Person: Carreño-Tarragona, Gonzalo
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First Name
Gonzalo
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Carreño-Tarragona
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CNIC
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Publication Janus kinase inhibitor ruxolitinib in combination with nilotinib and prednisone in patients with myelofibrosis (RuNiC study): A phase Ib, multicenter study(Wiley, 2023-04-16) Ayala, Rosa; Fernández, Rafael Alonso; García-Gutiérrez, Valentín; Alvarez-Larrán, Alberto; Osorio, Santiago; Sánchez-Pina, Jose M; Carreño-Tarragona, Gonzalo; Álvarez, Noemi; Gómez-Casares, María Teresa; Duran, Antonia; Gorrochategi, Julian; Hernández-Boluda, Juan Carlos; Martinez-Lopez, Joaquin; Instituto de Salud Carlos III; CRIS contra el Cáncer; Novartis FoundationThis phase Ib, non-randomized, open-label study evaluates the safety and tolerability of ruxolitinib in combination with nilotinib and prednisone in patients with na�ve or ruxolitinib-resistant myelofibrosis (MF). A total of 15 patients with primary or secondary MF received the study treatment; 13 patients had received prior ruxolitinib treatment (86.7%). Eight patients completed seven cycles (53.3%) and six patients completed twelve cycles of treatment (40%). All the patients experienced at least one adverse event (AE) during the study (the most common AEs were hyperglycemia, asthenia, and thrombocytopenia), and 14 patients registered at least one treatment-related AE (the most common treatment-related AEs were hyperglycemia (22.2%; three grade 3 cases). Five treatment-related serious AEs (SAEs) were reported in two patients (13.3%). No deaths were registered throughout the study. No dose-limiting toxicity was observed. Four out of fifteen (27%) patients experienced a 100% spleen size reduction at Cycle 7, and two additional patients achieved a�>50% spleen size reduction, representing an overall response rate of 40% at Cycle 7. In conclusion, the tolerability of this combination was acceptable, and hyperglycemia was the most frequent treatment-related AE. Ruxolitinib in combination with nilotinib and prednisone showed relevant clinical activity in patients with MF. This trial was registered with EudraCT Number 2016-005214-21.Publication Impact of FLT3-ITD Mutation Status and Its Ratio in a Cohort of 2901 Patients Undergoing Upfront Intensive Chemotherapy: A PETHEMA Registry Study.(Multidisciplinary Digital Publishing Institute (MDPI), 2022-11-24) Ayala, Rosa; Carreño-Tarragona, Gonzalo; Barragán, Eva; Boluda, Blanca; Larráyoz, María J; Chillón, María Carmen; Carrillo-Cruz, Estrella; Bilbao, Cristina; Sánchez-García, Joaquín; Bernal, Teresa; Martinez-Cuadron, David; Gil, Cristina; Serrano, Josefina; Rodriguez-Medina, Carlos; Bergua, Juan; Pérez-Simón, José A; Calbacho, María; Alonso-Domínguez, Juan M; Labrador, Jorge; Tormo, Mar; Amigo, Maria Luz; Herrera-Puente, Pilar; Rapado, Inmaculada; Sargas, Claudia; Vazquez, Iria; Calasanz, María J; Gomez-Casares, Teresa; García-Sanz, Ramón; Sanz, Miguel A; Martinez-Lopez, Joaquin; Montesinos, Pau; Instituto de Salud Carlos III; Unión Europea. Comisión Europea; CRIS contra el Cáncer; Research Institute Hospital 12 de OctubreFLT3−ITD results in a poor prognosis in terms of overall survival (OS) and relapse-free survival (RFS) in acute myeloid leukemia (AML). However, the prognostic usefulness of the allelic ratio (AR) to select post-remission therapy remains controversial. Our study focuses on the prognostic impact of FLT3−ITD and its ratio in a series of 2901 adult patients treated intensively in the pre-FLT3 inhibitor era and reported in the PETHEMA registry. A total of 579 of these patients (20%) harbored FLT3−ITD mutations. In multivariate analyses, patients with an FLT3−ITD allele ratio (AR) of >0.5 showed a lower complete remission (CR rate) and OS (HR 1.47, p = 0.009), while AR > 0.8 was associated with poorer RFS (HR 2.1; p < 0.001). Among NPM1/FLT3−ITD-mutated patients, median OS gradually decreased according to FLT3−ITD status and ratio (34.3 months FLT3−ITD-negative, 25.3 months up to 0.25, 14.5 months up to 0.5, and 10 months ≥ 0.5, p < 0.001). Post-remission allogeneic transplant (allo-HSCT) resulted in better OS and RFS as compared to auto-HSCT in NPM1/FLT3−ITD-mutated AML regardless of pre-established AR cutoff (≤0.5 vs. >0.5). Using the maximally selected log-rank statistics, we established an optimal cutoff of FLT3−ITD AR of 0.44 for OS, and 0.8 for RFS. We analyzed the OS and RFS according to FLT3−ITD status in all patients, and we found that the group of FLT3−ITD-positive patients with AR < 0.44 had similar 5-year OS after allo-HSCT or auto-HSCT (52% and 41%, respectively, p = 0.86), but worse RFS after auto-HSCT (p = 0.01). Among patients with FLT3−ITD AR > 0.44, allo-HSCT was superior to auto-HSCT in terms of OS and RFS. This study provides more evidence for a better characterization of patients with AML harboring FLT3−ITD mutations.Publication CNL and aCML should be considered as a single entity based on molecular profiles and outcomes.