor and a tool to refine risk stratification in pediatric ALL. This may lead to personalized treatment strategies based on epigenetic profiling.
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- 2024
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20. A Machine Learning Model Based on Tumor and Immune Biomarkers to Predict Undetectable Measurable Residual Disease (MRD) in Transplant-Eligible Multiple Myeloma (MM)
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Camila Guerrero, Noemi Puig, María Teresa Cedena, Ibai Goicoechea, Cristina Pérez Ruiz, Juan José Garcés, Cirino Botta, Maria Jose Calasanz, Norma C. Gutierrez, Maria Luisa Martin-Ramos, Albert Oriol, Rafael Rios, Miguel Hernández, Rafael Martínez, Joan Bargay, Felipe De Arriba, Luis Palomera, Ana Pilar Gonzalez, Adrián Mosquera Orgueira, Marta Sonia Gonzalez, Joaquín Martínez-López, Juan Jose Lahuerta, Laura Rosinol, Joan Bladé Creixenti, Maria-Victoria Mateos, Jesus San-Miguel, and Bruno Paiva
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
INTRODUCTION: There is expectation of using biomarkers to personalize treatment in MM. Yet, a successful treatment selection cannot be confirmed before 5 or 10 years of progression-free survival (PFS). Treatment individualization based on the probability of an individual patient to achieve undetectable MRD with a singular regimen, could represent a new model towards personalized treatment with fast assessment of its success. This idea has not been investigated previously. AIM: Develop a machine learning model to predict undetectable MRD in newly-diagnosed transplant-eligible MM patients, treated with a standard of care. METHODS: This study included a total of 278 newly-diagnosed and transplant-eligible MM patients treated with proteasome inhibitors, immunomodulatory drugs and corticosteroids. The training (n=152) and internal validation cohort (n=60) consisted of 212 active MM patients enrolled in the GEM2012MENOS65 trial. The external validation cohort was defined by 66 high-risk smoldering MM patients enrolled in the GEM-CESAR trial, which treatment differed only by the substitution of bortezomib by carfilzomib during induction and consolidation. RESULTS: We started by investigating patients' MRD status after VRD induction, HDT/ASCT and VRD consolidation according to their ISS and R-ISS, LDH levels, and cytogenetic alterations. Surprisingly, neither the ISS nor the R-ISS predicted significantly different MRD outcomes. Indeed, high LDH levels and del(17p13) were the only parameters associated with lower rates of undetectable MRD. Because these two features are relatively infrequent at diagnosis, we next aimed to evaluate other disease features and develop integrative, weighted and more effective models based on machine learning algorithms. Of 37 clinical and biological parameters evaluated, 17 were associated with MRD outcomes. These were subsequently modeled using logistic regression for machine learning classification, where the sum of the weighted coefficients multiplied by its input variable, is transformed into a probability outcome that ranges from 0 to 1 using a logit sigmoid function. The most effective model resulted from integrating cytogenetic [t(4;14) and/or del(17p13)], tumor burden (plasma cell [PC] clonality in bone marrow and CTCs in blood) and immune related (myeloid precursors, mature B cells, intermediate neutrophils, eosinophils, CD27 negCD38 pos T cells and CD56 brightCD27 neg NK cells) biomarkers. Of note, immune biomarkers displayed the highest coefficient weights and were determinant to predict patients' MRD status in this model. Data obtained for an individual patient can be substituted into our formula, which results in a numerical probability of achieving undetectable (>0.5) vs persistent (0.685 or Patients predicted to achieve undetectable MRD using standard and high-confidence values showed longer PFS and overall survival (OS) than those with probability of persistent MRD. In fact, patients with >0.687 probability of achieving undetectable MRD showed 86% PFS and 94% OS at five years, whereas those in whom persistent MRD was predicted ( CONCLUSION: We demonstrated that it is possible to predict patients' MRD status with significant accuracy, using an integrative, weighted model based on machine learning algorithms. Although immune biomarkers are not commonly used, the raw data from which these can be developed is generally obtained in diagnostic laboratories using flow cytometry to screen for PC clonality. Furthermore, we made the model available to facilitate its use in clinical practice at www.MRDpredictor.com. Disclosures Puig: Celgene, Janssen, Amgen, Takeda: Research Funding; Celgene: Speakers Bureau; Amgen, Celgene, Janssen, Takeda: Consultancy; Amgen, Celgene, Janssen, Takeda and The Binding Site: Honoraria. Cedena: Janssen, Celgene and Abbvie: Honoraria. Oriol: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. De Arriba: Amgen: Consultancy, Honoraria; Glaxo Smith Kline: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; BMS-Celgene: Consultancy, Honoraria, Speakers Bureau. Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy; Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Lahuerta: Celgene: Other: Travel accomodations and expenses; Celgene, Takeda, Amgen, Janssen and Sanofi: Consultancy. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Bladé Creixenti: Janssen, Celgene, Takeda, Amgen and Oncopeptides: Honoraria. Mateos: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Bluebird bio: Honoraria; GSK: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: 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; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Paiva: Bristol-Myers Squibb-Celgene, Janssen, and Sanofi: Consultancy; Adaptive, Amgen, Bristol-Myers Squibb-Celgene, Janssen, Kite Pharma, Sanofi and Takeda: Honoraria; Celgene, EngMab, Roche, Sanofi, Takeda: Research Funding.
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- 2021
21. Curative Strategy (GEM-CESAR) for High-Risk Smoldering Myeloma (SMM): Carfilzomib, Lenalidomide and Dexamethasone (KRd) As Induction Followed By HDT-ASCT, Consolidation with Krd and Maintenance with Rd
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Maria-Victoria Mateos, Joaquin Martinez Lopez, Paula Rodríguez-Otero, Veronica Gonzalez-Calle, Marta Sonia Gonzalez, Albert Oriol, Norma C. Gutierrez, Rafael Rios, Laura Rosinol, Miguel Angel Alvarez, Joan Bargay, Ana Pilar Gonzalez, Adrian Alegre, Fernando Escalante, Belén Iñigo, Javier de la Rubia, Ana Isabel Teruel, Felipe De Arriba, Luis Palomera, Miguel-Teodoro Hernández, Javier Lopez Jimenez, Aránzazu García Mateo, Marta Reinoso Segura, Enrique Ocio, Bruno Paiva, Noemi Puig, María Teresa Cedena, Joan Bladé, Juan Jose Lahuerta, and Jesús F. San-Miguel
