Publicaciones científicas

Se han encontrado 70 publicaciones con los criterios indicados.
González-Gil C, Morgades M, Lopes T, Fuster-Tormo F, García-Chica J, Zhao R, Montesinos P, Torrent A, Diaz-Beya M, Coll R, Hermosín L, Mercadal S, González-Campos J, Zamora L, Artola T, Vall-Llovera F, Tormo M, Gil-Cortés C, Barba P, Novo A, Ribera J, Bernal T, De Ugarriza PL, Queipo MP, Martínez-Sánchez P, Giménez A, González-Martínez T, Cladera A, Cervera J, Fernández-Martín R, Ardaiz MÁ, Vidal MJ, Baena Á, López-Bigas N, Bigas A, Maciejewski J, Orfao A, Ribera JM, Genescà E

Genomics improves risk stratification of adults with T-cell acute lymphoblastic leukemia patients enrolled in measurable residual disease-oriented trials.

Haematologica 3 Nov 2022, . Epub 3 Nov 2022
Genetic information has been crucial to understand the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) at diagnosis and at relapse, but still nowadays has a limited value in a clinical context. Few genetic markers are associated with the outcome of T-ALL patients, independently of measurable residual disease (MRD) status after therapy. In addition, the prognostic relevance of genetic features may be modulated by the specific treatment used. We analyzed the genetic profile of 145 T-ALL patients by targeted deep sequencing. Genomic information was integrated with the clinical-biological and survival data of a subset of 116 adult patients enrolled in two consecutive MRD-oriented trials of the Spanish PETHEMA (Programa Español de Tratamientos en Hematología) group. Genetic analysis revealed a mutational profile defined by DNMT3A/ N/KRAS/ MSH2/ U2AF1 gene mutations that identified refractory/resistant patients. Mutations in the DMNT3A gene were also found in the nonleukemic cell fraction of patients with T-ALL, revealing a possible mutational-driven clonal hematopoiesis event to prime T-ALL in elderly. The prognostic impact of this adverse genetic profile was independent of MRD status on day +35 of induction therapy. The combined WOG signature and MRD on day +35 allowed risk-stratification of T-ALL into standard or high-risk groups with significantly different 5-year overall survival (OS) (95% confidence interval [CI]) of 52% (37-67 %) and 17% (1-33%), respectively. These results confirm the relevance of the tumor genetic profile in predicting patient outcome in adult T-ALL and highlight the need for novel gene-targeted chemotherapeutic schedules to improve the OS of poor-prognosis T-ALL patients.
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Elsa Bernard, Heinz Tuechler, Peter L. Greenberg, Robert P. Hasserjian, Juan E. Arango Ossa, Yasuhito Nannya, Sean M. Devlin, Maria Creignou, Philippe Pinel, Lily Monnier, Gunes Gundem, Juan S. Medina-Martinez, Dylan Domenico, Martin Jädersten, Ulrich Germing, Guillermo Sanz, Arjan A. van de Loosdrecht, Olivier Kosmider, Matilde Y. Follo, Felicitas Thol, Lurdes Zamora, Ronald F. Pinheiro, Andrea Pellagatti, Harold K. Elias, Detlef Haase, Christina Ganster, Lionel Ades, Magnus Tobiasson, Laura Palomo, Matteo Giovanni Della Porta, Akifumi Takaori-Kondo, Takayuki Ishikawa, Shigeru Chiba, Senji Kasahara, Yasushi Miyazaki, Agnes Viale, Kety Huberman, Pierre Fenaux, Monika Belickova, Michael R. Savona, Virginia M. Klimek, Fabio P. S. Santos, Jacqueline Boultwood, Ioannis Kotsianidis, Valeria Santini, Francesc Solé, Uwe Platzbecker, Michael Heuser, Peter Valent, Kazuma Ohyashiki, Carlo Finelli, Maria Teresa Voso, Lee-Yung Shih, Michaela Fontenay, Joop H. Jansen, José Cervera, Norbert Gattermann, Benjamin L. Ebert, Rafael Bejar, Luca Malcovati, Mario Cazzola, Seishi Ogawa, Eva Hellström-Lindberg, Elli Papaemmanuil

Molecular International Prognostic Scoring System for Myelodysplastic Syndromes

NEJM Evidence 12 Jun 2022, . Epub 12 Jun 2022
Lopez-Millan B, Costales P, Gutiérrez-Agüera F, Díaz de la Guardia R, Roca-Ho H, Vinyoles M, Rubio-Gayarre A, Safi R, Castaño J, Romecín PA, Ramírez-Orellana M, Anguita E, Jeremias I, Zamora L, Rodríguez-Manzaneque JC, Bueno C, Morís F, Menendez P

The Multi-Kinase Inhibitor EC-70124 Is a Promising Candidate for the Treatment of FLT3-ITD-Positive Acute Myeloid Leukemia.

