94 results on '"Teresa Caballero-Velázquez"'
Search Results
2. Impact of disease burden and late loss of B cell aplasia on the risk of relapse after CD19 chimeric antigen receptor T Cell (Tisagenlecleucel) infusion in pediatric and young adult patients with relapse/refractory acute lymphoblastic leukemia: role of B-cell monitoring
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Águeda Molinos-Quintana, Anna Alonso-Saladrigues, Blanca Herrero, Teresa Caballero-Velázquez, Víctor Galán-Gómez, Melissa Panesso, Montserrat Torrebadell, Javier Delgado-Serrano, Concepción Pérez de Soto, Anna Faura, Berta González-Martínez, Ana Castillo-Robleda, Cristina Diaz-de-Heredia, Antonio Pérez-Martínez, José María Pérez-Hurtado, Susana Rives, and José Antonio Pérez-Simón
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B cell aplasia ,late B-cell recovery ,pre-infusion tumor burden ,CD19 CART-cells ,relapsed/refractory acute lymphoblastic leukemia ,tisagenlecleucel ,Immunologic diseases. Allergy ,RC581-607 - Abstract
IntroductionLoss of B-cell aplasia (BCA) is a well-known marker of functional loss of CD19 CAR-T. Most relapses and loss of BCA occur in the first months after CD19 CAR-T infusion. In addition, high tumor burden (HTB) has shown to have a strong impact on relapse, especially in CD19-negative. However, little is known about the impact of late loss of BCA or the relationship between BCA and pre-infusion tumor burden in patients infused with tisagenlecleucel for relapsed/refractory B-cell acute lymphoblastic leukemia. Therefore, the optimal management of patients with loss of BCA is yet to be defined.MethodsWe conducted a Spanish, multicentre, retrospective study in patients infused with tisagenlecleucel after marketing authorization. A total of 73 consecutively treated patients were evaluated. ResultsPrior to infusion, 39 patients had HTB (≥ 5% bone marrow blasts) whereas 34 had a low tumor burden (LTB) (
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- 2024
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3. Hematological Neoplasms with Eosinophilia
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Rosario M. Morales-Camacho, Teresa Caballero-Velázquez, Juan José Borrero, Ricardo Bernal, and Concepción Prats-Martín
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eosinophilia ,hematological neoplasm ,myeloid/lymphoid neoplasm with eosinophilia ,tyrosine kinase gene fusions ,acute leukemia ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Eosinophils in peripheral blood account for 0.3–5% of leukocytes, which is equivalent to 0.05–0.5 × 109/L. A count above 0.5 × 109/L is considered to indicate eosinophilia, while a count equal to or above 1.5 × 109/L is defined as hypereosinophilia. In bone marrow aspirate, eosinophilia is considered when eosinophils make up more than 6% of the total nuclear cells. In daily clinical practice, the most common causes of reactive eosinophilia are non-hematologic, whether they are non-neoplastic (allergic diseases, drugs, infections, or immunological diseases) or neoplastic (solid tumors). Eosinophilia that is associated with a hematological malignancy may be reactive or secondary to the production of eosinophilopoietic cytokines, and this is mainly seen in lymphoid neoplasms (Hodgkin lymphoma, mature T-cell neoplasms, lymphocytic variant of hypereosinophilic syndrome, and B-acute lymphoblastic leukemia/lymphoma). Eosinophilia that is associated with a hematological malignancy may also be neoplastic or primary, derived from the malignant clone, usually in myeloid neoplasms or with its origin in stem cells (myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions, acute myeloid leukemia with core binding factor translocations, mastocytosis, myeloproliferative neoplasms, myelodysplastic/myeloproliferative neoplasms, and myelodysplastic neoplasms). There are no concrete data in standardized cytological and cytometric procedures that could predict whether eosinophilia is reactive or clonal. The verification is usually indirect, based on the categorization of the accompanying hematologic malignancy. This review focuses on the broad differential diagnosis of hematological malignancies with eosinophilia.
