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3. Therapy-related myelodysplastic syndromes deserve specific diagnostic sub-classification and risk-stratification—an approach to classification of patients with t-MDS

Author

Kuendgen, A., Nomdedeu, M., Tuechler, H., Garcia-Manero, G., Komrokji, R. S., Sekeres, M. A., Della Porta, M. G., Cazzola, M., DeZern, A. E., Roboz, G. J., Steensma, D. P., Van de Loosdrecht, A. A., Schlenk, R. F., Grau, J., Calvo, X., Blum, S., Pereira, A., Valent, P., Costa, D., Giagounidis, A., Xicoy, B., Döhner, H., Platzbecker, U., Pedro, C., Lübbert, M., Oiartzabal, I., Díez-Campelo, M., Cedena, M. T., Machherndl-Spandl, S., López-Pavía, M., Baldus, C. D., Martinez-de-Sola, M., Stauder, R., Merchan, B., List, A., Ganster, C., Schroeder, T., Voso, M. T., Pfeilstöcker, M., Sill, H., Hildebrandt, B., Esteve, J., Nomdedeu, B., Cobo, F., Haas, R., Sole, F., Germing, U., Greenberg, P. L., Haase, D., and Sanz, G.

Published
2021
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4. Immunogenomic identification and characterization of granulocytic myeloid-derived suppressor cells in multiple myeloma

Author

Perez C., Botta C., Zabaleta A., Puig N., Cedena M. -T., Goicoechea I., Alameda D., Jose-Eneriz E. S., Merino J., Rodriguez-Otero P., Maia C., Alignani D., Maiso P., Manrique I., Lara-Astiaso D., Vilas-Zornoza A., Sarvide S., Riillo C., Rossi M., Rosinol L., Oriol A., Blanchard M. -J., Rios R., Sureda A., Martin J., Martinez R., Bargay J., de la Rubia J., Hernandez M. -T., Martinez-Lopez J., Orfao A., Agirre X., Prosper F., Mateos M. -V., Lahuerta J. -J., Blade J., San-Miguel J. F., Paiva B., Espinosa M. C., Zamudio J. L. G., Herranz E. R., Tamayo R. R., Sanchez J. M., Bernal L. P., Rodriguez A. P. G., Garcia M. E. G., Mayol A. S., Lleonart J. B., Suarez A., Garcia M. T. H., Gaisan C. M., Ruiz B. H., Montero F. C., de Miguel Llorente D., Ramos F. S., Garcia A. I., Manteca M. M., Martin J. M. H., Barrigon F. E., Frade J. G., de Coca A. G., Franco C. A., Gomez J. L., Perez E. C., Creixenti J. B., Balari A. M. S., Montes Y. G., Teigell L. E., Guinon A. G., Monreal E. A., Campos J. A. S., Tutusaus J. M. M., Rocafiguera A. O., Gorrochategui M. G., Mesa M. G., Silva C. C., Perez M. S. G., Loureiro A. D., Sanchez J. A. M., Irazu M. J. N., Parraga F. J. P., Palacios J. J. L., Barahona P. B., Rodriguez C. E., Rivas J. A. H., de Oteyza J. P., del Barrio R. I., de la Guia A. L., Amor A. A., Pareja E. P., Castello I. K., Rodriguez M. J. B., Martinez R. M., Grau R. R., Mesa E. G., Sainz E. R., de Arriba F., Jimenez J. M. M., Romera M., Cardoso F. P., Perez J. M. A., Pomposo M. P., Persona E. P., Casasus A. I. T., Garcia P. R., Ramos I. J., Lor M. B. V., Garcia P. L. F., Chamorro C. M., Perez C., Botta C., Zabaleta A., Puig N., Cedena M.-T., Goicoechea I., Alameda D., Jose-Eneriz E.S., Merino J., Rodriguez-Otero P., Maia C., Alignani D., Maiso P., Manrique I., Lara-Astiaso D., Vilas-Zornoza A., Sarvide S., Riillo C., Rossi M., Rosinol L., Oriol A., Blanchard M.-J., Rios R., Sureda A., Martin J., Martinez R., Bargay J., de la Rubia J., Hernandez M.-T., Martinez-Lopez J., Orfao A., Agirre X., Prosper F., Mateos M.-V., Lahuerta J.-J., Blade J., San-Miguel J.F., Paiva B., Espinosa M.C., Zamudio J.L.G., Herranz E.R., Tamayo R.R., Sanchez J.M., Bernal L.P., Rodriguez A.P.G., Garcia M.E.G., Mayol A.S., Lleonart J.B., Suarez A., Garcia M.T.H., Gaisan C.M., Ruiz B.H., Montero F.C., de Miguel Llorente D., Ramos F.S., Garcia A.I., Manteca M.M., Martin J.M.H., Barrigon F.E., Frade J.G., de Coca A.G., Franco C.A., Gomez J.L., Perez E.C., Creixenti J.B., Balari A.M.S., Montes Y.G., Teigell L.E., Guinon A.G., Monreal E.A., Campos J.A.S., Tutusaus J.M.M., Rocafiguera A.O., Gorrochategui M.G., Mesa M.G., Silva C.C., Perez M.S.G., Loureiro A.D., Sanchez J.A.M., Irazu M.J.N., Parraga F.J.P., Palacios J.J.L., Barahona P.B., Rodriguez C.E., Rivas J.A.H., de Oteyza J.P., del Barrio R.I., de la Guia A.L., Amor A.A., Pareja E.P., Castello I.K., Rodriguez M.J.B., Martinez R.M., Grau R.R., Mesa E.G., Sainz E.R., de Arriba F., Jimenez J.M.M., Romera M., Cardoso F.P., Perez J.M.A., Pomposo M.P., Persona E.P., Casasus A.I.T., Garcia P.R., Ramos I.J., Lor M.B.V., Garcia P.L.F., and Chamorro C.M.