Cancers (Basel) 21 Mar 2022, 14 (6) . Epub 21 Mar 2022
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Patients with AML harboring a constitutively active internal tandem duplication mutation (ITDMUT) in the FMS-like kinase tyrosine kinase (FLT3) receptor generally have a poor prognosis. Several tyrosine kinase/FLT3 inhibitors have been developed and tested clinically, but very few (midostaurin and gilteritinib) have thus far been FDA/EMA-approved for patients with newly diagnosed or relapse/refractory FLT3-ITDMUT AML. Disappointingly, clinical responses are commonly partial or not durable, highlighting the need for new molecules targeting FLT3-ITDMUT AML. Here, we tested EC-70124, a hybrid indolocarbazole analog from the same chemical space as midostaurin with a potent and selective inhibitory effect on FLT3. In vitro, EC-70124 exerted a robust and specific antileukemia activity against FLT3-ITDMUT AML primary cells and cell lines with respect to cytotoxicity, CFU capacity, apoptosis and cell cycle while sparing healthy hematopoietic (stem/progenitor) cells. We also analyzed its efficacy in vivo as monotherapy using two different xenograft models: an aggressive and systemic model based on MOLM-13 cells and a patient-derived xenograft model. Orally disposable EC-70124 exerted a potent inhibitory effect on the growth of FLT3-ITDMUT AML cells, delaying disease progression and debulking the leukemia. Collectively, our findings show that EC-70124 is a promising and safe agent for the treatment of AML with FLT3-ITDMUT.
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Diaz de la Guardia R, Velasco-Hernandez T, Gutierrez-Agüera F, Roca-Ho H, Molina O, Nombela-Arrieta C, Bataller A, Fuster JL, Anguita E, Vives S, Zamora L, Nomdedeu JF, Gomez-Casares MT, Ramírez-Orellana M, Lapillonne H, Ramos-Mejia V, Rodríguez-Manzaneque JC, Bueno C, Lopez-Millan B, Menendez P

Engraftment characterization of risk-stratified AML patients in NSGS mice.

Blood Adv 1 Sep 2021, . Epub 1 Sep 2021
Acute myeloid leukemia (AML) is the commonest acute leukemia in adults. Disease heterogeneity is well-documented and patient stratification determines treatment decisions. Patient-derived xenografts (PDXs) of risk-stratified AMLs are crucial for studying AML biology and testing novel therapeutics. Despite recent advances in PDX modeling of AML, reproducible engraftment of human AML is mainly limited to high-risk (HR) cases, with inconsistent or very protracted engraftment observed for favorable-risk (FR) and intermediate-risk (IR) patients. We have characterized the engraftment robustness/kinetics in NSGS mice of 28 AML patients grouped according to molecular/cytogenetic classification, and have assessed whether the orthotopic co-administration of patient-matched bone marrow mesenchymal stromal cells (BM-MSCs) improves AML engraftment. PDX event-free survival correlated well with the predictable prognosis of risk-stratified AML patients. The majority (85%-94%) of the mice were engrafted in BM independently of the risk group, although HR-AML patients showed engraftment levels significantly superior to those of FR- and IR-AML patients. Importantly, the engraftment levels observed in NSGS mice by week 6 remained stable overtime. Serial transplantation and long-term culture-initiating cell (LTC-IC) assays revealed long-term engraftment limited to HR-AML patients, fitter leukemia-initiating cells (LICs) in HR- than in FR- or IR-AML samples, and the presence of AML-LICs in the CD34- leukemic fraction, regardless the risk group. Finally, orthotopic co-administration of patient-matched BM-MSCs with AML cells resulted dispensable for BM engraftment levels but favored peripheralization of engrafted AML cells. This comprehensive characterization of human AML engraftment in NSGS mice offers a valuable platform for in vivo testing of targeted therapies in risk-stratified AML patient samples.
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Ribera JM, Morgades M, Ciudad J, Montesinos P, Esteve J, Genescà E, Barba P, Ribera J, García-Cadenas I, Moreno MJ, Martínez-Carballeira D, Torrent A, Martínez-Sánchez P, Monsalvo S, Gil C, Tormo M, Artola MT, Cervera M, González-Campos J, Rodríguez C, Bermúdez A, Novo A, Soria B, Coll R, Amigo ML, López-Martínez A, Fernández-Martín R, Serrano J, Mercadal S, Cladera A, Giménez-Conca A, Peñarrubia MJ, Abella E, Vall-Llovera F, Hernández-Rivas JM, Garcia-Guiñon A, Bergua JM, de Rueda B, Sánchez-Sánchez MJ, Serrano A, Calbacho M, Alonso N, Méndez-Sánchez JÁ, García-Boyero R, Olivares M, Barrena S, Zamora L, Granada I, Lhermitte L, Feliu E, Orfao A

Chemotherapy or allogeneic transplantation in high-risk Philadelphia chromosome-negative adult lymphoblastic leukemia.