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- 2024
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4. P1382: CIRCULATING CAR-T CELLS MONITORING OF KINETICS AND EXHAUSTION MARKERS AS PREDICTIVE FACTORS IN B-CELL MALIGNANCIES
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Belén Sierro Martínez, Clara Beatriz García-Calderón, Estefanía García-Guerrero, Luzalba Sanoja-Flores, Raquel Muñoz-García, Victoria Ruiz-Maldonado, Javier Delgado-Serrano, Águeda Molinos-Quintana, Beatriz Guijarro-Albaladejo, Inmaculada Carrasco-Brocal, Jose Manuel Lucena, José Raúl García-Lozano, Cristina Blázquez-Goñi, Juan Luis Reguera Ortega, María Francisca Gonzalez-Escribano, Marta Reinoso Segura, Javier Briones Meijide, Perez Simon Josè Antonio, and Teresa Caballero-Velázquez
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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5. Monitoring of kinetics and exhaustion markers of circulating CAR-T cells as early predictive factors in patients with B-cell malignancies
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Clara Beatriz García-Calderón, Belén Sierro-Martínez, Estefanía García-Guerrero, Luzalba Sanoja-Flores, Raquel Muñoz-García, Victoria Ruiz-Maldonado, María Reyes Jimenez-Leon, Javier Delgado-Serrano, Águeda Molinos-Quintana, Beatriz Guijarro-Albaladejo, Inmaculada Carrasco-Brocal, José-Manuel Lucena, José-Raúl García-Lozano, Cristina Blázquez-Goñi, Juan Luis Reguera-Ortega, María-Francisca González-Escribano, Marta Reinoso-Segura, Javier Briones, José Antonio Pérez-Simón, and Teresa Caballero-Velázquez
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CAR-T ,flow cytometry ,dPCR (digital PCR) ,monitoring ,biomarkers ,B-ALL ,Immunologic diseases. Allergy ,RC581-607 - Abstract
PurposeCAR-T cell therapy has proven to be a disruptive treatment in the hematology field, however, less than 50% of patients maintain long-term response and early predictors of outcome are still inconsistently defined. Here, we aimed to optimize the detection of CD19 CAR-T cells in blood and to identify phenotypic features as early biomarkers associated with toxicity and outcomes.Experimental designIn this study, monitoring by flow cytometry and digital PCR (dPCR), and immunophenotypic characterization of circulating CAR-T cells from 48 patients treated with Tisa-cel or Axi-cel was performed.ResultsValidation of the flow cytometry reagent for the detection of CAR-T cells in blood revealed CD19 protein conjugated with streptavidin as the optimal detection method. Kinetics of CAR-T cell expansion in blood confirmed median day of peak expansion at seven days post-infusion by both flow cytometry and digital PCR. Circulating CAR-T cells showed an activated, proliferative, and exhausted phenotype at the time of peak expansion. Patients with increased expansion showed more severe CRS and ICANs. Immunophenotypic characterization of CAR-T cells at the peak expansion identified the increased expression of co-inhibitory molecules PD1 and LAG3 and reduced levels of the cytotoxicity marker CD107a as predictors of a better long-term disease control. ConclusionsThese data show the importance of CAR-T cells in vivo monitoring and identify the expression of PD1LAG3 and CD107a as early biomarkers of long-term disease control after CAR-T cell therapy.
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- 2023
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6. Survival Outcomes and Health-Related Quality of Life in Older Adults Diagnosed with Acute Myeloid Leukemia Receiving Frontline Therapy in Daily Practice
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Fernando Ramos, María Lourdes Hermosín, Marta Fuertes-Núñez, Pilar Martínez, Carlos Rodriguez-Medina, Manuel Barrios, Francisco Ibáñez, Teresa Bernal, Maria Teresa Olave, Miguel Ángel Álvarez, María Vahí, Teresa Caballero-Velázquez, Bernardo González, Albert Altés, Lorena García, Pascual Fernández, María Antonia Durán, Rocío López, Montserrat Rafel, and Josefina Serrano
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acute myeloid leukemia ,elderly ,survival ,early death ,health-related quality of life ,life expectancy ,Medicine - Abstract
Acute myeloid leukemia has a poor prognosis in older adults, and its management is often unclear due to its underrepresentation in clinical trials. Both overall survival (OS) and health-related quality-of-life (HRQoL) are key outcomes in this population, and patient-reported outcomes may contribute to patient stratification and treatment assignment. This prospective study included 138 consecutive patients treated in daily practice with the currently available non-targeted therapies (intensive chemotherapy [IC], attenuated chemotherapy [AC], hypomethylating agents [HMA], or palliative care [PC]). We evaluated patients’ condition at diagnosis (Life expectancy [Lee Index for Older Adults], Geriatric Assessment in Hematology [GAH scale], HRQoL [EQ-5D-5L questionnaire], and fatigue [fatigue items of the QLQ-C30 scale]), OS, early death (ED), treatment tolerability (TT) and change in HRQoL over 12 months follow-up. The median OS was 7.1 months (IC not reached, AC 5.9, HMA 8.8, and PC 1.0). Poor risk AML category and receiving just palliative care, as well as a higher Lee index score in the patients receiving active therapy, independently predicted a shorter OS. The Lee Index and GAH scale were not useful for predicting TT. The white blood cell count was a valid predictor for ED. Patients’ HRQoL remained stable during follow-up.
