El linfoma de células del manto durante la última década. La búsqueda de un estándar terapéutico y disponibilidad de nuevos agentes

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 20-09-201

Clinical outcomes after CPX-351 in patients with high-risk acute myeloid leukemia: A comparison with a matched cohort from the Spanish PETHEMA registry

Acute myeloid leukemia; Clinical observations; Intensive chemotherapyLeucemia mieloide aguda; Observaciones clínicas; Quimioterapia intensivaLeucèmia mieloide aguda; Observacions clíniques; Quimioteràpia intensivaBackground CPX-351 is approved for the treatment of therapy related acute myeloid leukemia (t-AML) and AML with myelodysplastic related changes (MRC-AML). The benefits of this treatment over standard chemotherapy has not been addressed in well matched cohorts of real-life patients. Methods Retrospective analysis of AML patients treated with CPX-351 as per routine practice. A propensity score matching (PSM) was used to compare their main outcomes with those observed in a matched cohort among 765 historical patients receiving intensive chemotherapy (IC), all of them reported to the PETHEMA epidemiologic registry. Results Median age of 79 patients treated with CPX-351 was 67 years old (interquartile range 62–71), 53 were MRC-AML. The complete remission (CR) rate or CR without recovery (CRi) after 1 or 2 cycles of CPX-351 was 52%, 60-days mortality 18%, measurable residual disease <0.1% in 54% (12 out of 22) of them. Stem cell transplant (SCT) was performed in 27 patients (34%), median OS was 10.3 months, and 3-year relapse incidence was 50%. Using PSM, we obtained two comparable cohorts treated with CPX-351 (n = 52) or IC (n = 99), without significant differences in CR/CRi (60% vs. 54%) and median OS (10.3 months vs. 9.1 months), although more patients were bridged to SCT in the CPX-351 group (35% vs. 12%). The results were confirmed when only 3 + 7 patients were included in the historical cohort. In multivariable analyses, SCT was associated with better OS (HR 0.33 95% CI: 0.18–0.59), p < 0.001. Conclusion Larger post-authorization studies may provide evidence of the clinical benefits of CPX-351 for AML in the real-life setting.This study was funded in part by a research grant from the Jazz Pharmaceuticals

Mapping of Genomic Vulnerabilities in the Post-Translational Ubiquitination, SUMOylation and Neddylation Machinery in Breast Cancer

© 2021 by the authors.The dysregulation of post-translational modifications (PTM) transversally impacts cancer hallmarks and constitutes an appealing vulnerability for drug development. In breast cancer there is growing preclinical evidence of the role of ubiquitin and ubiquitin-like SUMO and Nedd8 peptide conjugation to the proteome in tumorigenesis and drug resistance, particularly through their interplay with estrogen receptor signaling and DNA repair. Herein we explored genomic alterations in these processes using RNA-seq and mutation data from TCGA and METABRIC datasets, and analyzed them using a bioinformatic pipeline in search of those with prognostic and predictive capability which could qualify as subjects of drug research. Amplification of UBE2T, UBE2C, and BIRC5 conferred a worse prognosis in luminal A/B and basal-like tumors, luminal A/B tumors, and luminal A tumors, respectively. Higher UBE2T expression levels were predictive of a lower rate of pathological complete response in triple negative breast cancer patients following neoadjuvant chemotherapy, whereas UBE2C and BIRC5 expression was higher in luminal A patients with tumor relapse within 5 years of endocrine therapy or chemotherapy. The transcriptomic signatures of USP9X and USP7 gene mutations also conferred worse prognosis in luminal A, HER2-enriched, and basal-like tumors, and in luminal A tumors, respectively. In conclusion, we identified and characterized the clinical value of a group of genomic alterations in ubiquitination, SUMOylation, and neddylation enzymes, with potential for drug development in breast cancer.Work in Alberto Ocaña’s lab is supported by the Instituto de Salud Carlos III (ISCIII, PI19/00808); ACEPAIN; Diputación de Albacete; and the CRIS Cancer Foundation. Work in Atanasio Pandiella’s lab is supported by the Ministry of Economy and Competitiveness of Spain (BFU2015- 71371-R, the Junta de Castilla y León (CSI146P20), and the CRIS Foundation. Balázs Györffy is financed by the 2018-2.1.17-TET-KR-00001 grant and by the Higher Education Institutional Excellence Programme of the Ministry for Innovation and Technology (MIT) in Hungary, within the framework of the Bionic thematic programme of the Semmelweis University