Subjects
Male, Transcription, Genetic, Neutrophils, T-Lymphocytes, Immunology, CD33, Biology, CD16, Biochemistry, Follow-Up Studie, Flow cytometry, Antigens, CD, medicine, Humans, Cytotoxic T cell, Lymphocyte Count, Tumor microenvironment, medicine.diagnostic_test, Myeloid-Derived Suppressor Cells, Cell Biology, Hematology, Middle Aged, Cell sorting, Neoplasm Proteins, medicine.anatomical_structure, T-Lymphocyte, Cancer research, Myeloid-derived Suppressor Cell, Female, Bone marrow, Multiple Myeloma, Human, Follow-Up Studies
Abstract

Granulocytic myeloid-derived suppressor cells (G-MDSCs) promote tumor growth and immunosuppression in multiple myeloma (MM). However, their phenotype is not well established for accurate monitoring or clinical translation. We aimed to provide the phenotypic profile of G-MDSCs based on their prognostic significance in MM, immunosuppressive potential, and molecular program. The preestablished phenotype of G-MDSCs was evaluated in bone marrow samples from controls and MM patients using multidimensional flow cytometry; surprisingly, we found that CD11b+CD14−CD15+CD33+HLADR− cells overlapped with common eosinophils and neutrophils, which were not expanded in MM patients. Therefore, we relied on automated clustering to unbiasedly identify all granulocytic subsets in the tumor microenvironment: basophils, eosinophils, and immature, intermediate, and mature neutrophils. In a series of 267 newly diagnosed MM patients (GEM2012MENOS65 trial), only the frequency of mature neutrophils at diagnosis was significantly associated with patient outcome, and a high mature neutrophil/T-cell ratio resulted in inferior progression-free survival (P < .001). Upon fluorescence-activated cell sorting of each neutrophil subset, T-cell proliferation decreased in the presence of mature neutrophils (0.5-fold; P = .016), and the cytotoxic potential of T cells engaged by a BCMA×CD3-bispecific antibody increased notably with the depletion of mature neutrophils (fourfold; P = .0007). Most interestingly, RNA sequencing of the 3 subsets revealed that G-MDSC–related genes were specifically upregulated in mature neutrophils from MM patients vs controls because of differential chromatin accessibility. Taken together, our results establish a correlation between the clinical significance, immunosuppressive potential, and transcriptional network of well-defined neutrophil subsets, providing for the first time a set of optimal markers (CD11b/CD13/CD16) for accurate monitoring of G-MDSCs in MM.