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- 2023
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7. Combined treatment of graft versus host disease using donor regulatory T cells and ruxolitinib
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Alfonso Rodríguez-Gil, Virginia Escamilla-Gómez, Melanie Nufer, Félix Andújar-Sánchez, Teresa Lopes-Ramos, José Antonio Bejarano-García, Estefanía García-Guerrero, Cristina Calderón-Cabrera, Teresa Caballero-Velázquez, Clara Beatriz García-Calderón, Paola Hernández-Díaz, Juan Luis Reguera-Ortega, Nancy Rodríguez-Torres, Nuria Martínez-Cibrián, José Ignacio Rodríguez-Barbosa, Javier Villadiego, and José Antonio Pérez-Simón
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Medicine ,Science - Abstract
Abstract Donor derived regulatory T lymphocytes and the JAK1/2 kinase inhibitor ruxolitinib are currently being evaluated as therapeutic options in the treatment of chronic graft versus host disease (cGvHD). In this work, we aimed to determine if the combined use of both agents can exert a synergistic effect in the treatment of GvHD. For this purpose, we studied the effect of this combination both in vitro and in a GvHD mouse model. Our results show that ruxolitinib favors the ratio of thymic regulatory T cells to conventional T cells in culture, without affecting the suppressive capacity of these Treg. The combination of ruxolitinib with Treg showed a higher efficacy as compared to each single treatment alone in our GvHD mouse model in terms of GvHD incidence, severity and survival without hampering graft versus leukemia effect. This beneficial effect correlated with the detection in the bone marrow of recipient mice of the infused donor allogeneic Treg after the adoptive transfer.
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- 2022
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8. Prognostic Value of Measurable Residual Disease in Patients with AML Undergoing HSCT: A Multicenter Study
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Teresa Caballero-Velázquez, Olga Pérez-López, Ana Yeguas Bermejo, Eduardo Rodríguez Arbolí, Enrique Colado Varela, Amparo Sempere Talens, María Belén Vidriales, María Solé-Rodríguez, Covadonga Quirós Caso, Estefanía Pérez López, Marta Reinoso Segura, Concepción Prats-Martín, Pau Montesinos, and Jose A. Pérez-Simón
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acute myeloid leukemia ,AML ,measurable residual disease ,MRD ,flow cytometry ,stem cell transplantation ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) represents the best therapeutic option for many patients with acute myeloid leukemia (AML). However, relapse remains the main cause of mortality after transplantation. The detection of measurable residual disease (MRD) by multiparameter flow cytometry (MFC) in AML, before and after HSCT, has been described as a powerful predictor of outcome. Nevertheless, multicenter and standardized studies are lacking. A retrospective analysis was performed, including 295 AML patients undergoing HSCT in 4 centers that worked according to recommendations from the Euroflow consortium. Among patients in complete remission (CR), MRD levels prior to transplantation significantly influenced outcomes, with overall (OS) and leukemia free survival (LFS) at 2 years of 76.7% and 67.6% for MRD-negative patients, 68.5% and 49.7% for MRD-low patients (MRD < 0.1), and 50.5% and 36.6% for MRD-high patients (MRD ≥ 0.1) (p < 0.001), respectively. MRD level did influence the outcome, irrespective of the conditioning regimen. In our patient cohort, positive MRD on day +100 after transplantation was associated with an extremely poor prognosis, with a cumulative incidence of relapse of 93.3%. In conclusion, our multicenter study confirms the prognostic value of MRD performed in accordance with standardized recommendations.
