Chillón, M.C. (María del Carmen)
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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.
- 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.
- Characteristics and outcomes of adult patients in the PETHEMA registry with relapsed or refractory FLT3-ITD mutation-positive acute myeloid leukemia(2022) Espadana, A. (Ana); García-Boyero, R. (Raimundo); Serrano, J. (Josefina); Martínez-López, J. (Joaquín); Amigo, M.L. (Mari Luz); Montesinos, P. (Pau); Martínez-Sánchez, P. (Pilar); Pérez-Encinas, M.M. (Manuel M.); Rodríguez-Gutiérrez, J.I. (Juan I.); López, A. (Andrés); López, J.A. (Juan A.); Vasconcelos, G. (Graça); Rodríguez-Veiga, R. (Rebeca); Vidriales, M.B. (María Belén); Rodríguez-Arbolí, E. (Eduardo); Bergua, J. (Juan); Mariz, J. (José); Bernal, T. (Teresa); Rodríguez-Medina, C. (Carlos); Tormo, M. (Mar); Labrador, J. (Jorge); Vives, S. (Susana); Martínez-Chamorro, C. (Carmen); Sanz, M.A. (Miguel A.); Algarra, L. (Lorenzo); Polo, M. (Marta); García-Fortes, M. (María); Barragán, E. (Eva); Noriega, V. (Víctor); Boluda, B. (Blanca); Chillón, M.C. (María del Carmen); Calasanz-Abinzano, M.J. (Maria Jose); Martínez-Cuadron, D. (David); Aguiar, E. (Eliana); Alonso-Domínguez, J.M. (Juan M.); Herrera, P. (Pilar); Gil, C. (Cristina); Sayas, M.J. (María J.)Simple Summary Most adult patients with acute myeloid leukemia (AML) relapse after achieving complete remission with chemotherapy; however, there is no standard second-line (salvage) treatment. We retrospectively investigated 404 patients aged >= 18 years with relapsed/refractory (R/R) AML with an FMS-like tyrosine kinase 3 (FLT3) mutation, treated at a PETHEMA (NCT02607059) site between 1998 and 2018. Patients received salvage treatment with intensive therapy (n = 261), non-intensive therapy (n = 63) or supportive care (n = 80). Complete remission was achieved by 48% of patients who received intensive therapy vs. 19% with non-intensive therapy. Intensive/non-intensive therapy prolonged overall survival significantly compared with supportive therapy. Of evaluable patients, 22% received an allogeneic stem-cell transplant after complete remission. The majority of patients with FLT3-mutated R/R AML received intensive salvage therapy, with the best outcomes being obtained when intensive salvage treatment was combined with stem-cell transplant. This retrospective study investigated outcomes of 404 patients with relapsed/refractory (R/R) FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) acute myeloid leukemia (AML) enrolled in the PETHEMA registry, pre-approval of tyrosine kinase inhibitors. Most patients (63%) had received first-line intensive therapy with 3 + 7. Subsequently, patients received salvage with intensive therapy (n = 261), non-intensive therapy (n = 63) or supportive care only (n = 80). Active salvage therapy (i.e., intensive or non-intensive therapy) resulted in a complete remission (CR) or CR without hematological recovery (CRi) rate of 42%. More patients achieved a CR/CRi with intensive (48%) compared with non-intensive (19%) salvage therapy (p < 0.001). In the overall population, median overall survival (OS) was 5.5 months; 1- and 5-year OS rates were 25% and 7%. OS was significantly (p < 0.001) prolonged with intensive or non-intensive salvage therapy compared with supportive therapy, and in those achieving CR/CRi versus no responders. Of 280 evaluable patients, 61 (22%) had an allogeneic stem-cell transplant after they had achieved CR/CRi. In conclusion, in this large cohort study, salvage treatment approaches for patients with FLT3-ITD mutated R/R AML were heterogeneous. Median OS was poor with both non-intensive and intensive salvage therapy, with best long-term outcomes obtained in patients who achieved CR/CRi and subsequently underwent allogeneic stem-cell transplant.
- Comparison of next-generation sequencing (NGS) and next-generation flow (NGF) for minimal residual disease (MRD) assessment in multiple myeloma(2020) Gonzalez-Calle, V. (Veronica); Cedena, M.T. (María Teresa); Montero, J. (Juan); 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); Orfao, A. (Alberto); Alcoceba, M. (Miguel); Medina, A. (Alejandro); Mateos, M.V. (María Victoria); Hernandez, M.T. (Miguel Teodoro); Rosiñol, L. (Laura); Puig, N. (Noemí); Lahuerta, J.J. (Juan José); Gutierrez, N.C. (Norma C.); Paiva, B. (Bruno); Oriol, A. (Albert); Chillón, M.C. (María del Carmen); San-Miguel, J.F. (Jesús F.); Jiménez, C. (Cristina)