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Introduction: SMM is an asymptomatic plasma cell disorder with heterogeneous clinical behavior. Both the Spanish Myeloma and ECOG Groups have demonstrated that patients (pts) at high risk of progression to active MM have prolonged time-to progression upon receiving early treatment with R-based regimens. Our next step was to perform a phase 2, single arm trial, focusing on the same population, but aiming at abrogating the risk of progression through the achievement of sustained minimal residual disease negativity (MRD-ve) at 3 and 5 years after HDT-ASCT. Patients and methods: Ninety SMM pts at high-risk of progression (>50% at 2 yrs), younger than 70 years and transplant candidates were included. The high risk was defined by the presence of both ≥PC 10% and MC ≥3g/dL (Mayo criteria) or ifonly one criterion was present, pts should have >95%of aberrant PCs within the total PCsBM compartment by immunophenotyping plus immunoparesis (Spanish criteria). Induction therapy consisted of six 4-weeks cycles of KRd in which K was given at dose of 36 mg/m 2 twice per week plus R at dose of 25 mg on days 1-21 and dexamethasone at dose of 40 mg weekly. Melphalan at dose of 200 mg/m 2 followed by ASCT was given as intensification therapy followed by two KRd consolidation cycles and maintenance with R at dose of 10 mg plus dexamethasone at dose of 20 mg weekly for up to 2 yrs. The primary end-point was to evaluate the MRD-ve rate by next generation flow (NGF) after ASCT and MRD-ve rate maintained at 3 and 5 years after ASCT. Results: Between June 2015 and June 2017, 90 high-risk SMM pts were recruited and 70 pts (78%) have completed the treatment protocol. The reasons for early discontinuations were: IC withdrawal (4 pts), adverse events (8 pts) or biological progression (BP), either biochemical or because of MRD conversion from negative to positive (1 pt during induction and 7 pts during maintenance). Thirty-one pts (34%) shared at least one of the biomarkers considered as myeloma defining events that currently reclassify SMM into active MM. In the intent-to-treat (ITT) pts' population, after induction, the ≥CR rate was 41% and increased to 65% after HDT-ASCT and 72% after consolidation. During maintenance therapy, 7 pts experienced biological progression (2 pts conversion from MRD-ve into +ve and 5 pts biochemical progression) and the ≥CR rate at the end of treatment was 63.3%. In the ITT population, MRD-ve rates at 10 -5 were observed in 40% of pts after induction, 63% after HDT-ASCT, 68% after consolidation and 52% after maintenance therapy. Among MRD-ve patients after maintenance therapy that had MRD assessed one year after, 67% showed sustained MRD-ve. After a median f/u of 55 months (range: 6.2-71), only three patients progressed to symptomatic disease and the three had at baseline anyone of the biomarkers defining myeloma-defining events. At 5 years, 94% of pts remain alive and progression-free and 95% of pts alive (Figure 1). Overall, twenty-six pts (29%) have experienced biological progression (19 of them were conversion of MRD-ve into +ve), 8 of them during treatment phase (1 during induction and 7 during maintenance) and 16 pts during the follow-up period. The only factors predicting biological progression was failure to achieve MRD-ve at the end of treatment and unsustained MRD-ve at 1 year after finalizing maintenance. Concerning toxicity, during induction, G3-4 neutropenia and thrombocytopenia were reported in 5 (6%) and 10 pts (11%), respectively. G3-4 infections were reported in 16 pts (18%), followed by skin rash in 8 pts (9%). One patient reported G1 atrial fibrillation and another cardiac failure secondary to respiratory infection. Three pts reported hypertension (G2 in two and G3 in one). In all but two of the pts, PBSC collection was successful with a median of 4.10 x 10 6/Kg CD34 cells collected. All pts engrafted but one patient developed late graft failure. During consolidation, 2 pts developed G3-4 neutropenia, 3 pts G3-4 infections and 1 pt skin rash. Seven pts had to discontinue maintenance therapy due to: G3-4 hematological toxicity (4 pts), SPM (2pts) and cardiac arrest (1pt). One additional patient withdrew the IC. Conclusions: These results suggest that early treatment with intention to abrogate risk of progression in transplant candidate high risk SMM patients is associated with a 94% PFS at 55 months and a sustained MRD negative rate at 1 year post treatment of 67%. Figure 1 Figure 1. Disclosures Mateos: Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: 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; Bluebird bio: Honoraria; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Oncopeptides: Honoraria. Rodríguez-Otero: Celgene-BMS, Janssen, Amgen, Sanofi, GSK, Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria. Gonzalez-Calle: BMS, Janssen, Amgen: Honoraria. Oriol: Celgene: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. de la Rubia: Takeda: Consultancy; Amgen, Bristol Myers Squibb,: Honoraria, Speakers Bureau; GSK: Consultancy; Celgene, Takeda, Janssen, Sanofi: Honoraria; Ablynx/Sanofi: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations; Celgene: Consultancy; AbbVie: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Sanofi: Membership on an entity's Board of Directors or advisory committees. De Arriba: Amgen: Consultancy, Honoraria; Glaxo Smith Kline: Consultancy, Honoraria; BMS-Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Ocio: MSD: Honoraria; Sanofi: Consultancy, Honoraria; Karyopharm: Consultancy; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Pfizer: Consultancy; Secura-Bio: Consultancy. Paiva: Bristol-Myers Squibb-Celgene, Janssen, and Sanofi: Consultancy; Adaptive, Amgen, Bristol-Myers Squibb-Celgene, Janssen, Kite Pharma, Sanofi and Takeda: Honoraria; Celgene, EngMab, Roche, Sanofi, Takeda: Research Funding. Puig: Celgene, Janssen, Amgen, Takeda: Research Funding; Celgene: Speakers Bureau; Amgen, Celgene, Janssen, Takeda: Consultancy; Amgen, Celgene, Janssen, Takeda and The Binding Site: Honoraria. Cedena: Janssen, Celgene and Abbvie: Honoraria. Lahuerta: Celgene: Other: Travel accomodations and expenses; Celgene, Takeda, Amgen, Janssen and Sanofi: Consultancy. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, Takeda: Consultancy, Other: Advisory board.
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- 2021
22. Selinexor, daratumumab, bortezomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma: results of the phase II, non-randomized, multicenter GEM-SELIBORDARA study
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Verónica González-Calle, Paula Rodríguez-Otero, Anna Sureda, Felipe de Arriba, Marta Reinoso, Paz Ribas, Ana Pilar González-Rodríguez, Yolanda González, Albert Oriol, Joaquín Martínez-López, Marta Sonia González, Miguel T. Hernández, Maialen Sirvent, Teresa Cedena, Noemí Puig, Bruno Paiva, Joan Bladé, Juan José Lahuerta, Jesús F. San-Miguel, and María-Victoria Mateos
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
The treatment landscape for multiple myeloma has significantly evolved in the last decade. Notwithstanding, a large proportion of patients continue to relapse and novel combinations continue to be needed. In this phase 2 study, selinexor, a first-in-class inhibitor of exportin-1 was evaluated in combination with standard daratumumab-bortezomib-dexamethasone (DVd), for the treatment of relapsed and refractory multiple myeloma (RRMM). The aim of the trial was to assess the efficacy and safety of the combination of selinexor with DVd (S-DVd). A total of 57 patients were enrolled in the two parts of the study. Part 1 enrolled a heavily pretreated population with at least 3 prior lines of therapy and part 2 enrolled an early relapse population with at least 1 prior therapy. The primary endpoint was complete response (CR) rate in part 2 and overall response rate (ORR) in part 1. In the latter, 24 patients were treated with a median of 3 prior lines. Overall response rate (ORR) was 50% with 2 CR. Median progressionfree survival (PFS) was 7 months. In part 2, 33 patients were enrolled, with a median of 1 prior lines. ORR was 82% and CR or better was 33%. Median PFS was 24 months. In lenalidomide refractory patients, a median PFS of 22.1 months was observed. Thrombocytopenia was the most common hematological adverse event (69%; grade 3-4: 34%) and nausea, the most frequent nonhematological AE (38%; grade 3-4: 6%). 62% of the patients required dose modifications. In summary, although the primary endpoint of the study was not met, the combination of S-DVd showed encouraging clinical efficacy with a generally manageable safety profile representing a potential option for the treatment of RRMM patients.