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- 2023
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9. ASXL1 mutation as a surrogate marker in acute myeloid leukemia with myelodysplasia‐related changes and normal karyotype
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Concepción Prats‐Martín, Sergio Burillo‐Sanz, Rosario M. Morales‐Camacho, Olga Pérez‐López, Milagros Suito, Maria T. Vargas, Teresa Caballero‐Velázquez, Estrella Carrillo‐Cruz, José González, Ricardo Bernal, and José A. Pérez‐Simón
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AML‐MRC ,ASXL1 ,myelodysplasia ,myeloid leukemia ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Acute myeloid leukemia with myelodysplasia‐related changes (AML‐MRC) are poor outcome leukemias. Its diagnosis is based on clinical, cytogenetic, and cytomorphologic criteria, last criterion being sometimes difficult to assess. A high frequency of ASXL1 mutations have been described in this leukemia. We sequenced ASXL1 gene mutations in 61 patients with AML‐MRC and 46 controls with acute myeloid leukemia without other specifications (AML‐NOS) to identify clinical, cytomorphologic, and cytogenetic characteristics associated with ASXL1 mutational status. Mutated ASXL1 (ASXL1+) was observed in 31% of patients with AML‐MRC compared to 4.3% in AML‐NOS. Its presence in AML‐MRC was associated with older age, a previous history of myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN), leukocytosis, presence of micromegakaryocytes in bone marrow, lower number of blasts in bone marrow, myelomonocytic/monocytic morphological features and normal karyotype. ASXL1 mutation was not observed in patients with myelodysplastic syndrome‐related cytogenetic abnormalities or TP53 mutations. Differences in terms of overall survival were found only in AML‐MRC patients without prior MDS or MDS/MPN and with intermediate‐risk karyotype, having ASXL1+ patients a worst outcome than ASXL1−. We conclude that the ASXL1 mutation frequency is high in AML‐MRC patients being its presence associated with specific characteristics including morphological signs of dysplasia. This association raises the possible role of ASXL1 as a surrogate marker in AML‐MRC, which could facilitate the diagnosis of patients within this group when the karyotype is normal, and especially when the assessment of multilineage dysplasia morphologically is difficult. This mutation could be used as a worst outcome marker in de novo AML‐MRC with intermediate‐risk karyotype.
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- 2020
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10. High-Dimensional Analysis of Single-Cell Flow Cytometry Data Predicts Relapse in Childhood Acute Lymphoblastic Leukaemia
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Salvador Chulián, Álvaro Martínez-Rubio, Víctor M. Pérez-García, María Rosa, Cristina Blázquez Goñi, Juan Francisco Rodríguez Gutiérrez, Lourdes Hermosín-Ramos, Águeda Molinos Quintana, Teresa Caballero-Velázquez, Manuel Ramírez-Orellana, Ana Castillo Robleda, and Juan Luis Fernández-Martínez
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Acute Lymphoblastic Leukaemia ,flow cytometry data ,Fisher’s Ratio ,CD38 ,mathematical oncology ,response biomarkers ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Artificial intelligence methods may help in unveiling information that is hidden in high-dimensional oncological data. Flow cytometry studies of haematological malignancies provide quantitative data with the potential to be used for the construction of response biomarkers. Many computational methods from the bioinformatics toolbox can be applied to these data, but they have not been exploited in their full potential in leukaemias, specifically for the case of childhood B-cell Acute Lymphoblastic Leukaemia. In this paper, we analysed flow cytometry data that were obtained at diagnosis from 56 paediatric B-cell Acute Lymphoblastic Leukaemia patients from two local institutions. Our aim was to assess the prognostic potential of immunophenotypical marker expression intensity. We constructed classifiers that are based on the Fisher’s Ratio to quantify differences between patients with relapsing and non-relapsing disease. We also correlated this with genetic information. The main result that arises from the data was the association between subexpression of marker CD38 and the probability of relapse.