Published
2020
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5. Differentiation stage of myeloma plasma cells: biological and clinical significance

Author

Paiva, B, Puig, N, Cedena, M T, de Jong, B G, Ruiz, Y, Rapado, I, Martinez-Lopez, J, Cordon, L, Alignani, D, Delgado, J A, van Zelm, M C, Van Dongen, J J M, Pascual, M, Agirre, X, Prosper, F, Martín-Subero, J I, Vidriales, M-B, Gutierrez, N C, Hernandez, M T, Oriol, A, Echeveste, M A, Gonzalez, Y, Johnson, S K, Epstein, J, Barlogie, B, Morgan, G J, Orfao, A, Blade, J, Mateos, M V, Lahuerta, J J, and San-Miguel, J F

Published
2017
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6. Therapy-related myelodysplastic syndromes deserve specific diagnostic sub-classification and risk-stratification—an approach to classification of patients with t-MDS

Author

Kuendgen, A., primary, Nomdedeu, M., additional, Tuechler, H., additional, Garcia-Manero, G., additional, Komrokji, R. S., additional, Sekeres, M. A., additional, Della Porta, M. G., additional, Cazzola, M., additional, DeZern, A. E., additional, Roboz, G. J., additional, Steensma, D. P., additional, Van de Loosdrecht, A. A., additional, Schlenk, R. F., additional, Grau, J., additional, Calvo, X., additional, Blum, S., additional, Pereira, A., additional, Valent, P., additional, Costa, D., additional, Giagounidis, A., additional, Xicoy, B., additional, Döhner, H., additional, Platzbecker, U., additional, Pedro, C., additional, Lübbert, M., additional, Oiartzabal, I., additional, Díez-Campelo, M., additional, Cedena, M. T., additional, Machherndl-Spandl, S., additional, López-Pavía, M., additional, Baldus, C. D., additional, Martinez-de-Sola, M., additional, Stauder, R., additional, Merchan, B., additional, List, A., additional, Ganster, C., additional, Schroeder, T., additional, Voso, M. T., additional, Pfeilstöcker, M., additional, Sill, H., additional, Hildebrandt, B., additional, Esteve, J., additional, Nomdedeu, B., additional, Cobo, F., additional, Haas, R., additional, Sole, F., additional, Germing, U., additional, Greenberg, P. L., additional, Haase, D., additional, and Sanz, G., additional

Published
2020
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7. PS1352 DISSECTING THE BONE MARROW IMMUNE MICROENVIRONMENT IN THE COMPLETE SPECTRUM OF MONOCLONAL GAMMOPATHIES: POTENTIAL IMPLICATIONS IN DISEASE PATHOGENESIS

Author

Puig, N., primary, Paíno, T., additional, Pérez, J.J., additional, Rodero, E., additional, Paiva, B., additional, Cedena, M.-T., additional, Díaz-Tejedor, A., additional, Aires-Mejía, I., additional, Contreras, T., additional, Pessoa, R., additional, Garayoa, M., additional, García-Sanz, R., additional, Gutiérrez, N., additional, de la Calle, V. González, additional, Oriol, A., additional, Rosiñol, L., additional, Bargay, J., additional, Escalante, F., additional, de la Rubia, J., additional, de Arriba, F., additional, Hernández, M.-T., additional, Mateo, A. García, additional, Bladé, J., additional, Lahuerta, J.J., additional, Miguel, J. San, additional, Mateos, M.-V., additional, and Ocio, E.M., additional

Published
2019
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8. PF609 HEAVY&LIGHT CHAIN MONITORING IN HIGH RISK SMOLDERING MULTIPLE MYELOMA PATIENTS INCLUDED IN THE GEM-CESAR TRIAL: COMPARISON WITH CONVENTIONAL AND MINIMAL RESIDUAL DISEASE IMWG RESPONSE ASSESSMENT

