García-Sanz, R. (Ramón)
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- Assessment of the clinical utility of four NGS panels in myeloid malignancies. Suggestions for NGS panel choice or design(2020) Ariceta, B. (Beñat); Fernandez-Mercado, M. (Marta); Aguilera-Díaz, A. (Almudena); Prieto-Conde, M.I. (María Isabel); García-Sanz, R. (Ramón); Palomino-Echeverría, S. (Sara); Mañú, A. (Amagoia); Alfonso-Piérola, A. (Ana); Vazquez, I. (Iria); Larrayoz, M.J. (María J.); Prosper-Cardoso, F. (Felipe); Chillón, M.C. (María del Carmen); Blasco-Iturri, Z. (Zuriñe); Calasanz-Abinzano, M.J. (Maria Jose)The diagnosis of myeloid neoplasms (MN) has significantly evolved through the last few decades. Next Generation Sequencing (NGS) is gradually becoming an essential tool to help clinicians with disease management. To this end, most specialized genetic laboratories have implemented NGS panels targeting a number of different genes relevant to MN. The aim of the present study is to evaluate the performance of four different targeted NGS gene panels based on their technical features and clinical utility. A total of 32 patient bone marrow samples were accrued and sequenced with 3 commercially available panels and 1 custom panel. Variants were classified by two geneticists based on their clinical relevance in MN. There was a difference in panel¿s depth of coverage. We found 11 discordant clinically relevant variants between panels, with a trend to miss long insertions. Our data show that there is a high risk of finding different mutations depending on the panel of choice, due both to the panel design and the data analysis method. Of note, CEBPA, CALR and FLT3 genes, remains challenging the use of NGS for diagnosis of MN in compliance with current guidelines. Therefore, conventional molecular testing might need to be kept in place for the correct diagnosis of MN for now.
- Pegylated liposomal doxorubicin, melphalan and prednisone therapy for elderly patients with multiple myeloma(Wiley-Blackwell, 2006) Alegre, A. (A.); García-Sanz, R. (Ramón); Hernandez, J.M. (J. M.); Mateos, M.V. (María Victoria); Barez, A. (A.); Garcia-Laraña, J. (J.); Prosper-Cardoso, F. (Felipe); Sureda-Balari, A. M. (Anna Maria); San-Miguel, J.F. (Jesús F.)Melphalan&Prednisone (MP) is considered as the standard therapy for Multiple Myeloma (MM) patients not eligible for high-dose therapy. Here, we report the results of a phase I–II study to evaluate the feasibility and efficacy of the association of PLDto the conventionalMP regimen during the first six cycles of the front-line therapy for untreatedMMpatients older than 70. Thirty patients were included in the study with a median age of 77 years (71–84) and a M/F ratio of 17/13. The phase I of the study demonstrated that the maximum tolerable dose of PLD in this setting was 30mg/m2, so itwas the final dose evaluated in the study. Twenty-nine patients were valuable for response, which was: complete in 4 (14%) partial in 15 (52%) minor/ no changes in 7 (24%) and progressive in 3 (10%). The median progression free survival (PFS) was 24 months. The median overall survival (OS) has not been reached yet, with a 3-year probability for OS and PFS of 52 and 37%, respectively. Haematological toxicity was frequent but usually weak/moderate (grades 1&2 of theWHOscale) and itwas resolved only with dose delays. Infection was a relatively frequent event (30%of patients), but only in 4 cases it was of grade 3. No cases of palmar-plantar erythrodysesthesia were observed. In conclusion, pegylated liposomal doxorubicin can be safely added to the other chemotherapeutic drugs in the treatment of elderly MM patients, which can be very useful for patients in whomnovel agents are not tolerated or inefficient.