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- 2024
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23. Improved Personalized Survival Prediction of Patients With Diffuse Large B-cell Lymphoma Using Gene Expression Profiling
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Orgueira, Adrián Mosquera, primary, Arias, José Ángel Díaz, additional, López, Miguel Cid, additional, Raindo, Andres Peleteiro, additional, Rodriguez, Beatriz Antelo, additional, Santos, Carlos Aliste, additional, Vence, Natalia Alonso, additional, Lopez, Angeles Bendaña, additional, Blanco, Aitor Abuin, additional, Perez, Laura Bao, additional, Perez, Marta Sonia Gonzalez, additional, Encinas, Manuel Mateo Perez, additional, Rodriguez, Maximo Francisco Fraga, additional, and Lopez, Jose Luis Bello, additional
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- 2020
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24. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study
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Michel Attal, Paul G Richardson, S Vincent Rajkumar, Jesus San-Miguel, Meral Beksac, Ivan Spicka, Xavier Leleu, Fredrik Schjesvold, Philippe Moreau, Meletios A Dimopoulos, Jeffrey Shang-Yi Huang, Jiri Minarik, Michele Cavo, H Miles Prince, Sandrine Macé, Kathryn P Corzo, Frank Campana, Solenn Le-Guennec, Franck Dubin, Kenneth C Anderson, Paul G. Richardson, Vincent Rajkumar, Meletios A. Dimopoulos, H. Miles Prince, Kathryn P. Corzo, Kenneth C. Anderson, Simon Harrison, Wojt Janowski, Ian Kerridge, Andrew Spencer, Michel Delforge, Karel Fostier, Philip Vlummens, Ka Lung Wu, Richard Leblanc, Michel Pavic, Michael Sebag, Roman Hajek, Vladimir Maisnar, Ludek Pour, Henrik Gregersen, Lotfi Benbouker, Denis Caillot, Martine Escoffre-Barbe, Thierry Facon, Laurent Frenzel, Cyrille Hulin, Lionel Karlin, Brigitte Kolb, Brigitte Pegourie, Aurore Perrot, Mourad Tiab, Laure Vincent, Dietger Niederwieser, Achilles Anagnostopoulos, Sosana Delimpasi, Marie-Christine Kyrtsonis, Anargyros Symeonidis, Arpad Illes, Gabor Mikala, Zsolt Nagy, Sara Bringen, Paolo Corradini, Ciceri Fabio, Roberto Lemoli, Anna Liberati, Chiara Nozzoli, Renato Zambello, Shinsuke Iida, Takashi Ikeda, Satoshi Iyama, Morio Matsumoto, Chihiro Shimazaki, Kazutaka Sunami, Kenshi Suzuki, Michihiro Uchiyama, Youngil Koh, Kihyun Kim, Jae Hoon Lee, Chang-Ki Min, Hillary Blacklock, Hugh Goodman, Annette Neylon, David Simpson, Sebastian Grosicki, Artur Jurczyszyn, Adam Walter-Croneck, Krzysztof Warzocha, Luis Araujo, Claudia Moreira, Vadim Doronin, Larisa Mendeleeva, Vladimir Vorobyev, Andrej Vranovsky, Adrian Alegre, Mercedes Gironella, Marta Sonia Gonzalez Perez, Carmen Montes, Enrique Ocio, Paula Rodriguez, Mats Hardling, Birgitta Lauri, Ming-Chung Wang, Su-Peng Yeh, Mutlu Arat, Fatih Demirkan, Zafer Gulbas, Sevgi Kalayoglu Besisik, Ihsan Karadogan, Tulin Tuglular, Ali Unal, Filiz Vural, Jonathan Sive, Matthew Streetly, Kwee Yong, Jason Tache, Attal, Michel, Richardson, Paul G, Rajkumar, S Vincent, San-Miguel, Jesu, Beksac, Meral, Spicka, Ivan, Leleu, Xavier, Schjesvold, Fredrik, Moreau, Philippe, Dimopoulos, Meletios A, Huang, Jeffrey Shang-Yi, Minarik, Jiri, Cavo, Michele, Prince, H Mile, Macé, Sandrine, Corzo, Kathryn P, Campana, Frank, Le-Guennec, Solenn, Dubin, Franck, Anderson, Kenneth C, and ICARIA-MM study group
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Male ,medicine.medical_specialty ,Asia ,030204 cardiovascular system & hematology ,Antibodies, Monoclonal, Humanized ,Gastroenterology ,Antibodies ,Dexamethasone ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Monoclonal ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,030212 general & internal medicine ,Progression-free survival ,Aged ,Antibodies, Monoclonal ,Europe ,Female ,Middle Aged ,Multiple Myeloma ,Neoplasm Recurrence, Local ,North America ,Progression-Free Survival ,Thalidomide ,Treatment Outcome ,Multiple myeloma ,Lenalidomide ,Isatuximab ,business.industry ,Bortezomib ,General Medicine ,Pomalidomide ,medicine.disease ,Neoplasm Recurrence ,Local ,business ,Isatuximab, pomalidomide, low-dose dexamethasone ,medicine.drug - Abstract
BACKGROUND: Isatuximab is a monoclonal antibody that binds a specific epitope on the human CD38 receptor and has antitumour activity via multiple mechanisms of action. In a previous phase 1b study, around 65% of patients with relapsed and refractory multiple myeloma achieved an overall response with a combination of isatuximab with pomalidomide and low-dose dexamethasone. The aim of this study was to determine the progression-free survival benefit of isatuximab plus pomalidomide and dexamethasone compared with pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma. METHODS: We did a randomised, multicentre, open-label, phase 3 study at 102 hospitals in 24 countries in Europe, North America, and the Asia-Pacific regions. Eligible participants were adult patients with relapsed and refractory multiple myeloma who had received at least two previous lines of treatment, including lenalidomide and a proteasome inhibitor. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. We randomly assigned patients (1:1) to either isatuximab 10 mg/kg plus pomalidomide 4 mg plus dexamethasone 40 mg (20 mg for patients aged ≥75 years), or pomalidomide 4 mg plus dexamethasone 40 mg. Randomisation was done using interactive response technology and stratified according to the number of previous lines of treatment (2-3 vs >3) and age (
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- 2019
25. Corrigendum: Evaluation of the Stellae-123 prognostic gene expression signature in acute myeloid leukemia
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Adrián Mosquera Orgueira, Andrés Peleteiro Raíndo, José Ángel Díaz Arias, Beatriz Antelo Rodríguez, Mónica López Riñón, Claudio Cerchione, Adolfo de la Fuente Burguera, Marta Sonia González Pérez, Giovanni Martinelli, Pau Montesinos Fernández, and Manuel Mateo Pérez Encinas
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leukemia ,transcriptome ,machine learning ,survival ,risk ,prediction ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
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26. Curativestategy (GEM-CESAR) for High-Risk Smoldering Myeloma (SMM): Carfilzomib, Lenalidomide and Dexamethasone (KRd) As Induction Followed By HDT-ASCT, Consolidation with Krd and Maintenance with Rd
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Maria-Victoria Mateos, Joaquin Martínez-López, Paula Rodriguez Otero, Enrique M. Ocio, Marta Sonia Gonzalez, Albert Oriol, Norma C. Gutierrez, Bruno Paiva, Rafael Rios, Laura Rosinol, Miguel Angel Alvarez, Maria Jose Calasanz, Joan Bargay, Ana Pilar Gonzalez, Adrián Alegre, Fernando Escalante, Rafael Martínez, Noemi Puig, Javier De La Rubia, Ana Isabel Teruel, María Teresa Cedena, Felipe De Arriba, Luis Palomera, Miguel T Hernández, Javier Lopez Jimenez, Jesús Martín, Esther Piensa, Aránzazu García Mateo, Veronica Gonzalez De La Calle, Joan Bladé, Juan Jose Lahuerta, and Jesus F San-Miguel
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Immunology ,Cell Biology ,Hematology ,Biochemistry ,health care economics and organizations - Abstract
Introduction:SMM is an asymptomatic and heterogeneous plasma cell disorder. The Spanish Myeloma Group demonstrated that patients at high risk of progression benefit from early treatment with Rd. In addition, our preliminary results of the curative approach (GEM-CESAR) showed encouraging results (Mateos ASH 2017). Aim: The primary end-point was to evaluate the Minimal Residual Disease negative (MRD-ve) rate by next generation flow (NGF) after induction and ASCT and the sustained MRD-ve rate at 3 and 5 yrs after ASCT as secondary end-points. Our aim was to increase the MRD -ve rate from 34% (reported in NDMM patients after VTD and ASCT) to 50%. As all patients have completed induction and ASCT, we report the results of the primary end point, efficacy and safety after induction and ASCT. Methods: In this phase II single arm trial, 90 SMM patients at high-risk of progression (>50% at 2 yrs), younger than 70 yrs and transplant candidates were included. The high risk was defined by the presence of both ≥PC 10% and MC ≥3g/dL (Mayo criteria) or ifonly one criterion was present, patients must have a proportionof aberrant PCs within the total PCsBM compartment by immunophenotypingof 95% plus immunoparesis (Spanish criteria). Asymptomatic MM patients with any of the three biomarkers recently included into the definition of active MM were allowed to be included. Induction therapy consisted on six 4-weeks cycles of KRd in which K was given at dose of 36 mg/m2twice per week plus R at dose of 25 mg on days 1-21 and