Author

Puig, N., primary, Contreras, T., additional, Paiva, B., additional, Cedena, M.-T., additional, Pérez, J.J., additional, Aires, I., additional, Agullo, C., additional, Martínez-López, J., additional, Rodríguez-Otero, P., additional, González de la Calle, V., additional, González, M.-S., additional, Oriol, A., additional, Gutiérrez, N.-C., additional, Rios, R., additional, Rosiñol, L., additional, Alvarez, M.A., additional, Calasanz, M.J., additional, Bargay, J., additional, González, A.P., additional, Alegre, A., additional, Escalante, F., additional, Martínez, R., additional, de la Rubia, J., additional, Teruel, A.I., additional, de Arriba, F., additional, Palomera, L., additional, Hernández, M.T., additional, López, J., additional, Martín, J., additional, Mateo, A. García, additional, Ocio, E.M., additional, Bladé, J., additional, Lahuerta, J.J., additional, Miguel, J. San, additional, and Mateos, M.V., additional

Published
2019
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9. S871 CURATIVE STRATEGY (GEM-CESAR) FOR HIGH-RISK SMOLDERING MYELOMA: CARFILZOMIB, LENALIDOMIDE AND DEXAMETHASONE (KRD) AS INDUCTION FOLLOWED BY HDT-ASCT, CONSOLIDATION WITH KRD AND MAINTENANCE WITH RD

Author

Mateos, M.-V., primary, Martínez-López, J., additional, Rodríguez-Otero, P., additional, González de la Calle, V., additional, González, M.-S., additional, Oriol, A., additional, Gutiérrez, N.-C., additional, Paiva, B., additional, Rios, R., additional, Rosiñol, L., additional, Alvarez, M.-A., additional, Calasanz, M.-J., additional, Bargay, J., additional, González, A.-P., additional, Alegre, A., additional, Escalante, F., additional, Martínez, R., additional, Puig, N., additional, de la Rubia, J., additional, Teruel, A.-I., additional, Cedena, M.-T., additional, de Arriba, F., additional, Palomera, L., additional, Hernández, M.-T., additional, López, J., additional, Martín, J., additional, García-Mateo, A., additional, Ocio, E., additional, Bladé, J., additional, Lahuerta, J.-J., additional, and San Miguel, J., additional

Published
2019
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10. Analytical and clinical validation of a novel in-house deep-sequencing method for minimal residual disease monitoring in a phase II trial for multiple myeloma

Author

Martinez-Lopez, J, primary, Sanchez-Vega, B, additional, Barrio, S, additional, Cuenca, I, additional, Ruiz-Heredia, Y, additional, Alonso, R, additional, Rapado, I, additional, Marin, C, additional, Cedena, M-T, additional, Paiva, B, additional, Puig, N, additional, Mateos, M-V, additional, Ayala, R, additional, Hernández, M-T, additional, Jimenez, C, additional, Rosiñol, L, additional, Martínez, R, additional, Teruel, A-I, additional, Gutiérrez, N, additional, Martin-Ramos, M-L, additional, Oriol, A, additional, Bargay, J, additional, Bladé, J, additional, San-Miguel, J, additional, Garcia-Sanz, R, additional, and Lahuerta, J-J, additional

Published
2017
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11. Prognostic value of antigen expression in multiple myeloma: a PETHEMA/GEM study on 1265 patients enrolled in four consecutive clinical trials

Author

Arana, P, Paiva, B, Cedena, M-T, Puig, N, Cordon, L, Vidriales, M-B, Gutierrez, N C, Chiodi, F, Burgos, L, Anglada, L-L, Martinez-Lopez, J, Hernandez, M-T, Teruel, A-I, Gironella, M, Echeveste, M-A, Rosiñol, L, Martinez, R, Oriol, A, De la Rubia, J, Orfao, A, Blade, J, Lahuerta, J-J, Mateos, M-V, and San Miguel, J-F

