Martínez-Cuadron, D. (David)
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- A precision medicine test predicts clinical response after idarubicin and cytarabine induction therapy in AML patients(Elsevier BV, 2019) García-Boyero, R. (Raimundo); Serrano, J. (Josefina); Ballesteros, J. (Joan); Martínez-López, J. (Joaquín); Perez-Simon, J.A. (José Antonio); Pérez-Oteyza, J. (Jaime); Rodríguez-Macías, G. (Gabriela); Montesinos, P. (Pau); Jiménez-Bravo, S. (Santiago); López, J.A. (Juan A.); Vidriales, M.B. (María Belén); Bergua, J. (Juan); Troconiz, I.F. (Iñaki F.); Rojas, J.L. (José Luis); Hernández-Campo, P. (Pilar); Lavilla, E. (Esperanza); Tormo, M. (Mar); Colorado, M. (Mercedes); Moscardó, F. (Federico); Vives, S. (Susana); Primo, D. (Daniel); Gorrochategui, J. (Julián); Villoria, J. (Jesús); Sanz, M. (Miguel); Martínez-Cuadron, D. (David); Spanish PETHEMA group; Linares-Gómez, M. (María); Herrera, P. (Pilar); Gil, C. (Cristina)Complete remission (CR) after induction therapy is the first treatment goal in acute myeloid leukemia (AML) patients and has prognostic impact. Our purpose is to determine the correlation between the observed CR/CRi rate after idarubicin (IDA) and cytarabine (CYT) 3 + 7 induction and the leukemic chemosensitivity measured by an ex vivo test of drug activity. Bone marrow samples from adult patients with newly diagnosed AML were included in this study. Whole bone marrow samples were incubated for 48 h in well plates containing IDA, CYT, or their combination. Pharmacological response parameters were estimated using population pharmacodynamic models. Patients attaining a CR/CRi with up to two induction cycles of 3 + 7 were classified as responders and the remaining as resistant. A total of 123 patients fulfilled the inclusion criteria and were evaluable for correlation analyses. The strongest clinical predictors were the area under the curve of the concentration response curves of CYT and IDA. The overall accuracy achieved using MaxSpSe criteria to define positivity was 81%, predicting better responder (93%) than non-responder patients (60%). The ex vivo test provides better yet similar information than cytogenetics, but can be provided before treatment representing a valuable in-time addition. After validation in an external cohort, this novel ex vivo test could be useful to select AML patients for 3 + 7 regimen vs. alternative schedules.
- 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.
- PLZF-RAR(alpha), NPM1-RAR(alpha), and other acute promyelocytic leukemia variants: the PETHEMA registry experience and systematic literature review(2020) Rodríguez-Macías, G. (Gabriela); Montesinos, P. (Pau); Talarn-Forcadell, M.C. (Maria Carme); Mariz, J. (José); Mela-Osorio, M.J. (María J.); Rodríguez-Medina, C. (Carlos); Esteve, J. (Jordi); Cornago-Navascués, J. (Javier); Barrios, M. (M.); Escoda, L. (Lourdes); Fernandez, I. (Isolda); García-Pérez, M.J. (María J.); Sokól, A. (Agniezska); Sanz, M.A. (Miguel A.); Barragán, E. (Eva); Calasanz-Abinzano, M.J. (Maria Jose); Martínez-Cuadron, D. (David); Sobas, M. (Marta); Alonso-Domínguez, J.M. (Juan M.); Murciano-Carrillo, T. (Thais); Amutio, E. (Elena)It has been suggested that 1-2% of acute promyelocytic leukemia (APL) patients present variant rearrangements of retinoic acid receptor alpha (RAR alpha) fusion gene, with the promyelocytic leukaemia zinc finger (PLZF)/RAR(alpha) being the most frequent. Resistance to all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has been suggested in PLZF/RAR(alpha) and other variant APLs. Herein, we analyze the incidence, characteristics, and outcomes of variant APLs reported to the multinational PETHEMA (Programa para el Tratamiento de Hemopatias Malignas) registry, and we perform a systematic review in order to shed light on strategies to improve management of these extremely rare diseases. Of 2895 patients with genetically confirmed APL in the PETHEMA registry, 11 had variant APL (0.4%) (9 PLZF-RAR(alpha) and 2 NPM1-RAR(alpha)), 9 were men, with median age of 44.6 years (3 months to 76 years), median leucocytes (WBC) 16.8 x 10(9)/L, and frequent coagulopathy. Eight patients were treated with ATRA plus chemotherapy-based regimens, and 3 with chemotherapy-based. As compared to previous reports, complete remission and survival was slightly better in our cohort, with 73% complete remission (CR) and 73% survival despite a high relapse rate (43%). After analyzing our series and performing a comprehensive and critical review of the literature, strong recommendations on appropriate management of variant APL are not possible due to the low number and heterogeneity of patients reported so far.