dexamethasone at dose of 40 mg weekly. Melphalan at dose of 200 mg/m2followed by ASCT was given as intensification therapy and three months later, patients received two KRd consolidation cycles followed by maintenance with R at dose of 10 mg on days 1-21 plus dex at dose of 20 mg weekly for up to 2 yrs Results: Between June 2015 and June 2017, the 90 SMM patients at high risk of progression were recruited. Twenty-eight pts (32%) shared at least one of the new biomarkers predicting imminent risk of progression to MM. The primary end point of the trial was met, since 55% of the patients who completed induction and ASCT achieved MRD -ve by NGF (sensitivity 3 x 10-6). Upon analyzing the results after induction, 88 patients completed the 6 induction cycles and were evaluable for response (two patients early discontinued): the ORR was 98% including 41% of ≥CR (32% sCR and 9% CR) and 41% of VGPR rate. Two patients were mobilization failures and one patient rejected ASCT. Two additional patients experienced biological progression before ASCT and went off the study. Eighty-three patients, therefore, proceeded to HDT-ASCT and were evaluable at day +100: the ORR was 100% including ≥CR in 63% of the patients (51% sCR and 12% CR) and VGPR rate in 23%. The MRD-ve rate increased from 31% after induction to 55% with the ASCT. No differences in outcome have been observed according neither to the definition of high risk (Mayo or Spanish model) nor ultra high risk SMM. Concerning toxicity, during induction, G3-4 neutropenia and thrombocytopenia were reported in 5 (6%) and 10 pts (11%), respectively. G3-4 infections were the most frequent non-hematological AE observed in 16 pts (18%), followed by skin rash in 8 pts (9%). One patient reported G1 atrial fibrillation and another cardiac failure secondary to respiratory infection. Three patients reported hypertension (G2 in two and G3 in one). Thirteen patients required lenalidomide dose reduction whilst carfilzomib was not reduced in any patient. In four patients, dexamethasone was reduced. In all but two of the pts, PBSC collection was successful with a median of 4.10 x 106/Kg CD34 cells collected. All patients engrafted. Consolidation and maintenance phases are ongoing. After a median follow-up of 17 months (5-36), 94% of patients remain alive and free of progression and 97% of them alive. Three patients experienced biological progression and discontinued the study: one of them was refractory to the rescue therapies and died and the other two are receiving rescue therapies. One additional patient died early during induction due to a massive ischemic stroke unrelated to the treatment. Conclusions: Although longer follow-up is required, this "curative strategy for high risk SMM" continues being encouraging with an acceptable toxicity profile. The study has met its primary endpoint. The depth of response improved over the treatment: 63% of patients who completed induction and ASCT achieved ≥CR with a MRD-ve rate of 55%. Disclosures Mateos: Takeda: Consultancy, Honoraria, 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: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rodriguez Otero:Takeda: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Clínica Universidad de Navarra: Employment. Ocio:AbbVie: Consultancy; Pharmamar: Consultancy; Seattle Genetics: Consultancy; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS: Consultancy; Takeda: Consultancy, Honoraria; Sanofi: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding. Oriol:Celgene: 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, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rios:Amgen, Celgene, Janssen, and Takeda: Consultancy. Rosinol:Janssen, Celgene, Amgen, Takeda: Honoraria. Alegre:Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Puig:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. García Mateo:Binding Site: Research Funding; Amgen: Honoraria; Celgene: Honoraria. Bladé:Janssen: Honoraria. Lahuerta:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: 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. San-Miguel:Novartis: Honoraria; Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Roche: Honoraria.
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- 2018
27. A prognostic model based on gene expression parameters predicts a better response to bortezomib-containing immunochemotherapy in diffuse large B-cell lymphoma
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Adrián Mosquera Orgueira, Jose Ángel Díaz Arías, Rocio Serrano Martín, Victor Portela Piñeiro, Miguel Cid López, Andrés Peleteiro Raíndo, Laura Bao Pérez, Marta Sonia González Pérez, Manuel Mateo Pérez Encinas, Máximo Francisco Fraga Rodríguez, Juan Carlos Vallejo Llamas, and José Luis Bello López
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machie learning ,DLBCL - diffuse large B cell lymphoma ,bortezomib ,R-CHOP ,lymphoma ,genomics ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Diffuse Large B-cell Lymphoma (DLBCL) is the most common type of aggressive lymphoma. Approximately 60% of fit patients achieve curation with immunochemotherapy, but the remaining patients relapse or have refractory disease, which predicts a short survival. Traditionally, risk stratification in DLBCL has been based on scores that combine clinical variables. Other methodologies have been developed based on the identification of novel molecular features, such as mutational profiles and gene expression signatures. Recently, we developed the LymForest-25 profile, which provides a personalized survival risk prediction based on the integration of transcriptomic and clinical features using an artificial intelligence system. In the present report, we studied the relationship between the molecular variables included in LymForest-25 in the context of the data released by the REMoDL-B trial, which evaluated the addition of bortezomib to the standard treatment (R-CHOP) in the upfront setting of DLBCL. For this, we retrained the machine learning model of survival on the group of patients treated with R-CHOP (N=469) and then made survival predictions for those patients treated with bortezomib plus R-CHOP (N=459). According to these results, the RB-CHOP scheme achieved a 30% reduction in the risk of progression or death for the 50% of DLBCL patients at higher molecular risk (p-value 0.03), potentially expanding the effectiveness of this treatment to a wider patient population as compared with other previously defined risk groups.
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- 2023
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28. Unsupervised machine learning improves risk stratification in newly diagnosed multiple myeloma: an analysis of the Spanish Myeloma Group
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Adrian Mosquera Orgueira, Marta Sonia González Pérez, Jose Diaz Arias, Laura Rosiñol, Albert Oriol, Ana Isabel Teruel, Joaquin Martinez Lopez, Luis Palomera, Miguel Granell, Maria Jesus Blanchard, Javier de la Rubia, Ana López de la Guia, Rafael Rios, Anna Sureda, Miguel Teodoro Hernandez, Enrique Bengoechea, María José Calasanz, Norma Gutierrez, Maria Luis Martin, Joan Blade, Juan-Jose Lahuerta, Jesús San Miguel, Maria Victoria Mateos, and the PETHEMA/GEM Cooperative Group
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract The International Staging System (ISS) and the Revised International Staging System (R-ISS) are commonly used prognostic scores in multiple myeloma (MM). These methods have significant gaps, particularly among intermediate-risk groups. The aim of this study was to improve risk stratification in newly diagnosed MM patients using data from three different trials developed by the Spanish Myeloma Group. For this, we applied an unsupervised machine learning clusterization technique on a set of clinical, biochemical and cytogenetic variables, and we identified two novel clusters of patients with significantly different survival. The prognostic precision of this clusterization was superior to those of ISS and R-ISS scores, and appeared to be particularly useful to improve risk stratification among R-ISS 2 patients. Additionally, patients assigned to the low-risk cluster in the GEM05 over 65 years trial had a significant survival benefit when treated with VMP as compared with VTD. In conclusion, we describe a simple prognostic model for newly diagnosed MM whose predictions are independent of the ISS and R-ISS scores. Notably, the model is particularly useful in order to re-classify R-ISS score 2 patients in 2 different prognostic subgroups. The combination of ISS, R-ISS and unsupervised machine learning clusterization brings a promising approximation to improve MM risk stratification.