Abstract

Persistence of minimal residual disease (MRD) after treatment for myeloma predicts inferior outcomes, but within MRD-positive patients there is great heterogeneity with both early and very late relapses. Among different MRD techniques, flow cytometry provides additional information about antigen expression on tumor cells, which could potentially contribute to stratify MRD-positive patients. We investigated the prognostic value of those antigens required to monitor MRD in 1265 newly diagnosed patients enrolled in the GEM2000, GEM2005MENOS65, GEM2005MAS65 and GEM2010MAS65 protocols. Overall, CD19pos, CD27neg, CD38lo, CD45pos, CD81pos, CD117negand CD138loexpression predicted inferior outcomes. Through principal component analysis, we found that simultaneous CD38lowCD81posCD117negexpression emerged as the most powerful combination with independent prognostic value for progression-free survival (HR:1.69; P=0.002). This unique phenotypic profile retained prognostic value among MRD-positive patients. We then used next-generation flow to determine antigen stability throughout the course of the disease, and found that the expression of antigens required to monitor MRD is mostly stable from diagnosis to MRD stages, except for CD81 whose expression progressively increased from baseline to chemoresistant tumor cells (14 vs 28%). Altogether, we showed that the phenotypic profile of tumor cells provides additional prognostic information, and could be used to further predict risk of relapse among MRD-positive patients.

Published
2018
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12. STUDY OF THE CLINICAL RELEVANCE AND GENOMIC PROFILE OF MINIMAL RESIDUAL MULTIPLE MYELOMA DISEASE IN PATIENTS WITH STANDARD RISK AND HIGH CYTOGENETIC RISK

Author

Goicoechea, I., Puig, N., Cedena, M. T., Cordon, L., Vidriales, M. B., Burgos, L., Flores-Montero, J., Gutierrez, N. C., Calasanz, M. J., Martin-Ramos, M. L., Lara-Astiaso, D., Botta, C., Garcia-Sanz, R., Joaquin Martinez-Lopez, Oriol, A., Rios, R., Martin, J., Martinez, R., Orfao, A., Rosinol, L., Mateos, M., Lahuerta, J. J., Blade, J., San-Miguel, J. F., and Paiva, B.

13. COMPARISON OF CYTOGENETIC ABERRATIONS IN 1590 PATIENTS WITH THERAPY-RELATED MDS (T-MDS) AND 4738 PATIENTS FROM THE REVISED INTERNATIONAL PROGNOSTIC SCORING SYSTEM DATABASE WITH PRIMARY-MDS (P-MDS)

Author

Kuendgen, A., Nomdedeu, M., Tuechler, H., Garcia-Manero, G., Komrokji, R., Sekeres, M., Della Porta, M., Cazzola, M., LUCA MALCOVATI, Dezern, A., Roboz, G., Steensma, D., Haase, D., Stauder, R., Cedena, M. T., Loosdrecht, A., Schlenk, R., Blum, S., Grau, J., Calvo, X., Valent, P., Costa, D., Pereira, A., Xicoy, B., Doehner, H., Platzbecker, U., Giagounidis, A., Pedro, C., Luebbert, M., Oiartzabal, I., Diez-Campelo, M., Machherndl-Spandl, S., Lopez-Pavia, M., Martinez-De-Sola, M., Merchan, B., Ganster, C., Schroeder, T., Voso, M. T., Hildebrandt, B., Esteve, J., Nomdedeu, B., Cobo, F., Haas, R., Sole, F., Germing, U., Greenberg, P., Sill, H., Pfeilstoecker, M., and Sanz, G.

15. CRITICAL ANALYSIS OF THE STRINGENT COMPLETE RESPONSE IN MULTIPLE MYELOMA. UPDATING DATA BASED ON PHASE 3 STUDY PETHEMA/GEM2012MINUS65

Author

Jimenez Ubieto, A., Martinez Lopez, J., Bruno, P., Rosinol, L., Gonzalez Medina, J., Puig, N., Cedena, M. T., Calasanz, M. J., Ramos, M. L., Alonso, R., Oriol, A., Blanchard, M. J., Rios, R., Martin, J., Martinez, R., Sarra, J., Hernandez, M. T., La Rubia, J., Krnisk, I., Moraleda, J. M., Palomera, L., Mateos, M., Blade, J., San Miguel, J., and Juan José Lahuerta