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- 2020
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11. Selection of Tumor-Specific Cytotoxic T Lymphocytes in Acute Myeloid Leukemia Patients Through the Identification of T-Cells Capable to Establish Stable Interactions With the Leukemic Cells: 'Doublet Technology'
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Estefanía García-Guerrero, Luís I. Sánchez-Abarca, Esther Domingo, Teresa L. Ramos, Jose A. Bejarano-García, Jose A. Gonzalez-Campos, Teresa Caballero-Velázquez, and Jose A. Pérez-Simón
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immunotherapy ,tumor-specific T cells ,acute myeloid leukemia ,cell selection ,T cell-tumor cell synapse ,Immunologic diseases. Allergy ,RC581-607 - Abstract
The relevance of the immune system in cancer has long been studied. Autologous adoptive T cell therapies, based on the use of tumor infiltrating lymphocytes (TILs), have made great progress in recent years for the treatment of solid tumors, especially melanoma. However, further work is needed to isolate tumor-reactive T cells among patients diagnosed with hematologic malignancies. The dynamics of the interaction between T cells and antigen presenting cells (APC) dictate the quality of the immune responses. While stable joints between target cells and T lymphocytes lead to the induction of T cell activation and immune response, brief contacts contribute to the induction of immune-tolerance. Taking advantage of the strong interaction between target cell and activated T-cells, we show the feasibility to identify and isolate tumor-specific cytotoxic T lymphocytes (CTLs) from acute myeloid leukemia (AML) patients by flow cytometry. Using this technology, CTLs bound through T cell receptor (TCR) to tumor cells can be identified in peripheral blood and bone marrow and subsequently selected and isolated by FACS-based cell sorting. These CTLs display higher percentage of effector cells and marked cytotoxic activity against AML blasts. In conclusion, we have developed a new procedure to identify and select specific cytotoxic T cells in patients diagnosed with acute myeloid leukemia.
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- 2018
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12. Human Bone Marrow Stromal Cells Differentiate into Corneal Tissue and Prevent Ocular Graft-Versus-Host Disease in Mice
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Luis Ignacio Sánchez-Abarca, Emiliano Hernández-Galilea M.D., Rebeca Lorenzo, Carmen Herrero, Almudena Velasco, Soraya Carrancio, Teresa Caballero-Velázquez, José Ignacio Rodríguez-Barbosa, Marta Parrilla, Consuelo Del Cañizo, Jesús San Miguel, José Aijón, and José Antonio Pérez-Simón M.D., Ph.D.
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Medicine - Abstract
Clinical trials have assessed the use of human bone marrow stromal cells (hBMSCs) for the treatment of immune-related disorders such as graft-versus-host disease (GVHD). In the current study, we show that GFP + -transduced hBMSCs generated from bone marrow migrate and differentiate into corneal tissue after subconjunctival injection in mice. Interestingly, these hBMSCs display morphological features of epithelial, stromal, and endothelial cells and appear at different layers and with different morphologies depending on their position within the epithelium. Furthermore, these cells display ultrastructural properties, such as bundles of intermediate filaments, interdigitations, and desmosomes with GFP - cells, which confirms their differentiation into corneal tissues. GFP + -transduced hBMSCs were injected at different time points into the right eye of lethally irradiated mice undergoing bone marrow transplantation, which developed ocular GVHD (oGVHD). Remarkably, hBMSCs massively migrate to corneal tissues after subconjunctival injection. Both macroscopic and histopathological examination showed minimal or no evidence of GVHD in the right eye, while the left eye, where no hBMSCs were injected, displayed features of GVHD. Thus, in the current study, we confirm that hBMSCs may induce their therapeutic effect at least in part by differentiation and regeneration of damaged tissues in the host. Our results provide experimental evidence that hBMSCs represent a potential cellular therapy to attenuate oGVHD.