Blood 8 Abr 2021, 137 (14) 1879-1894.
The need for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) with high-risk (HR) features and adequate measurable residual disease (MRD) clearance remains unclear. The aim of the ALL-HR-11 trial was to evaluate the outcomes of HR Ph- adult ALL patients following chemotherapy or allo-HSCT administered based on end-induction and consolidation MRD levels. Patients aged 15 to 60 years with HR-ALL in complete response (CR) and MRD levels (centrally assessed by 8-color flow cytometry) <0.1% after induction and <0.01% after early consolidation were assigned to receive delayed consolidation and maintenance therapy up to 2 years in CR. The remaining patients were allocated to allo-HSCT. CR was attained in 315/348 patients (91%), with MRD <0.1% after induction in 220/289 patients (76%). By intention-to-treat, 218 patients were assigned to chemotherapy and 106 to allo-HSCT. The 5-year (±95% confidence interval) cumulative incidence of relapse (CIR), overall survival (OS), and event-free survival probabilities for the whole series were 43% ± 7%, 49% ± 7%, and 40% ± 6%, respectively, with CIR and OS rates of 45% ± 8% and 59% ± 9% for patients assigned to chemotherapy and of 40% ± 12% and 38% ± 11% for those assigned to allo-HSCT, respectively. Our results show that avoiding allo-HSCT does not hamper the outcomes of HR Ph- adult ALL patients up to 60 years with adequate MRD response after induction and consolidation. Better postremission alternative therapies are especially needed for patients with poor MRD clearance. This trial was registered at as # NCT01540812.
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Pamela Acha, Laura Palomo, Francisco Fuster-Tormo, Bianca Xicoy, Mar Mallo, Ana Manzanares, Javier Grau, Silvia Marcé, Isabel Granada, Marta Rodríguez-Luaces, María Díez-Campelo, Lurdes Zamora, Francesc Solé

Analysis of Intratumoral Heterogeneity in Myelodysplastic Syndromes with Isolated del(5q) Using a Single Cell Approach

Cancers 2021, 13(4), 841 17 Feb 2021, .
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological diseases. Among them, the most well characterized subtype is MDS with isolated chromosome 5q deletion (MDS del(5q)), which is the only one defined by a cytogenetic abnormality that makes these patients candidates to be treated with lenalidomide. During the last decade, single cell (SC) analysis has emerged as a powerful tool to decipher clonal architecture and to further understand cancer and other diseases at higher resolution level compared to bulk sequencing techniques. In this study, a SC approach was used to analyze intratumoral heterogeneity in four patients with MDS del(5q). Single CD34+CD117+CD45+CD19- bone marrow hematopoietic stem progenitor cells were isolated using the C1 system (Fluidigm) from diagnosis or before receiving any treatment and from available follow-up samples. Selected somatic alterations were further analyzed in SC by high-throughput qPCR (Biomark HD, Fluidigm) using specific TaqMan assays. A median of 175 cells per sample were analyzed. Inferred clonal architectures were relatively simple and either linear or branching. Similar to previous studies based on bulk sequencing to infer clonal architecture, we were able to observe that an ancestral event in one patient can appear as a secondary hit in another one, thus reflecting the high intratumoral heterogeneity in MDS del(5q) and the importance of patient-specific molecular characterization.
M Cabezón, R Malinverni, B Xicoy, S Marcé, J Bargay, A Garrido, M Tormo, L Arenillas, R Coll, J Borras, M Hoyos, D Valcárcel, L Escoda, F Vall-Llovera, A Garcia, L L Font, E Rámila, M J Jiménez, M Buschbeck, L Zamora, CETLAM group

Different methylation signatures at diagnosis in patients with high-risk myelodysplastic syndromes and secondary acute myeloid leukemia predict azacitidine response and longer survival