16. SPRESAS (SPANISH REGISTRY OF ERYTHROPOIETIC STIMULATING AGENTS STUDY) SUBANALYSIS: IMPACT OF COMORBIDITIES AND CENTER LEVEL ON RESPONSE TO ESAS IN LOWER RISK MDS

Author

Davila Valls, J., Sanchez Barba, M., Lopez Pavia, M., Such, E., Teresa Bernal, Luno, E., Ramos, F., Calabuig, M., Pomares, H., Gonzalez, B., Merchan, B., Barranco, E., Sancho Tello, R., Callejas, M., Requena, M. J., Jimenez, M. J., Pedreno, M., Medina, A., Vicente, A. I., Campeny, A., Cortes Sansa, M., Pedro, C., Falantes, J. F., Arilla, M. J., Barez, A., Garcia, R., Arcos, M. J., Gomez, V., Munoz, C., Cervero, C., Casano, J., Paz, R., Amigo, L., Insunza, A., Munoz, J. A., Cedena, M. T., Gomez, M., Font, P., Del Campo, R., Fernandez Lago, C., Gonzalez Hurtado, J. A., Linares Latorre, M. D., Mora Casado, A., Vahi, M., Benlloch, L., Sanz, G. F., Del Canizo Fernandez-Roldan, M. C., and Diez Campelo, M.

17. NEW GENERATION ALTERNATIVES FOR THE DETECTION AND QUANTIFICATION OF MINIMUM RESIDUAL DISEASE (EMR) IN PATIENTS WITH MULTIPLE MYELOMA

Author

Medina-Herrera, A., Jimenez, C., Puig, N., Sanchez-Vega, B., Gonzalez, M., Ayala, R., Sarasquete, M. E., Paiva, B., Cedena, M. T., Rapado, I., Rosinol, L., Ocio, E. M., Oriol, A., Miller, J., Fernandez-Ruicobo, F., Hernandez, M. T., Martinez Martinez, R., Mateos, M., Juan José Lahuerta, Blade, J., San Miguel, J. F., Martinez-Lopez, J., and Garcia-Sanz, R.

18. PREDICTORS OF EARLY DEATH RELATED TO ACTIVE MULTIPLE MYELOMA IN ELDERLY PATIENTS RECEIVING OPTIMIZED FRONTLINE TREATMENT COMBINATIONS

Author

Rodriguez Otero, P., Mateos, M. V., Joaquin, M. -L, Miguel Teodoro, H., Enrique M, O., Rosinol, L., Martinez, R., Teruel, A. -I, Gutierrez, N. C., Oriol, A., Martin-Calvo, N., Paiva, B., Bargay, J., Bengoechea, E., Gonzalez, Y., Perez Oteyza, J., Gironella, M., Encinas, C., Martin, J., Cabrera, C., Palomera, L., Arriba, F., Cedena, M. T., Puig, N., Blade, J., Juan José Lahuerta, and San Miguel, J. F.

20. ANALYSIS OF RESIDUAL DISEASE IN PERIPHERAL BLOOD BY MEANS OF MASS SPECTROMETRY IN PATIENTS WITH MULTIPLE MYELOMA OF THE GEM 2012 MINUS65. COMPARISON WITH THE IMWG STANDARD RESPONSE AND RESIDUAL DISEASE CRITERIA

Author

Puig, N., Contreras, T., Paiva, B., Cedena, M. T., Rosinol, L., Garcia-Sanz, R., Martinez-Lopez, J., Oriol, A., Blanchard, M. J., Rios, R., Martin, J., Sureda, A., Hernandez, M. T., La Rubia, J., Krsnik, I., Moraleda, J. M., Palomera, L., Inigo, M., Agullo, C., Bargay, J., Blade, J., San Miguel, J. F., Juan José Lahuerta, and Mateos, M.