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- 2022
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29. Evaluation of the Stellae-123 prognostic gene expression signature in acute myeloid leukemia
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Adrián Mosquera Orgueira, Andrés Peleteiro Raíndo, José Ángel Díaz Arias, Beatriz Antelo Rodríguez, Mónica López Riñón, Claudio Cerchione, Adolfo de la Fuente Burguera, Marta Sonia González Pérez, Giovanni Martinelli, Pau Montesinos Fernández, and Manuel Mateo Pérez Encinas
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leukemia ,transcriptome ,machine learning ,survival ,risk ,prediction ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Risk stratification in acute myeloid leukemia (AML) has been extensively improved thanks to the incorporation of recurrent cytogenomic alterations into risk stratification guidelines. However, mortality rates among fit patients assigned to low or intermediate risk groups are still high. Therefore, significant room exists for the improvement of AML prognostication. In a previous work, we presented the Stellae-123 gene expression signature, which achieved a high accuracy in the prognostication of adult patients with AML. Stellae-123 was particularly accurate to restratify patients bearing high-risk mutations, such as ASXL1, RUNX1 and TP53. The intention of the present work was to evaluate the prognostic performance of Stellae-123 in external cohorts using RNAseq technology. For this, we evaluated the signature in 3 different AML cohorts (2 adult and 1 pediatric). Our results indicate that the prognostic performance of the Stellae-123 signature is reproducible in the 3 cohorts of patients. Additionally, we evidenced that the signature was superior to the European LeukemiaNet 2017 and the pediatric clinical risk scores in the prediction of survival at most of the evaluated time points. Furthermore, integration with age substantially enhanced the accuracy of the model. In conclusion, Stellae-123 is a reproducible machine learning algorithm based on a gene expression signature with promising utility in the field of AML.
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- 2022
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30. Prognostic Stratification of Multiple Myeloma Using Clinicogenomic Models: Validation and Performance Analysis of the IAC-50 Model
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Adrián Mosquera Orgueira, Marta Sonia González Pérez, José Ángel Díaz Arias, Beatriz Antelo Rodríguez, and María-Victoria Mateos
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
A growing need to evaluate risk-adapted treatments in multiple myeloma (MM) exists. Several clinical and molecular scores have been developed in the last decades, which individually explain some of the variability in the heterogeneous clinical behavior of this neoplasm. Recently, we presented Iacobus-50 (IAC-50), which is a machine learning-based survival model based on clinical, biochemical, and genomic data capable of risk-stratifying newly diagnosed MM patients and predicting the optimal upfront treatment scheme. In the present study, we evaluated the prognostic value of the IAC-50 gene expression signature in an external cohort composed of patients from the Total Therapy trials 3, 4, and 5. The prognostic value of IAC-50 was validated, and additionally we observed a better performance in terms of progression-free survival and overall survival prediction compared with the UAMS70 gene expression signature. The combination of the IAC-50 gene expression signature with traditional prognostic variables (International Staging System [ISS] score, baseline B2-microglobulin, and age) improved the performance well above the predictability of the ISS score. IAC-50 emerges as a powerful risk stratification model which might be considered for risk stratification in newly diagnosed myeloma patients, in the context of clinical trials but also in real life.
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- 2022
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31. Outcomes of Cord Blood Transplantation Using Reduced Intensity Conditioning for Chronic Lymphocytic Leukemia: A Retrospective Study on Behalf of Eurocord, SFGM-TC and Cqwp-EBMT
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Jean-Henri Bourhis, Regis Peffault de la Tour, Hendrik Veelken, Eliane Gluckman, Erick Xavier, Annalisa Ruggeri, Mohamad Mohty, Nicolaus Kroeger, Anne Corby, Mauricette Michallet, Eric Deconinck, Marta Sonia Gonzalez Perez, Vanderson Rocha, Jean-Yves Cahn, Thierry de Revel, Simona Sica, Patrice Chevallier, Anna Huynh, Patrice Ceballos, Pascal Turlure, Johannes Schetelig, Stephanie Nguyen-coq, Didier Blaise, Noel Milpied, Niels Smedegaard Andersen, Irene Donnini, Christian Berthou, Jan J. Cornelissen, Natacha Maillard, and Jérôme Cornillon
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medicine.medical_specialty ,Univariate analysis ,Cyclophosphamide ,business.industry ,Chronic lymphocytic leukemia ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Gastroenterology ,Chemotherapy regimen ,Fludarabine ,Surgery ,Transplantation ,Autologous stem-cell transplantation ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and is performed in patients (pts) with high-risk features at diagnosis (del17p/p53 mutations) or advanced disease. Although approximately 30% of pts have matched siblings, alternative stem cell sources such as umbilical cord blood, extend the use of HSCT to pts lacking a conventional donor. However, little is known about outcomes after umbilical cord blood transplantation (UCBT) for CLL/SLL. We analyzed 68 pts (50 males) who underwent a single (n=16) or double (n=52) HLA-mismatched UCBT between 2004 and 2012 in 34 EBMT centers. Median age at UCBT was 57 years (yrs) (range, 27-68). At diagnosis, 56 pts had CLL/SLL, 8 prolymphocytic leukemia (4 B-cell and 4 T-cell) and 4 Richter transformations. Cytogenetic was available in 70% (48/68) of pts. Seventy-three percent had abnormal karyotype (36% del17p/p53, 17% del13q, 8% del11q and 12% others) and 27% normal. Median time from diagnosis to UCBT was 54 months (range, 3-358). Thirty-seven pts were in partial remission (PR) at UCBT, 23 in complete remission (CR) and 8 had refractory disease (RD). The hematopoietic stem cell comordibity index (HCT-CI) at UCBT was 0 in 60% of pts, 1-2 in 25% and 3-4 in 15%. Sixty-five percent of pts received ≥3 chemotherapy lines prior to UCBT, 28% were refractory to purine analogues and 16% underwent previous autologous stem cell transplantation (ASCT). Sixty patients received low-dose TBI (2-4 Gy) from which the Minnesota RIC regimen (TBI-Cyclophosphamide-Fludarabine: TCF) was given to 57 pts; 15 pts received ATG and GVHD prophylaxis was CsA+MMF in 61 pts. Median TNC collected was 3.7x107/Kg (1.8-7.1) for single and 5x107/Kg (2.0-9.7) for double UCBT. Units were HLA matched to the recipient at 5-6 loci in 30% of pts and at ≤4 in 70%. Median follow-up was 37 months (range, 3-98). OS and PFS at 3 yrs were, respectively, 53±7% and 45±7%. The cumulative incidences (CI) of neutrophils and platelets engraftment were 84±5% and 72±6%, respectively with a median time for engraftment of 21(range, 5-67) and 43 (range, 1-189) days, respectively. CI of acute graft-versus-host disease (aGVHD) at 100 days was 43%±6 for grade II-IV and 19±5% for grade III-IV with a median time of onset of 23 days (9-95). Three yrs CI of chronic GVHD (cGVHD) was 32±6% (12 limited and 6 extensive) with a median time of onset of 130 (range, 101-393) days. CI of relapse and NRM at 3 yrs were,16±5% and 39±6%, respectively. In a univariate analysis the use of TCF conditioning was associated with improved OS (62% vs 15%, p The use of TCF (HR: 0.34 (0.14-0.82), p=0.02), fludarabine sensitive disease at transplantation (HR: 0.41 (0.20-0.81), p=0.01) and HCT-CI ≤2 (HR: 0.38 (0.17-0.87), p=0.02) were associated with improved PFS in multivariate analysis. Acute GVHD grade III-IV was associated with lower OS (HR: 3.4 (1.6-7.4), p=0.002) and PFS (HR: 2.8 (1.4-5.8), p=0.005) in a time-dependent model. Overall, 32 patients died; 7 died of relapse and 25 of transplant related causes (10 infections, 4 post-transplant lymphoprolypherative diseases, 3 aGVHD, 3 toxicities, 1 secondary lung cancer and 4 other causes). In conclusion, RIC-UCBT appears to be a valid option for CLL/SLL patients. Strategies to optimize infection prophylaxis, use of low-dose TBI RIC conditionings and to perform the UCBT before development of fludarabine resistance may improve overall outcome. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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- 2014