- Preneoplastic somatic mutations including MYD88(L265P) in lymphoplasmacytic lymphoma(2022) Reinhardt, H.C. (Hans Christian); Vilas, A. (Amaia); Sanchez-Garcia, I. (Isidro); Perez, C. (Cristina); Paiva, A. (Artur); López-de-Arancibia, A. (Aitziber); Sacco, A. (Antonio); Santos, S. (S.); Celay, J. (Jon); Sarvide, S. (Sarai); García-Sanz, R. (Ramón); Goicoechea, I. (Ibai); García-Barchino, M.J. (María José); Martinez-Climent, J.A. (José Ángel); Gárate-Luzuriaga, S. (Sonia); Carrasco, Y.R. (Yolanda R.); Panizo, C. (Carlos); Larrayoz, M. (Marta); Vitoria, H. (Helena); Puig, N. (Noemí); Botta, C. (Cirino); Rodríguez-Díaz, S. (Saray); Garcés-Latre, J.J. (Juan José); Motta, M. (Marina); Geraldes, C. (Catarina); Lamo-de-Espinosa-Vázquez-de-Sola, J.M. (José María); Alignani, D. (Diego); Duarte, S. (Sara); Paiva, B. (Bruno); Larrayoz, M.J. (María J.); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Roccaro, A.M. (Aldo M.); Fuerte, G. (Gema); Tucci, A. (Alessandra); San-Miguel, J.F. (Jesús F.); Gentile, M. (Massimo); Jiménez, C. (Cristina)Normal cell counterparts of solid and myeloid tumors accumulate mutations years before disease onset; whether this occurs in B lymphocytes before lymphoma remains uncertain. We sequenced multiple stages of the B lineage in elderly individuals and patients with lymphoplasmacytic lymphoma, a singular disease for studying lymphomagenesis because of the high prevalence of mutated MYD88. We observed similar accumulation of random mutations in B lineages from both cohorts and unexpectedly found MYD88(L265P) in normal precursor and mature B lymphocytes from patients with lymphoma. We uncovered genetic and transcriptional pathways driving malignant transformation and leveraged these to model lymphoplasmacytic lymphoma in mice, based on mutated MYD88 in B cell precursors and BCL2 overexpression. Thus, MYD88(L265P) is a preneoplastic event, which challenges the current understanding of lymphomagenesis and may have implications for early detection of B cell lymphomas.
- Molecular profiling of immunoglobulin heavychain gene rearrangements unveils new potential prognostic markers for multiple myeloma patients(2020) Gonzalez-Calle, V. (Veronica); Martínez-López, J. (Joaquín); Garcia-Alvarez, M. (María); Gonzalez, M. (Marcos); Gironella, M. (Mercedes); Bladé, J. (Joan); Prieto-Conde, M.I. (María Isabel); Sarasquete, M.E. (María E.); García-Sanz, R. (Ramón); Alcoceba, M. (Miguel); Medina, A. (Alejandro); Mateos, M.V. (María Victoria); Hernandez, M.T. (Miguel Teodoro); Balanzategui, A. (Ana); Puig, N. (Noemí); Barrio, S. (Santiago); Pérez-Cuenca, I. (Isabel); Lahuerta-Vargas, J.J. (Juan José); Gutierrez, N.C. (Norma C.); Escalante, L.F. (Luis Fernando); Oriol, A. (Albert); Sureda-Balari, A. M. (Anna Maria); Chillón, M.C. (María del Carmen); Calasanz-Abinzano, M.J. (Maria Jose); San-Miguel, J.F. (Jesús F.); Jiménez, C. (Cristina)Multiple myeloma is a heterogeneous disease whose pathogenesis has not been completely elucidated. Although B-cell receptors play a crucial role in myeloma pathogenesis, the impact of clonal immunoglobulin heavy-chain features in the outcome has not been extensively explored. Here we present the characterization of complete heavychain gene rearrangements in 413 myeloma patients treated in Spanish trials, including 113 patients characterized by next-generation sequencing. Compared to the normal B-cell repertoire, gene selection was biased in myeloma, with significant overrepresentation of IGHV3, IGHD2 and IGHD3, as well as IGHJ4 gene groups. Hypermutation was high in our patients (median: 8.8%). Interestingly, regarding patients who are not candidates for transplantation, a high hypermutation rate (≥7%) and the use of IGHD2 and IGHD3 groups were associated with improved prognostic features and longer survival rates in the univariate analyses. Multivariate analysis revealed prolonged progression-free survival rates for patients using IGHD2/IGHD3 groups (HR: 0.552, 95% CI: 0.361−0.845, p = 0.006), as well as prolonged overall survival rates for patients with hypermutation ≥7% (HR: 0.291, 95% CI: 0.137−0.618, p = 0.001). Our results provide new insights into the molecular characterization of multiple myeloma, highlighting the need to evaluate some of these clonal rearrangement characteristics as new potential prognostic markers.