22. SPRESAS (SPANISH REGISTRY OF ERYTHROPOIETIC STIMULATING AGENTS STUDY): THE LARGEST RETROSPECTIVE STUDY OF TREATMENT WITH ESAS IN LOWER RISK MDS

Author

Diez Campelo, M., Lorenzo, J. I., Benlloch, L. I., Davila, J., Teresa Bernal, Luno, E., Lopez-Pavia, M., Such, E., Ramos, F., Calabuig, M., Pomares, H., Gonzalez, B., Merchan, B., Barranco, E., Sancho Tello, R., Callejas, M., Requena, M. J., Jimenez, M. J., Pedreno, M., Vicente, A. I., Medina, A., Campeny, A., Cortes Sansa, M., Pedro, C., Falantes, J. F., Arilla, M. J., Barez, A., Garcia, R., Arcos, M. J., Gomez, V., Munoz, C., Cervero, C., Casano, J., Paz, R., Amigo, M. L., Insunza, A., Munoz, J. A., Cedena, M. T., Gomez, M., Font, P., Del Campo, R., Fernandez Lago, C., Gonzalez Hurtado, J. A., Linares Latorre, M. D., Mora Casado, A., Vahi, M., Sanz, G., and Del Canizo, C.

24. Biological and clinical significance of dysplastic hematopoiesis in patients with newly diagnosed multiple myeloma

Author

Norma C. Gutiérrez, Felipe Prosper, Gorka Alkorta, Rafael Martínez, Felipe de Arriba, José de Jesús Pérez, Francisco Javier Gracia-Aznárez, Ibai Goicoechea, Diego Alignani, Leire Burgos, Noemi Puig, Maria-Teresa Cedena, Juan José Lahuerta, Bruno Paiva, Marcos González, Albert Oriol, Maria-Jose Calasanz, Maria-Victoria Mateos, Raquel de Paz, Alberto Orfao, Rafael Valdés-Mas, Catarina Maia, Jesús F. San Miguel, Juana Merino, Joan Bladé, Joaquin Martinez-Lopez, Sergio Matarraz, Cirino Botta, Laura Rosiñol, M C Chillón, Ana-Isabel Teruel, Miguel T. Hernandez, Luis Palomera, Iria Vázquez, Ramón García-Sanz, Sarai Sarvide, Cristina Moreno, Paula Martínez de Aguirre, Maia C., Puig N., Cedena M.-T., Goicoechea I., Valdes-Mas R., Vazquez I., Chillon M.-C., Aguirre P., Sarvide S., Gracia-Aznarez F.J., Alkorta G., Calasanz M.-J., Garcia-Sanz R., Gonzalez M., Gutierrez N.C., Martinez-Lopez J., Perez J.J., Merino J., Moreno C., Burgos L., Alignani D., Botta C., Prosper F., Matarraz S., Orfao A., Oriol A., Teruel A.-I., de Paz R., de Arriba F., Hernandez M.T., Palomera L., Martinez R., Rosinol L., Mateos M.-V., Lahuerta J.-J., Blade J., San Miguel J.F., and Paiva B.

Subjects
Male, Oncology, Physics::Instrumentation and Detectors, medicine.medical_treatment, Kaplan-Meier Estimate, Hematopoietic stem cell transplantation, Biochemistry, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Tumor Microenvironment, Prospective Studies, Computer Science::Operating Systems, In Situ Hybridization, Fluorescence, Multiple myeloma, Randomized Controlled Trials as Topic, Computer Science::Cryptography and Security, Hazard ratio, Hematopoietic Stem Cell Transplantation, High-Throughput Nucleotide Sequencing, Hematology, Middle Aged, Flow Cytometry, Prognosis, Combined Modality Therapy, Progression-Free Survival, medicine.anatomical_structure, Female, Clonal Hematopoiesis, Multiple Myeloma, medicine.medical_specialty, Immunology, Transplantation, Autologous, Internal medicine, medicine, Humans, Clinical significance, Progression-free survival, Computer Science::Distributed, Parallel, and Cluster Computing, Aged, Antineoplastic Combined Chemotherapy Protocol, business.industry, Cell Biology, medicine.disease, Transplantation, Clinical Trials, Phase III as Topic, Myelodysplastic Syndromes, Mutation, Bone marrow, business, Monoclonal gammopathy of undetermined significance
Abstract