32. Prognostic Stratification of Diffuse Large B-cell Lymphoma Using Clinico-genomic Models: Validation and Improvement of the LymForest-25 Model
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Adrián Mosquera Orgueira, Jose Ángel Díaz Arías, Miguel Cid López, Andrés Peleteiro Raíndo, Alberto López García, Rosanna Abal García, Marta Sonia González Pérez, Beatriz Antelo Rodríguez, Carlos Aliste Santos, Manuel Mateo Pérez Encinas, Máximo Francisco Fraga Rodríguez, and José Luis Bello López
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Despite notable therapeutic advances in the last decades, 30%–40% of affected patients develop relapsed or refractory disease that frequently precludes an infamous outcome. With the advent of new therapeutic options, it becomes necessary to predict responses to the standard treatment based on rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). In a recent communication, we presented a new machine learning model (LymForest-25) that was based on 25 clinical, biochemical, and gene expression variables. LymForest-25 achieved high survival prediction accuracy in patients with DLBCL treated with upfront immunochemotherapy. In this study, we aimed to evaluate the performance of the different features that compose LymForest-25 in a new UK-based cohort, which contained 481 patients treated with upfront R-CHOP for whom clinical, biochemical and gene expression information for 17 out of 19 transcripts were available. Additionally, we explored potential improvements based on the integration of other gene expression signatures and mutational clusters. The validity of the LymForest-25 gene expression signature was confirmed, and indeed it achieved a substantially greater precision in the estimation of mortality at 6 months and 1, 2, and 5 years compared with the cell-of-origin (COO) plus molecular high-grade (MHG) classification. Indeed, this signature was predictive of survival within the MHG and all COO subgroups, with a particularly high accuracy in the “unclassified” group. Integration of this signature with the International Prognostic Index (IPI) score provided the best survival predictions. However, the increased performance of molecular models with the IPI score was almost exclusively restricted to younger patients (
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- 2022
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33. Improved personalized survival prediction of patients with diffuse large B-cell Lymphoma using gene expression profiling
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Adrián Mosquera Orgueira, José Ángel Díaz Arias, Miguel Cid López, Andrés Peleteiro Raíndo, Beatriz Antelo Rodríguez, Carlos Aliste Santos, Natalia Alonso Vence, Ángeles Bendaña López, Aitor Abuín Blanco, Laura Bao Pérez, Marta Sonia González Pérez, Manuel Mateo Pérez Encinas, Máximo Francisco Fraga Rodríguez, and José Luis Bello López
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DLBCL ,Lymphoma ,Survival ,Prediction ,Transcriptomics ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Thirty to forty percent of patients with Diffuse Large B-cell Lymphoma (DLBCL) have an adverse clinical evolution. The increased understanding of DLBCL biology has shed light on the clinical evolution of this pathology, leading to the discovery of prognostic factors based on gene expression data, genomic rearrangements and mutational subgroups. Nevertheless, additional efforts are needed in order to enable survival predictions at the patient level. In this study we investigated new machine learning-based models of survival using transcriptomic and clinical data. Methods Gene expression profiling (GEP) of in 2 different publicly available retrospective DLBCL cohorts were analyzed. Cox regression and unsupervised clustering were performed in order to identify probes associated with overall survival on the largest cohort. Random forests were created to model survival using combinations of GEP data, COO classification and clinical information. Cross-validation was used to compare model results in the training set, and Harrel’s concordance index (c-index) was used to assess model’s predictability. Results were validated in an independent test set. Results Two hundred thirty-three and sixty-four patients were included in the training and test set, respectively. Initially we derived and validated a 4-gene expression clusterization that was independently associated with lower survival in 20% of patients. This pattern included the following genes: TNFRSF9, BIRC3, BCL2L1 and G3BP2. Thereafter, we applied machine-learning models to predict survival. A set of 102 genes was highly predictive of disease outcome, outperforming available clinical information and COO classification. The final best model integrated clinical information, COO classification, 4-gene-based clusterization and the expression levels of 50 individual genes (training set c-index, 0.8404, test set c-index, 0.7942). Conclusion Our results indicate that DLBCL survival models based on the application of machine learning algorithms to gene expression and clinical data can largely outperform other important prognostic variables such as disease stage and COO. Head-to-head comparisons with other risk stratification models are needed to compare its usefulness.
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- 2020
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34. Correction: Gene expression profiling identifies FLT3 mutation-like cases in wild-type FLT3 acute myeloid leukemia
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Adrián Mosquera Orgueira, Andrés Peleteiro Raíndo, Miguel Cid López, Beatriz Antelo Rodríguez, José Ángel Díaz Arias, Roi Ferreiro Ferro, Natalia Alonso Vence, Ángeles Bendaña López, Aitor Abuín Blanco, Laura Bao Pérez, Paula Melero Valentín, Marta Sonia González Pérez, Claudio Cerchione, Giovanni Martinelli, Pau Montesinos Fernández, Manuel Mateo Pérez Encinas, and José Luis Bello López
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Medicine ,Science - Published
- 2022
35. Personally Tailored Survival Prediction of Patients With Follicular Lymphoma Using Machine Learning Transcriptome-Based Models
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Adrián Mosquera Orgueira, Miguel Cid López, Andrés Peleteiro Raíndo, Aitor Abuín Blanco, Jose Ángel Díaz Arias, Marta Sonia González Pérez, Beatriz Antelo Rodríguez, Laura Bao Pérez, Roi Ferreiro Ferro, Carlos Aliste Santos, Manuel Mateo Pérez Encinas, Máximo Francisco Fraga Rodríguez, Claudio Cerchione, Pablo Mozas, and José Luis Bello López
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machine learning ,lymphoma ,follicular ,gene expression ,survival ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Follicular Lymphoma (FL) has a 10-year mortality rate of 20%, and this is mostly related to lymphoma progression and transformation to higher grades. In the era of personalized medicine it has become increasingly important to provide patients with an optimal prediction about their expected outcomes. The objective of this work was to apply machine learning (ML) tools on gene expression data in order to create individualized predictions about survival in patients with FL. Using data from two different studies, we were able to create a model which achieved good prediction accuracies in both cohorts (c-indexes of 0.793 and 0.662 in the training and test sets). Integration of this model with m7-FLIPI and age rendered high prediction accuracies in the test set (cox c-index 0.79), and a simplified approach identified 4 groups with remarkably different outcomes in terms of survival. Importantly, one of the groups comprised 27.35% of patients and had a median survival of 4.64 years. In summary, we have created a gene expression-based individualized predictor of overall survival in FL that can improve the predictions of the m7-FLIPI score.