- Networking for advanced molecular diagnosis in acute myeloid leukemia patients is possible: the PETHEMA NGS-AML project(2021) García-Boyero, R. (Raimundo); Serrano, J. (Josefina); Yébenes-Ramírez, M. (Manuel); Martínez-López, J. (Joaquín); Perez-Simon, J.A. (José Antonio); Amigo, M.L. (Mari Luz); Montesinos, P. (Pau); Martínez-Sánchez, P. (Pilar); García-Sanz, R. (Ramón); Florido-Ortega, Y. (Yanira); Sánchez-García, J. (Joaquín); Bergua, J. (Juan); Bernal, T. (Teresa); Ayala, R. (Rosa); Lavilla, E. (Esperanza); Tormo, M. (Mar); Costilla-Barriga, L. (Lisette); Llop, M. (Marta); Rapado, I. (Inmaculada); Janusz, K. (Kamila); Sanz, M.A. (Miguel A.); Herrera-Puente, P. (Pilar); Algarra, L. (Lorenzo); González-Díaz, M. (Marcos); Pérez-Santolalla, E. (Esther); Gomez-Casares, M.T. (María T.); Vazquez, I. (Iria); Barragán, E. (Eva); Noriega, V. (Víctor); Larrayoz, M.J. (María J.); Botella, C. (Carmen); Sargas, C. (Claudia); Soria, E. (Elena); Chillón, M.C. (María del Carmen); Calasanz-Abinzano, M.J. (Maria Jose); Martínez-Cuadron, D. (David); Alonso-Domínguez, J.M. (Juan M.); Marchante, I. (Inmaculada); Bilbao, C. (Cristina); Sayas, M.J. (María J.); Carrillo-Cruz, E. (Estrella)Next-Generation Sequencing has recently been introduced to efficiently and simultaneously detect genetic variations in acute myeloid leukemia. However, its implementation in the clinical routine raises new challenges focused on the diversity of assays and variant reporting criteria. To overcome this challenge, the PETHEMA group established a nationwide network of reference laboratories aimed to deliver molecular results in the clinics. We report the technical cross-validation results for next-generation sequencing panel genes during the standardization process and the clinical validation in 823 samples of 751 patients with newly diagnosed or refractory/relapse acute myeloid leukemia. Two cross-validation rounds were performed in seven nationwide reference laboratories in order to reach a consensus regarding quality metrics criteria and variant reporting. In the pre-standardization cross-validation round, an overall concordance of 60.98% was obtained with a great variability in selected genes and conditions across laboratories. After consensus of relevant genes and optimization of quality parameters the overall concordance rose to 85.57% in the second cross-validation round. We show that a diagnostic network with harmonized next-generation sequencing analysis and reporting in seven experienced laboratories is feasible in the context of a scientific group.
- Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: updated time-to-events results and prognostic factors for time to progression(Fondazione Ferrata Storti, 2008) Alegre, A. (A.); Mateo, G. (Gemma); Bladé, J. (Joan); García-Sanz, R. (Ramón); Hernandez, J.M. (J. M.); Mateos, M.V. (María Victoria); Arriba, F. (Felipe) de; Esseltine, D.L. (D. L.); Hernandez, M.T. (Miguel Teodoro); Carrera, D. (D,); Garcia-Sanchez, P. (P.); Palomera, L. (Luis); Terol, M.J. (María José); Velde, H. (Helgi) van de; Lahuerta, J.J. (Juan José); Gutierrez, N.C. (Norma C.); Fuertes, M. (M.); Ribas, P. (Paz); Garcia-Laraña, J. (J.); Oriol, A. (Albert); Rubia, J. (Javier) de la; Prosper-Cardoso, F. (Felipe); Sureda-Balari, A. M. (Anna Maria); Bargay, J. (Joan); San-Miguel, J.F. (Jesús F.)New treatment options offering enhanced activity in elderly, newly diagnosed patients with multiple myeloma are required. One strategy is to combine melphalan and prednisone with novel agents. We previously reported an 89% response rate, including 32% complete responses and 11% near complete responses, in our phase 1/2 study of bortezomib plus melphalan and prednisone (VMP) in 60 newly diagnosed multiple myeloma patients with a median age of 75 years. Here, we report updated time-to-events data and the impact of poor prognosis factors on outcome.