2021 Jan 14;13(1):9 14 Ene 2021, .
Background: Epigenetic therapy, using hypomethylating agents (HMA), is known to be effective in the treatment of high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients who are not suitable for intensive chemotherapy and/or allogeneic stem cell transplantation. However, response rates to HMA are low and there is an unmet need in finding prognostic and predictive biomarkers of treatment response and overall survival. We performed global methylation analysis of 75 patients with high-risk MDS and secondary AML who were included in CETLAM SMD-09 protocol, in which patients received HMA or intensive treatment according to age, comorbidities and cytogenetic. Results: Unsupervised analysis of global methylation pattern at diagnosis did not allow patients to be differentiated according to the cytological subtype, cytogenetic groups, treatment response or patient outcome. However, after a supervised analysis we found a methylation signature defined by 200 probes, which allowed differentiating between patients responding and non-responding to azacitidine (AZA) treatment and a different methylation pattern also defined by 200 probes that allowed to differentiate patients according to their survival. On studying follow-up samples, we confirmed that AZA decreases global DNA methylation, but in our cohort the degree of methylation decrease did not correlate with the type of response. The methylation signature detected at diagnosis was not useful in treated samples to distinguish patients who were going to relapse or progress. Conclusions: Our findings suggest that in a subset of specific CpGs, altered DNA methylation patterns at diagnosis may be useful as a biomarker for predicting AZA response and survival.
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Pamela Acha, Montserrat Hoyos, Marta Pratcorona, Francisco Fuster-Tormo, Laura Palomo, Esther Ortega, Lurdes Zamora, Susana Vives, Isabel Granada, Julia Montoro, Antoni Garcia, Montserrat Arnan, Marta Cervera, Marta Canet, David Gallardo, Leonor Arenillas, Jordi Esteve, Joan Baragay, Olga Salamero, Cristina Motlló, Xavier Ortín, Jordi Sierra, Francesc Solé

Genetic characterization of acute myeloid leukemia patients with mutations in IDH1/2 genes

Leuk Res . 2021 Jan 11;101:106492. 11 Ene 2021, .
Highlights • IDH1/2 cases account for 23% of the studied cohort. • Mutual exclusivity was confirmed for IDH1 and IDH2 mutations. • IDH1 (86%) and IDH2 (89%) mutations frequently constitute an ancestral event.
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Sorigue M, Junca J, Ferra C, Marce S, Ruiz-Xivillé N, Pinyol L, Cabezon M, Espasa A, Dominguez D, Lopez-Viaplana L, Ruiz R, Buch J, Plensa E, Mostacedo SZ, Aranda J, Vergara S, Raya M, Granada I, Tapia G, Navarro JT, Beà S, Zamora L

FMOD expression in whole blood aids in distinguishing between chronic lymphocytic leukemia and other leukemic lymphoproliferative disorders. A pilot study.

Cytometry B Clin Cytom Sep 2020, 98 (5) 421-428. Epub 12 Jun 2020
Background: Within the hematopoietic compartment, fibromodulin (FMOD) is almost exclusively expressed in chronic lymphocytic leukemia (CLL) lymphocytes. We set out to determine whether FMOD could be of help in diagnosing borderline lymphoproliferative disorders (LPD). Methods: We established 3 flow cytometry-defined groups (CLL [n = 65], borderline LPD [n = 28], broadly defined as those with CLLflow score between 35 and -20 or discordant CD43 and CLLflow, and non-CLL LPD [n = 40]). FMOD expression levels were determined by standard RT-PCR in whole-blood samples. Patients were included regardless of lymphocyte count but with tumor burden ≥40%. Results: FMOD expression levels distinguished between CLL (median 98.5, interquartile range [IQR] 37.8-195.1) and non-CLL LPD (median 0.012, IQR 0.003-0.033) with a sensitivity and specificity of 1. Most borderline LPDs were CD5/CD23/CD200-positive with no loss of B-cell antigens and negative or partial expression of CD43. 16/22 patients with available cytogenetic analysis showed trisomy 12. In 25/28 (89%) of these patients, FMOD expression levels fell between CLL and non-CLL (median 3.58, IQR 1.06-6.21). Discussion: This study could suggest that borderline LPDs may constitute a distinct group laying in the biological spectrum of chronic leukemic LPDs. Future studies will have to confirm these results with other biological data. Quantification of FMOD can potentially be of help in the diagnosis of phenotypically complex LPDs.
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Comes M, Batlle M, Ribera JM

Treatment adapted to pregnancy in a patient with Burkitt lymphoma.

Med Clin (Barc) 12 Jun 2020, 154 (11) 470-471. Epub 20 Jul 2019Más información