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- 2022
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36. Personalized Survival Prediction of Patients With Acute Myeloblastic Leukemia Using Gene Expression Profiling
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Adrián Mosquera Orgueira, Andrés Peleteiro Raíndo, Miguel Cid López, José Ángel Díaz Arias, Marta Sonia González Pérez, Beatriz Antelo Rodríguez, Natalia Alonso Vence, Laura Bao Pérez, Roi Ferreiro Ferro, Manuel Albors Ferreiro, Aitor Abuín Blanco, Emilia Fontanes Trabazo, Claudio Cerchione, Giovanni Martinnelli, Pau Montesinos Fernández, Manuel Mateo Pérez Encinas, and José Luis Bello López
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acute myeloid leukemia ,cancer ,survival ,machine learning ,gene expression ,prognosis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Acute Myeloid Leukemia (AML) is a heterogeneous neoplasm characterized by cytogenetic and molecular alterations that drive patient prognosis. Currently established risk stratification guidelines show a moderate predictive accuracy, and newer tools that integrate multiple molecular variables have proven to provide better results. In this report, we aimed to create a new machine learning model of AML survival using gene expression data. We used gene expression data from two publicly available cohorts in order to create and validate a random forest predictor of survival, which we named ST-123. The most important variables in the model were age and the expression of KDM5B and LAPTM4B, two genes previously associated with the biology and prognostication of myeloid neoplasms. This classifier achieved high concordance indexes in the training and validation sets (0.7228 and 0.6988, respectively), and predictions were particularly accurate in patients at the highest risk of death. Additionally, ST-123 provided significant prognostic improvements in patients with high-risk mutations. Our results indicate that survival of patients with AML can be predicted to a great extent by applying machine learning tools to transcriptomic data, and that such predictions are particularly precise among patients with high-risk mutations.
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- 2021
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37. Detection of new drivers of frequent B-cell lymphoid neoplasms using an integrated analysis of whole genomes.
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Adrián Mosquera Orgueira, Roi Ferreiro Ferro, José Ángel Díaz Arias, Carlos Aliste Santos, Beatriz Antelo Rodríguez, Laura Bao Pérez, Natalia Alonso Vence, Ággeles Bendaña López, Aitor Abuin Blanco, Paula Melero Valentín, And Res Peleteiro Raindo, Miguel Cid López, Manuel Mateo Pérez Encinas, Marta Sonia González Pérez, Máximo Francisco Fraga Rodríguez, and José Luis Bello López
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Medicine ,Science - Abstract
B-cell lymphoproliferative disorders exhibit a diverse spectrum of diagnostic entities with heterogeneous behaviour. Multiple efforts have focused on the determination of the genomic drivers of B-cell lymphoma subtypes. In the meantime, the aggregation of diverse tumors in pan-cancer genomic studies has become a useful tool to detect new driver genes, while enabling the comparison of mutational patterns across tumors. Here we present an integrated analysis of 354 B-cell lymphoid disorders. 112 recurrently mutated genes were discovered, of which KMT2D, CREBBP, IGLL5 and BCL2 were the most frequent, and 31 genes were putative new drivers. Mutations in CREBBP, TNFRSF14 and KMT2D predominated in follicular lymphoma, whereas those in BTG2, HTA-A and PIM1 were more frequent in diffuse large B-cell lymphoma. Additionally, we discovered 31 significantly mutated protein networks, reinforcing the role of genes such as CREBBP, EEF1A1, STAT6, GNA13 and TP53, but also pointing towards a myriad of infrequent players in lymphomagenesis. Finally, we report aberrant expression of oncogenes and tumor suppressors associated with novel noncoding mutations (DTX1 and S1PR2), and new recurrent copy number aberrations affecting immune check-point regulators (CD83, PVR) and B-cell specific genes (TNFRSF13C). Our analysis expands the number of mutational drivers of B-cell lymphoid neoplasms, and identifies several differential somatic events between disease subtypes.
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- 2021
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38. Gene expression profiling identifies FLT3 mutation-like cases in wild-type FLT3 acute myeloid leukemia.
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Adrián Mosquera Orgueira, Andrés Peleteiro Raíndo, Miguel Cid López, Beatriz Antelo Rodríguez, José Ángel Díaz Arias, Roi Ferreiro Ferro, Natalia Alonso Vence, Ángeles Bendaña López, Aitor Abuín Blanco, Laura Bao Pérez, Paula Melero Valentín, Marta Sonia González Pérez, Claudio Cerchione, Giovanni Martinelli, Pau Montesinos Fernández, Manuel Mateo Pérez Encinas, and José Luis Bello López
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Medicine ,Science - Abstract
BackgroundFLT3 mutation is present in 25-30% of all acute myeloid leukemias (AML), and it is associated with adverse outcome. FLT3 inhibitors have shown improved survival results in AML both as upfront treatment and in relapsed/refractory disease. Curiously, a variable proportion of wild-type FLT3 patients also responded to these drugs.MethodsWe analyzed 6 different transcriptomic datasets of AML cases. Differential expression between mutated and wild-type FLT3 AMLs was performed with the Wilcoxon-rank sum test. Hierarchical clustering was used to identify FLT3-mutation like AMLs. Finally, enrichment in recurrent mutations was performed with the Fisher's test.ResultsA FLT3 mutation-like gene expression pattern was identified among wild-type FLT3 AMLs. This pattern was highly enriched in NPM1 and DNMT3A mutants, and particularly in combined NPM1/DNMT3A mutants.ConclusionsWe identified a FLT3 mutation-like gene expression pattern in AML which was highly enriched in NPM1 and DNMT3A mutations. Future analysis about the predictive role of this biomarker among wild-type FLT3 patients treated with FLT3 inhibitors is envisaged.