On behalf of the PETHEMA/GEM Cooperative Group., Risk of developing myelodysplastic syndrome (MDS) is significantly increased in both multiple myeloma (MM) and monoclonal gammopathy of undetermined significance, suggesting that it is therapy independent. However, the incidence and sequelae of dysplastic hematopoiesis at diagnosis are unknown. Here, we used multidimensional flow cytometry (MFC) to prospectively screen for the presence of MDS-associated phenotypic alterations (MDS-PA) in the bone marrow of 285 patients with MM enrolled in the PETHEMA/GEM2012MENOS65 trial (#NCT01916252). We investigated the clinical significance of monocytic MDS-PA in a larger series of 1252 patients enrolled in 4 PETHEMA/GEM protocols. At diagnosis, 33 (11.6%) of 285 cases displayed MDS-PA. Bulk and single-cell–targeted sequencing of MDS recurrently mutated genes in CD34+ progenitors (and dysplastic lineages) from 67 patients revealed clonal hematopoiesis in 13 (50%) of 26 cases with MDS-PA vs 9 (22%) of 41 without MDS-PA; TET2 and NRAS were the most frequently mutated genes. Dynamics of MDS-PA at diagnosis and after autologous transplant were evaluated in 86 of 285 patients and showed that in most cases (69 of 86 [80%]), MDS-PA either persisted or remained absent in patients with or without MDS-PA at diagnosis, respectively. Noteworthy, MDS-associated mutations infrequently emerged after high-dose therapy. Based on MFC profiling, patients with MDS-PA have altered hematopoiesis and T regulatory cell distribution in the tumor microenvironment. Importantly, the presence of monocytic MDS-PA at diagnosis anticipated greater risk of hematologic toxicity and was independently associated with inferior progression-free survival (hazard ratio, 1.5; P = .02) and overall survival (hazard ratio, 1.7; P = .01). This study reveals the biological and clinical significance of dysplastic hematopoiesis in newly diagnosed MM, which can be screened with moderate sensitivity using cost-effective MFC.

Published
2020

25. Response to azacitidine in patients with chronic myelomonocytic leukemia according to overlap myelodysplastic/myeloproliferative neoplasms criteria.

Author

Triguero A, Xicoy B, Zamora L, Jiménez MJ, García O, Calabuig M, Díaz-Beyá M, Arzuaga J, Ramos F, Medina A, Bernal T, Talarn C, Coll R, Collado R, Chen TH, Borrás J, Brunet S, Marchante I, Marco V, López-Cadenas F, Calbacho M, Simiele A, Cortés M, Cedena MT, Pedreño M, Aguilar C, Pedró C, Fernández M, Stoica C, Ribera JM, and Sanz G

Subjects
Humans, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes drug therapy, Myelodysplastic-Myeloproliferative Diseases drug therapy, Retrospective Studies, Azacitidine adverse effects, Azacitidine therapeutic use, Leukemia, Myelomonocytic, Chronic drug therapy
Abstract

Background: Azacitidine (AZA) is approved for the treatment of high-risk chronic myelomonocytic leukemia (CMML) of myelodysplastic (MD) subtype. Data of response rates using the specific response criteria for this disease are scarce. The aim of this study was to evaluate the response to AZA in patients diagnosed with CMML from the Spanish Registry of Myelodysplastic Syndromes (MDS) applying the overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN) response criteria., Methods: We retrospectively studied 91 patients with CMML treated with at least one cycle of AZA from the Spanish Registry of MDS. As it was a real-world study, the response rate was evaluated between cycle 4 and 6, applying the MDS/MPN response criteria FINDINGS: The overall response rate at cycle 4-6 was 58%. Almost half of the patients achieved transfusion independence and one quarter showed clinical benefit, regardless of the CMML French-American-British (FAB) and World Health Organization (WHO) subtypes and CMML Specific Prognosis Scoring (CPSS) risk groups. Toxicity was higher in the MD-CMML subtype., Interpretation: In our series, most CMML patients achieved an overall response rate with AZA according to the overlap-MDS/MPN response criteria regardless of the CMML FAB and WHO subtypes and CPSS risk groups. Thus, AZA may also be a treatment option for patients with the myeloproliferative CMML subtype and those with a lower-risk CPSS, but symptomatic., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Published
2022
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