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- 2015
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13. The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation
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Teresa Caballero-Velázquez, Luis Ignacio Sánchez-Abarca, Silvia Gutierrez-Cosio, Belén Blanco, Cristina Calderon, Carmen Herrero, Soraya Carrancio, Concepción Serrano, Consuelo del Cañizo, Jesús F. San Miguel, and José A. Pérez-Simón
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background We have previously shown that bortezomib induces a depletion of alloreactive T cells and allows the expansion of T cells with suppressive properties. In the current study, we analyzed the potential synergistic effect of bortezomib in conjunction with sirolimus in order to reduce-graft-versus-host disease without hampering graft-versus-leukemia effect in the allogeneic transplant setting.Design and Methods We evaluated the effect of sirolimus, bortezomib or the combination of both in the proliferation and activation of in vitro stimulated T lymphocytes. Pathways involved in this synergy were also analyzed using Western blot assays. Finally, BALB/c mice receiving C57BL/6 allogeneic donor bone marrow with splenocytes were used to measure in vivo the effect of this novel combination on the risk of graft-versus-host disease.Results The combination of both drugs synergistically inhibited both activation and proliferation of stimulated T cells. Also, the production of Th1 cytokines (IFN γ, IL-2 and TNF) was significantly inhibited. This effect was due, at least in part, to the inhibition of Erk and Akt phosphorylation. In vivo, the combination reduced the risk of graft-versus-host disease without hampering graft-versus-leukemia effect, as shown in mice receiving graft-versus-host disease prophylaxis with sirolimus plus bortezomib being infused with tumor WEHI cells plus C57BL/6 donor BM and splenocytes.Conclusions The current study reveals a synergistic effect of the combination sirolimus and bortezomib to prevent graft-versus-host disease while maintaining the graft-versus-leukemia effect.
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- 2012
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14. The shape of cancer relapse: Topological data analysis predicts recurrence in paediatric acute lymphoblastic leukaemia.
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Salvador Chulián, Bernadette J. Stolz, álvaro Martínez-Rubio, Cristina Blázquez Goñi, Juan F. Rodríguez Gutiérrez, Teresa Caballero Velázquez, águeda Molinos Quintana, Manuel Ramirez-Orellana, Ana Castillo Robleda, José Luis Fuster Soler, Alfredo Minguela Puras, María V. Martínez Sánchez, María Rosa, Víctor M. Pérez-García, and Helen M. Byrne
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- 2023
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15. Supplementary Data 4 from Vitamin D Modifies the Incidence of Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation Depending on the Vitamin D Receptor (VDR) Polymorphisms
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José A. Pérez-Simón, Teresa Lopes Ramos, José A. Bejarano-García, Alfonso Rodríguez-Gil, Teresa Caballero-Velázquez, Miguel Alcoceba, Lucía López-Corral, Rocío Parody, Marian Cuesta, Oriana López-Godino, David Valcárcel, Christelle Ferra i Coll, Isabel Montero Cuadrado, Fermín M. Sánchez-Guijo, Francisco J. Márquez-Malaver, José R. García-Lozano, and Estrella Carrillo-Cruz
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Impact of patients VDR polymorphisms on the incidence of overall and moderate-severe chronic GVHD.
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- 2023
16. Supplementary Data 1 from Vitamin D Modifies the Incidence of Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation Depending on the Vitamin D Receptor (VDR) Polymorphisms
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José A. Pérez-Simón, Teresa Lopes Ramos, José A. Bejarano-García, Alfonso Rodríguez-Gil, Teresa Caballero-Velázquez, Miguel Alcoceba, Lucía López-Corral, Rocío Parody, Marian Cuesta, Oriana López-Godino, David Valcárcel, Christelle Ferra i Coll, Isabel Montero Cuadrado, Fermín M. Sánchez-Guijo, Francisco J. Márquez-Malaver, José R. García-Lozano, and Estrella Carrillo-Cruz
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Characteristics of the patients.
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- 2023
17. Supplementary Table 1. Toxicity. from Immunomodulatory Effect of Vitamin D after Allogeneic Stem Cell Transplantation: Results of a Prospective Multicenter Clinical Trial
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José A. Pérez-Simón, Francisco J. Márquez-Malaver, Lucía López-Corral, Luis I. Sánchez-Abarca, Antonio Carrillo-Vico, Marian Cuesta, Christelle Ferra i Coll, Oriana López-Godino, David Valcarcel, Raquel Saldaña, Rocío Parody, Fermín Sánchez-Guijo, Isabel Montero, and Teresa Caballero-Velázquez
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Toxicities according to the criteria by National Cancer Institute are described in this table.