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- 2021
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39. Results of an Early Access Treatment Protocol of Daratumumab Monotherapy in Spanish Patients With Relapsed or Refractory Multiple Myeloma
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Adrián Alegre, Javier de la Rubia, Anna Sureda Balari, Cristina Encinas Rodríguez, Alexia Suárez, María Jesús Blanchard, Joan Bargay Lleonart, Paula Rodríguez-Otero, Andrés Insunza, Luis Palomera, María Jesús Peñarrubia, Rafael Ríos-Tamayo, Luis Felipe Casado Montero, Marta Sonia González, Anna Potamianou, Catherine Couturier, Huiling Pei, Henar Hevia, Iordanis Milionis, Maren Gaudig, and María-Victoria Mateos
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract. Daratumumab is a human CD38-targeted monoclonal antibody approved as monotherapy for heavily pretreated relapsed and refractory multiple myeloma. We report findings for the Spanish cohort of an open-label treatment protocol that provided early access to daratumumab monotherapy and collected safety and patient-reported outcomes data for patients with relapsed or refractory multiple myeloma. At 15 centers across Spain, intravenous daratumumab (16 mg/kg) was administered to 73 patients who had ≥3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or who were double refractory to both. The median duration of daratumumab treatment was 3.3 (range: 0.03–13.17) months, with a median number of 12 (range: 1–25) infusions. Grade 3/4 treatment-emergent adverse events were reported in 74% of patients and included lymphopenia (28.8%), thrombocytopenia (27.4%), neutropenia (21.9%), leukopenia (19.2%), and anemia (15.1%). Common (>5%) serious treatment-emergent adverse events included respiratory tract infection (9.6%), general physical health deterioration (6.8%), and back pain (5.5%). Infusion-related reactions occurred in 45% of patients. The median change from baseline in all domains of the EQ-5D-5L and EORTC QLQ-C30 was mostly 0. A total of 18 (24.7%) patients achieved a partial response or better, with 10 (13.7%) patients achieving a very good partial response or better. Median progression-free survival was 3.98 months. The results of this early access treatment protocol are consistent with previously reported trials of daratumumab monotherapy and confirm its safety and antitumoral efficacy in Spanish patients with heavily treated relapsed or refractory multiple myeloma. European Clinical Trials Database number: 2015-002993-19
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- 2020
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40. New Recurrent Structural Aberrations in the Genome of Chronic Lymphocytic Leukemia Based on Exome-Sequencing Data
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Adrián Mosquera Orgueira, Beatriz Antelo Rodríguez, José Ángel Díaz Arias, Marta Sonia González Pérez, and José Luis Bello López
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copy number aberration ,chronic lymphocytic leukemia ,driver ,time to treatment ,overall survival ,Genetics ,QH426-470 - Abstract
Chronic lymphocytic leukemia (CLL) is the most frequent lymphoproliferative syndrome in Western countries, and it is characterized by recurrent large genomic rearrangements. During the last decades, array techniques have expanded our knowledge about CLL’s karyotypic aberrations. The advent of large sequencing databases expanded our knowledge cancer genomics to an unprecedented resolution and enabled the detection of small-scale structural aberrations in the cancer genome. In this study, we have performed exome-sequencing-based copy number aberration (CNA) and loss of heterozygosity (LOH) analysis in order to detect new recurrent structural aberrations. We describe 54 recurrent focal CNAs enriched in cancer-related pathways, and their association with gene expression and clinical evolution. Furthermore, we discovered recurrent large copy number neutral LOH events affecting key driver genes, and we recapitulate most of the large CNAs that characterize the CLL genome. These results provide “proof-of-concept” evidence supporting the existence of new genes involved in the pathogenesis of CLL.
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- 2019
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41. Time to Treatment Prediction in Chronic Lymphocytic Leukemia Based on New Transcriptional Patterns
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Adrián Mosquera Orgueira, Beatriz Antelo Rodríguez, Natalia Alonso Vence, Ángeles Bendaña López, José Ángel Díaz Arias, Nicolás Díaz Varela, Marta Sonia González Pérez, Manuel Mateo Pérez Encinas, and José Luis Bello López
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chronic lymphocytic leukemia ,time to treatment prediction ,gene expression ,RNAseq ,machine learning ,prognostic factors ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Chronic lymphocytic leukemia (CLL) is the most frequent lymphoproliferative syndrome in western countries. CLL evolution is frequently indolent, and treatment is mostly reserved for those patients with signs or symptoms of disease progression. In this work, we used RNA sequencing data from the International Cancer Genome Consortium CLL cohort to determine new gene expression patterns that correlate with clinical evolution.We determined that a 290-gene expression signature, in addition to immunoglobulin heavy chain variable region (IGHV) mutation status, stratifies patients into four groups with notably different time to first treatment. This finding was confirmed in an independent cohort. Similarly, we present a machine learning algorithm that predicts the need for treatment within the first 5 years following diagnosis using expression data from 2,198 genes. This predictor achieved 90% precision and 89% accuracy when classifying independent CLL cases. Our findings indicate that CLL progression risk largely correlates with particular transcriptomic patterns and paves the way for the identification of high-risk patients who might benefit from prompt therapy following diagnosis.
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- 2019
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42. Detection of Rare Germline Variants in the Genomes of Patients with B-Cell Neoplasms
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Adrián Mosquera Orgueira, Miguel Cid López, Andrés Peleteiro Raíndo, José Ángel Díaz Arias, Beatriz Antelo Rodríguez, Laura Bao Pérez, Natalia Alonso Vence, Ángeles Bendaña López, Aitor Abuin Blanco, Paula Melero Valentín, Roi Ferreiro Ferro, Carlos Aliste Santos, Máximo Francisco Fraga Rodríguez, Marta Sonia González Pérez, Manuel Mateo Pérez Encinas, and José Luis Bello López
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germline ,rare variant ,cancer ,lymphoid ,B-cell ,lymphoma ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
There is growing evidence indicating the implication of germline variation in cancer predisposition and prognostication. Here, we describe an analysis of likely disruptive rare variants across the genomes of 726 patients with B-cell lymphoid neoplasms. We discovered a significant enrichment for two genes in rare dysfunctional variants, both of which participate in the regulation of oxidative stress pathways (CHMP6 and GSTA4). Additionally, we detected 1675 likely disrupting variants in genes associated with cancer, of which 44.75% were novel events and 7.88% were protein-truncating variants. Among these, the most frequently affected genes were ATM, BIRC6, CLTCL1A, and TSC2. Homozygous or germline double-hit variants were detected in 28 cases, and coexisting somatic events were observed in 17 patients, some of which affected key lymphoma drivers such as ATM, KMT2D, and MYC. Finally, we observed that variants in six different genes were independently associated with shorter survival in CLL. Our study results support an important role for rare germline variation in the pathogenesis and prognosis of B-cell lymphoid neoplasms.
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- 2021
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43. A simple score to predict early severe infections in patients with newly diagnosed multiple myeloma
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Cristina Encinas, José-Ángel Hernandez-Rivas, Albert Oriol, Laura Rosiñol, María-Jesús Blanchard, José-María Bellón, Ramón García-Sanz, Javier de la Rubia, Ana López de la Guía, Ana Jímenez-Ubieto, Isidro Jarque, Belén Iñigo, Victoria Dourdil, Felipe de Arriba, Clara Cuéllar Pérez-Ávila, Yolanda Gonzalez, Miguel-Teodoro Hernández, Joan Bargay, Miguel Granell, Paula Rodríguez-Otero, Maialen Silvent, Carmen Cabrera, Rafael Rios, Adrián Alegre, Mercedes Gironella, Marta-Sonia Gonzalez, Anna Sureda, Antonia Sampol, Enrique M. Ocio, Isabel Krsnik, Antonio García, Aránzazu García-Mateo, Joan-Alfons Soler, Jesús Martín, José-María Arguiñano, María-Victoria Mateos, Joan Bladé, Jesús F. San-Miguel, Juan-José Lahuerta, Joaquín Martínez-López, and GEM/PETHEMA (Grupo Español de Mieloma/Programa para el Estudio de la Terapéutica en Hemopatías Malignas) cooperative study group
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Infections remain a common complication in patients with multiple myeloma (MM) and are associated with morbidity and mortality. A risk score to predict the probability of early severe infection could help to identify the patients that would benefit from preventive measures. We undertook a post hoc analysis of infections in four clinical trials from the Spanish Myeloma Group, involving a total of 1347 patients (847 transplant candidates). Regarding the GEM2010 > 65 trial, antibiotic prophylaxis was mandatory, so we excluded it from the final analysis. The incidence of severe infection episodes within the first 6 months was 13.8%, and majority of the patients experiencing the first episode before 4 months (11.1%). 1.2% of patients died because of infections within the first 6 months (1% before 4 months). Variables associated with increased risk of severe infection in the first 4 months included serum albumin ≤30 g/L, ECOG > 1, male sex, and non-IgA type MM. A simple risk score with these variables facilitated the identification of three risk groups with different probabilities of severe infection within the first 4 months: low-risk (score 0–2) 8.2%; intermediate-risk (score 3) 19.2%; and high-risk (score 4) 28.3%. Patients with intermediate/high risk could be candidates for prophylactic antibiotic therapies.
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- 2022
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