- Pembrolizumab as consolidation strategy in patients with multiple myeloma: Results of the GEM-Pembresid clinical trial(MDPI AG, 2020) Paino, T. (Teresa); Gonzalez-Calle, V. (Veronica); Blanchard, M.J. (María Jesús); Pérez-Morán, J. (José); Bladé, J. (Joan); García-Sanz, R. (Ramón); Ocio, E.M. (Enrique M.); Mateos, M.V. (María Victoria); Dávila, J. (Julio); Arriba, F. (Felipe) de; Puig, N. (Noemí); Lahuerta, J.J. (Juan José); Paiva, B. (Bruno); Corchete-Sánchez, L.A. (Luis A.); Oriol, A. (Albert); Rubia, J. (Javier) de la; Martín-Sánchez, J. (Jesús); San-Miguel, J.F. (Jesús F.)PD1 expression in CD4+ and CD8+ T cells is increased after treatment in multiple myeloma patients with persistent disease. The GEM-Pembresid trial analyzed the efficacy and safety of pembrolizumab as consolidation in patients achieving at least very good partial response but with persistent measurable disease after first- or second-line treatment. Moreover, the characteristics of the immune system were investigated to identify potential biomarkers of response to pembrolizumab. One out of the 17 evaluable patients showed a decrease in the amount of M-protein, although a potential late effect of high-dose melphalan could not be ruled out. Fourteen adverse events were considered related to pembrolizumab, two of which (G3 diarrhea and G2 pneumonitis) prompted treatment discontinuation and all resolving without sequelae. Interestingly, pembrolizumab induced a decrease in the percentage of NK cells at cycle 3, due to the reduction of the circulating and adaptive subsets (0.615 vs. 0.43, p = 0.007; 1.12 vs. 0.86, p = 0.02). In the early progressors, a significantly lower expression of PD1 in CD8+ effector memory T cells (MFI 1327 vs. 926, p = 0.03) was observed. In conclusion, pembrolizumab used as consolidation monotherapy shows an acceptable toxicity profile but did not improve responses in this MM patient population. The trial was registered at clinicaltrials.gov with identifier NCT02636010 and with EUDRACT number 2015-003359-23.
- Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study(American Society of Hematology, 2006) Alegre, A. (A.); Mateo, G. (Gemma); Bladé, J. (Joan); García-Sanz, R. (Ramón); Hernandez, J.M. (J. M.); Mateos, M.V. (María Victoria); Arriba, F. (Felipe) de; Esseltine, D.L. (D. L.); Hernandez, M.T. (Miguel Teodoro); Carrera, D. (D,); Palomera, L. (Luis); Terol, M.J. (María José); Velde, H. (Helgi) van de; Lahuerta, J.J. (Juan José); Gutierrez, N.C. (Norma C.); Fuertes, M. (M.); Ribas, P. (Paz); Garcia-Laraña, J. (J.); Oriol, A. (Albert); Rubia, J. (Javier) de la; Diaz-Mediavilla, J. (J.); Prosper-Cardoso, F. (Felipe); Sureda-Balari, A. M. (Anna Maria); Bargay, J. (Joan); San-Miguel, J.F. (Jesús F.)Standard first-line treatment for elderly multiple myeloma (MM) patients ineligible for stem cell transplantation is melphalan plus prednisone (MP). However, complete responses (CRs) are rare. Bortezomib is active in patients with relapsed MM, including elderly patients. This phase 1/2 trial in 60 untreated MM patients aged at least 65 years (half older than 75 years) was designed to determine dosing, safety, and efficacy of bortezomib plus MP(VMP). VMP response rate was 89%, including 32% immunofixation-negative CRs, of whom half of the IF– CR patients analyzed achieved immunophenotypic remission (no detectable plasma cells at 10 4 to 10 5 sensitivity). VMP appeared to overcome the poor prognosis conferred by retinoblastoma gene deletion and IgH translocations. Results compare favorably with our historical control data for MP—notably, response rate (89% versus 42%), event-free survival at 16 months (83% versus 51%), and survival at 16 months (90% versus 62%). Side effects were predictable and manageable; principal toxicities were hematologic, gastrointestinal, and peripheral neuropathy and were more evident during early cycles and in patients aged 75 years or more. In conclusion, in elderly patients ineligible for transplantation, the combination of bortezomib plus MP appears significantly superior to MP, producing very high CR rates, including immunophenotypic CRs, even in patients with poor prognostic features.