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- 2023
18. Supplementary Table 4. Serum levels of vitamin D. from Immunomodulatory Effect of Vitamin D after Allogeneic Stem Cell Transplantation: Results of a Prospective Multicenter Clinical Trial
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José A. Pérez-Simón, Francisco J. Márquez-Malaver, Lucía López-Corral, Luis I. Sánchez-Abarca, Antonio Carrillo-Vico, Marian Cuesta, Christelle Ferra i Coll, Oriana López-Godino, David Valcarcel, Raquel Saldaña, Rocío Parody, Fermín Sánchez-Guijo, Isabel Montero, and Teresa Caballero-Velázquez
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Serum levels of vitamin D. Serum levels of vitamin D. The plasma levels of 25-hydroxi-VitD are summarized in this table
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- 2023
19. Data from Immunomodulatory Effect of Vitamin D after Allogeneic Stem Cell Transplantation: Results of a Prospective Multicenter Clinical Trial
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José A. Pérez-Simón, Francisco J. Márquez-Malaver, Lucía López-Corral, Luis I. Sánchez-Abarca, Antonio Carrillo-Vico, Marian Cuesta, Christelle Ferra i Coll, Oriana López-Godino, David Valcarcel, Raquel Saldaña, Rocío Parody, Fermín Sánchez-Guijo, Isabel Montero, and Teresa Caballero-Velázquez
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Purpose: We describe the results of a prospective multicenter phase I/II trial evaluating the impact of the use of vitamin D (VitD) from day −5 to +100 on the outcome of patients undergoing allogeneic transplantation (EudraCT: 2010-023279-25; ClinicalTrials.gov: NCT02600988).Experimental Design: A total of 150 patients were included in three consecutive cohorts of 50 patients each group: control group (CG, not receive VitD); low-dose group (LdD, received 1,000 IU VitD daily); and high-dose group (HdD, 5,000 IU VitD daily). We measured levels of VitD, cytokines, and immune subpopulations after transplantation.Results: No significant differences were observed in terms of cumulative incidence of overall and grades 2–4 acute GVHD in terms of relapse, nonrelapse mortality, and overall survival. However, a significantly lower cumulative incidence of both overall and moderate plus severe chronic GVHD (cGVHD) at 1 year was observed in LdD (37.5% and 19.5%, respectively) and HdD (42.4% and 27%, respectively) as compared with CG (67.5% and 44.7%, respectively; P < 0.05). In multivariable analysis, treatment with VitD significantly decreased the risk of both overall (for LdD: HR = 0.31, P = 0.002; for HdD: HR = 0.36, P = 0.006) and moderate plus severe cGVHD (for LdD: HR = 0.22, P = 0.001; for HdD: HR = 0.33, P = 0.01). VitD modified the immune response, decreasing the number of B cells and naïve CD8 T cells, with a lower expression of CD40L.Conclusions: This is the first prospective trial that analyzes the effect of VitD postransplant. We observed a significantly lower incidence of cGVHD among patients receiving VitD. Interestingly, VitD modified the immune response after allo-SCT. Clin Cancer Res; 22(23); 5673–81. ©2016 AACR.
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- 2023
20. Supplementary Data 3 from Vitamin D Modifies the Incidence of Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation Depending on the Vitamin D Receptor (VDR) Polymorphisms
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José A. Pérez-Simón, Teresa Lopes Ramos, José A. Bejarano-García, Alfonso Rodríguez-Gil, Teresa Caballero-Velázquez, Miguel Alcoceba, Lucía López-Corral, Rocío Parody, Marian Cuesta, Oriana López-Godino, David Valcárcel, Christelle Ferra i Coll, Isabel Montero Cuadrado, Fermín M. Sánchez-Guijo, Francisco J. Márquez-Malaver, José R. García-Lozano, and Estrella Carrillo-Cruz
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Linkage disequilibrium of patients VDR polymorphisms.
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- 2023
21. Supplementary Figure A1 online only. from Immunomodulatory Effect of Vitamin D after Allogeneic Stem Cell Transplantation: Results of a Prospective Multicenter Clinical Trial
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José A. Pérez-Simón, Francisco J. Márquez-Malaver, Lucía López-Corral, Luis I. Sánchez-Abarca, Antonio Carrillo-Vico, Marian Cuesta, Christelle Ferra i Coll, Oriana López-Godino, David Valcarcel, Raquel Saldaña, Rocío Parody, Fermín Sánchez-Guijo, Isabel Montero, and Teresa Caballero-Velázquez
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Cumulative incidence of relapse (A) or NRM (B): No significant differences between the different cohorts of patients were observed in terms of cumulative incidence of relapse or NRM (p=0.1 and p= 0.8).