First line treatment with rituximab-Hyper-CVAD alternating with rituximab-Methotrexate-Cytarabine and followed by consolidation with 90Y-Ibritumomab-Tiuxetan in patients with mantle cell lymphoma. Results of a phase 2 pilot multicenter trial from the GELT

D. First line treatment with rituximab-Hyper-CVAD alternating with rituximab-Methotrexate-Cytarabine and followed by consolidation with 90Y-Ibritumomab-Tiuxetan in patients with mantle cell lymphoma. Results of a phase 2 pilot multicenter trial from th

Fomento del talento, según Ken Róbinson. Inquietudes del adolescente y actividades de búsqueda de la vocación profesional

Los adelantos tecnológicos que acontecen a gran velocidad, unidos a la globalización, y la crisis económica, han provocado un cambio en las necesidades humanas que parece requerir una renovación del sistema educativo. El presente trabajo tiene como objetivo investigar acerca de la visión de los jóvenes sobre sí mismos y sobre su entorno, con el fin de descubrir sus inquietudes, así como la creación de un marco de actuación para ayudar al alumno de cara a la elección de unos estudios y un itinerario profesional. Para este propósito se ha realizado una encuesta en la que han participado 39 estudiantes de Educación Secundaria Obligatoria (ESO) y Bachillerato. Con los datos obtenidos, se han podido conocer las inquietudes de los adolescentes en diversos campos. Posteriormente, y guiados por las ideas de Ken Robinson en su libro “El Elemento”, así como revisando la bibliografía existente en cuanto a cuestionarios y test de orientación académica y profesional, se han creado tres actividades orientadas a la búsqueda de la propia vocación profesional para alumnos de cuarto de ESO y Bachillerato. Con vistas a una futura investigación más completa, estos ejercicios deberán ser perfeccionados y completados con asesoramiento del departamento de orientación y se deberán poner en práctica, de manera que pueda determinarse su eficacia

Clinical outcomes after CPX-351 in patients with high-risk acute myeloid leukemia: A comparison with a matched cohort from the Spanish PETHEMA registry

Background CPX-351 is approved for the treatment of therapy related acute myeloid leukemia (t-AML) and AML with myelodysplastic related changes (MRC-AML). The benefits of this treatment over standard chemotherapy has not been addressed in well matched cohorts of real-life patients. Methods Retrospective analysis of AML patients treated with CPX-351 as per routine practice. A propensity score matching (PSM) was used to compare their main outcomes with those observed in a matched cohort among 765 historical patients receiving intensive chemotherapy (IC), all of them reported to the PETHEMA epidemiologic registry. Results Median age of 79 patients treated with CPX-351 was 67 years old (interquartile range 62–71), 53 were MRC-AML. The complete remission (CR) rate or CR without recovery (CRi) after 1 or 2 cycles of CPX-351 was 52%, 60-days mortality 18%, measurable residual disease <0.1% in 54% (12 out of 22) of them. Stem cell transplant (SCT) was performed in 27 patients (34%), median OS was 10.3 months, and 3-year relapse incidence was 50%. Using PSM, we obtained two comparable cohorts treated with CPX-351 (n = 52) or IC (n = 99), without significant differences in CR/CRi (60% vs. 54%) and median OS (10.3 months vs. 9.1 months), although more patients were bridged to SCT in the CPX-351 group (35% vs. 12%). The results were confirmed when only 3 + 7 patients were included in the historical cohort. In multivariable analyses, SCT was associated with better OS (HR 0.33 95% CI: 0.18–0.59), p < 0.001. Conclusion Larger post-authorization studies may provide evidence of the clinical benefits of CPX-351 for AML in the real-life setting.Jazz Pharmaceuticals4.711 Q2 JCR 20211.188 Q1 SJR 2022No data IDR 2021UE