- Fratris Sebastiani Garsiae augutiniani philosophiae in Valentina Academia ... Oratio Panegyrica habita Valentiae apud sacras Sapientiae ...(Valentiae : apud Iohannem Chrysostomum Garriz, 2013-10-02) García-Sanz, R. (Ramón)
- Phenotypic and genomic analysis of multiple myeloma minimal residual disease tumor cells: a new model to understand chemoresistance(American Society of Hematology, 2016) Gironella, M. (Mercedes); Bladé, J. (Joan); Barlogie, B. (Bart); García-Sanz, R. (Ramón); Orfao, A. (Alberto); Vidriales, M.B. (María Belén); Sanchez, M.L. (Maria Luz); Ocio, E.M. (Enrique M.); Gonzalez, Y. (Yolanda); Mateos, M.V. (María Victoria); Maiso, P. (Patricia); Arriba, F. (Felipe) de; Epstein, J. (Joshua); Rodriguez, I. (Idoia); Hernandez, M.T. (Miguel Teodoro); Puig, N. (Noemí); Burgos, L. (Leire); Alignani, D. (Diego); Palomera, L. (Luis); Lahuerta, J.J. (Juan José); Paiva, B. (Bruno); Oriol, A. (Albert); Corchete, L.A. (Luis A.); Barcena, P. (Paloma); San-Miguel, J.F. (Jesús F.); Johnson, S.K. (Sarah K.); Echeveste, M.A. (Maria Asuncion)Persistence of chemoresistant minimal residual disease (MRD) plasma cells (PCs) is associated with inferior survival in multiple myeloma (MM). Thus, characterization of the minor MRD subclone may represent a unique model to understand chemoresistance, but to our knowledge, the phenotypic and genetic features of the MRD subclone have never been investigated. Here, we compared the antigenic profile of MRD vs diagnostic clonal PCs in 40 elderly MM patients enrolled in the GEM2010MAS65 study and showed that the MRD subclone is enriched in cells overexpressing integrins (CD11a/CD11c/CD29/CD49d/CD49e), chemokine receptors (CXCR4), and adhesion molecules (CD44/CD54). Genetic profiling of MRD vs diagnostic PCs was performed in 12 patients; 3 of them showed identical copy number alterations (CNAs), in another 3 cases, MRD clonal PCs displayed all genetic alterations detected at diagnosis plus additional CNAs that emerged at the MRD stage, whereas in the remaining 6 patients, there were CNAs present at diagnosis that were undetectable in MRD clonal PCs, but also a selected number of genetic alterations that became apparent only at the MRD stage. The MRD subclone showed significant downregulation of genes related to protein processing in endoplasmic reticulum, as well as novel deregulated genes such as ALCAM that is prognostically relevant in MM and may identify chemoresistant PCs in vitro. Altogether, our results suggest that therapy-induced clonal selection could be already present at the MRD stage, where chemoresistant PCs show a singular phenotypic signature that may result from the persistence of clones with different genetic and gene expression profiles. This trial was registered at www.clinicaltrials.gov as #NCT01237249.