(Elsevier, 2023-05-09) Carreño-Tarragona, Gonzalo; Álvarez-Larrán, Alberto; Harrison, Claire; Martínez-Ávila, José Carlos; Hernández-Boluda, Juan Carlos; Ferrer-Marín, Francisca; Radia, Deepti H; Mora, Elvira; Francis, Sebastian; González-Martínez, Teresa; Goddard, Kathryn; Pérez-Encinas, Manuel; Narayanan, Srinivasan; Raya, José María; Singh, Vikram; Gutiérrez, Xabier; Toth, Peter; Amat-Martínez, Paula; Mcilwaine, Louisa; Alobaidi, Magda; Mayani, Karan; McGregor, Andrew; Stuckey, Ruth; Psaila, Bethan; Segura, Adrián; Alvares, Caroline; Davidson, Kerri; Osorio, Santiago; Cutting, Robert; Sweeney, Caroline P; Rufián, Laura; Moreno, Laura; Cuenca, Isabel; Smith, Jeffery; Morales, María Luz; Gil-Manso, Rodrigo; Koutsavlis, Ioannis; Wang, Lihui; Mead, Adam J; Rozman, María; Martinez-Lopez, Joaquin; Ayala, Rosa; Cross, Nicholas C P; Instituto de Salud Carlos III; CRIS contra el Cáncer; Research Institute Hospital 12 de OctubreChronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) are rare myeloid disorders that are challenging with regard to diagnosis and clinical management. To study the similarities and differences between these disorders, we undertook a multicenter international study of one of the largest case series (CNL, n = 24; aCML, n = 37 cases, respectively), focusing on the clinical and mutational profiles (n = 53 with molecular data) of these diseases. We found no differences in clinical presentations or outcomes of both entities. As previously described, both CNL and aCML share a complex mutational profile with mutations in genes involved in epigenetic regulation, splicing, and signaling pathways. Apart from CSF3R, only EZH2 and TET2 were differentially mutated between them. The molecular profiles support the notion of CNL and aCML being a continuum of the same disease that may fit best within the myelodysplastic/myeloproliferative neoplasms. We identified 4 high-risk mutated genes, specifically CEBPA (β = 2.26, hazard ratio [HR] = 9.54, P = .003), EZH2 (β = 1.12, HR = 3.062, P = .009), NRAS (β = 1.29, HR = 3.63, P = .048), and U2AF1 (β = 1.75, HR = 5.74, P = .013) using multivariate analysis. Our findings underscore the relevance of molecular-risk classification in CNL/aCML as well as the importance of CSF3R mutations in these diseases.Publication The pluripotency factor NANOG controls primitive hematopoiesis and directly regulates Tal1(EMBO Press, 2019-04-01) Sainz de Aja, Julio; Menchero, Sergio; Rollan, Isabel; Barral, Antonio; Tiana, Maria; Jawaid, Wajid; Cossio, Itziar; Alvarez, Alba; Carreño-Tarragona, Gonzalo; Badia-Careaga, Claudio; Nichols, Jennifer; Göttgens, Berthold; Isern, Joan; Manzanares, Miguel; Ministerio de Ciencia, Innovación y Universidades (España); Wellcome Trust; Fundación ProCNICProgenitors of the first hematopoietic cells in the mouse arise in the early embryo from Brachyury-positive multipotent cells in the posterior-proximal region of the epiblast, but the mechanisms that specify primitive blood cells are still largely unknown. Pluripotency factors maintain uncommitted cells of the blastocyst and embryonic stem cells in the pluripotent state. However, little is known about the role played by these factors during later development, despite being expressed in the postimplantation epiblast. Using a dual transgene system for controlled expression at postimplantation stages, we found that Nanog blocks primitive hematopoiesis in the gastrulating embryo, resulting in a loss of red blood cells and downregulation of erythropoietic genes. Accordingly, Nanog-deficient embryonic stem cells are prone to erythropoietic differentiation. Moreover, Nanog expression in adults prevents the maturation of erythroid cells. By analysis of previous data for NANOG binding during stem cell differentiation and CRISPR/Cas9 genome editing, we found that Tal1 is a direct NANOG target. Our results show that Nanog regulates primitive hematopoiesis by directly repressing critical erythroid lineage specifiers.