Outcome of Second Allogeneic Hematopoietic Cell Transplantation after Relapse of Myeloid Malignancies following Allogeneic Hematopoietic Cell Transplantation : A Retrospective Cohort on Behalf of the Grupo Español de Trasplante Hematopoyetico

Allogeneic stem cell transplantation (allo-HCT) represents the most effective immunotherapy for acute myeloid leukemia (AML) and myeloid malignancies. However, disease relapse remains the most common cause of treatment failure. By performing a second allo-HCT, durable remission can be achieved in some patients. However, a second allo-HCT is of no benefit for the majority of patients, so this approach requires further understanding. We present a retrospective cohort of 116 patients diagnosed with AML, myelodysplastic syndromes, and myeloproliferative disorders who consecutively underwent a second allo-HCT for disease relapse. The median age was 38 years (range, 4 to 69 years). Sixty-three patients were alive at last follow-up. The median follow-up of the whole cohort was 193 days (range, 2 to 6724 days) and the median follow-up of survivors was 1628 days (range, 52 to 5518 days). Overall survival (OS) at 5 years was 32% (SE ± 4.7%). Multivariate analysis identified active disease status (P <.001) and second allo-HCT < 430 days (the median of the time to second transplantation) after the first transplantation (P <.001) as factors for poor prognosis, whereas the use of an HLA-identical sibling donor for the second allo-HCT was identified as a good prognostic factor (P <.05) for OS. The use of myeloablative conditioning (P =.01), active disease (P =.02), and a donor other than an HLA-identical sibling (others versus HLA-identical siblings) (P =.009) were factors statistically significant for nonrelapse mortality in multivariate analysis. Time to second transplantation was statistically significant (P =.001) in the relapse multivariate analysis, whereas multivariate analysis identified active disease status (P <.001) and time to second transplantation (P <.001) as poor prognosis factors for disease-free survival. This study confirms active disease and early relapse as dismal prognostic factors for a second allo-HCT. Using a different donor at second allo-HCT did not appear to change outcome, but using an HLA-identical sibling donor for a second transplantation appears to be associated with better survival. Further studies are warranted

Kinetics of Cytomegalovirus (CMV) pp65 and IE-1-Specific IFNγ CD8+ and CD4+ T Cells During Episodes of Viral DNAemia in Allogeneic Stem Cell Transplant Recipients: Potential Implications for the Management of Active CMV Infection

International audienceThe dynamics of CMV pp65 and IE-1-specific IFNγ-producing CD8+ (IFNγ CD8+) and CD4+ (IFNγ CD4+) T cells and CMV DNAemia were assessed in 19 pre-emptively-treated episodes of active CMV infection. Peripheral counts of IFNγ CD8+ and IFNγ CD4+ T cells inversely correlated with CMV DNAemia levels (P=<0.001 and P=0.003, respectively). A threshold value of 1.3 cells/µL predicting CMV DNAemia clearance was established for IFNγ CD8+ T cells (PPV, 100%; NPV, 93%) and for IFNγ CD4+ T cells (PPV, 100%; NPV, 75%). Undetectable T-cell responses were usually observed at the time of initiation of pre-emptive therapy. Either a rapid (within 7 days) or a delayed (median 31 days) expansion of both T-cell populations concomitant with CMV DNAemia clearance was observed in 5 and 8 episodes, respectively. An inconsistent or a lack of expansion of both T-cell subsets was related to a persistent CMV DNAemia. Robust and maintained CMV-specific T-cell responses after CMV DNAemia clearance and cessation of antiviral therapy were associated with a null incidence of relapsing infections at least during the following month. Data obtained in the present study may be helpful in the design of therapeutic strategies for the management of active CMV infections in the allo-SCT recipient