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- 2023
22. Supplementary Table 3. Serum levels of cytokines by flow cytometry. from Immunomodulatory Effect of Vitamin D after Allogeneic Stem Cell Transplantation: Results of a Prospective Multicenter Clinical Trial
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José A. Pérez-Simón, Francisco J. Márquez-Malaver, Lucía López-Corral, Luis I. Sánchez-Abarca, Antonio Carrillo-Vico, Marian Cuesta, Christelle Ferra i Coll, Oriana López-Godino, David Valcarcel, Raquel Saldaña, Rocío Parody, Fermín Sánchez-Guijo, Isabel Montero, and Teresa Caballero-Velázquez
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Serum levels of cytokines by flow cytometry. Serum levels of Th1/Th2 cytokines are summarized in this table.
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- 2023
23. Data from Vitamin D Modifies the Incidence of Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation Depending on the Vitamin D Receptor (VDR) Polymorphisms
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José A. Pérez-Simón, Teresa Lopes Ramos, José A. Bejarano-García, Alfonso Rodríguez-Gil, Teresa Caballero-Velázquez, Miguel Alcoceba, Lucía López-Corral, Rocío Parody, Marian Cuesta, Oriana López-Godino, David Valcárcel, Christelle Ferra i Coll, Isabel Montero Cuadrado, Fermín M. Sánchez-Guijo, Francisco J. Márquez-Malaver, José R. García-Lozano, and Estrella Carrillo-Cruz
- Abstract
Purpose:The biologically active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 (vit D), has immunoregulatory properties via binding vitamin D receptor (VDR). In a prospective trial, we previously reported a reduction in the incidence of chronic GvHD (cGvHD) among patients who received vit D after allogeneic stem cell transplantation (allo-HSCT; Clinical Trials.gov: NCT02600988). Here we analyze the role of patients and donors' VDR SNPs on the immunomodulatory effect of vit D.Patients and Methods:Patients undergoing allo-HSCT were included in a prospective phase I/II clinical trial (Alovita) in three consecutive cohorts: control (without vit D), low-dose (1,000 IU/day), and high-dose (5,000 IU/day) groups. Vit D was given from day −5 until +100 after transplant. Genotyping of four SNPs of the VDR gene, FokI, BsmI, ApaI, and TaqI, were performed using TaqMan SNP genotyping assays.Results:We observed a decrease in the incidence of overall cGvHD at 1 year after allo-HSCT depending on the use or not of vit D among patients with FokI CT genotype (22.5% vs 80%, P = 0.0004) and among those patients without BsmI/ApaI/TaqI ATC haplotype (22.2% vs 68.8%, P = 0.0005). In a multivariate analysis, FokI CT genotype significantly influenced the risk of cGvHD in patients treated with vit D as compared with the control group (HR 0.143, Pinteraction < 0.001).Conclusions:Our results show that the immunomodulatory effect of vit D depends on the VDR SNPs, and patients carrying the FokI CT genotype display the highest benefit from receiving vit D after allo-HSCT.
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- 2023
24. Supplementary Data from Vitamin D Modifies the Incidence of Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation Depending on the Vitamin D Receptor (VDR) Polymorphisms
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José A. Pérez-Simón, Teresa Lopes Ramos, José A. Bejarano-García, Alfonso Rodríguez-Gil, Teresa Caballero-Velázquez, Miguel Alcoceba, Lucía López-Corral, Rocío Parody, Marian Cuesta, Oriana López-Godino, David Valcárcel, Christelle Ferra i Coll, Isabel Montero Cuadrado, Fermín M. Sánchez-Guijo, Francisco J. Márquez-Malaver, José R. García-Lozano, and Estrella Carrillo-Cruz
- Abstract
Supplementary table 5. Impact of donor VDR polymorphisms on the incidence of overall and moderate to severe chronic GVHD.
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- 2023
25. Supplementary Table 2, online only. Immune recovery after allo-stem cell transplantation from Immunomodulatory Effect of Vitamin D after Allogeneic Stem Cell Transplantation: Results of a Prospective Multicenter Clinical Trial
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José A. Pérez-Simón, Francisco J. Márquez-Malaver, Lucía López-Corral, Luis I. Sánchez-Abarca, Antonio Carrillo-Vico, Marian Cuesta, Christelle Ferra i Coll, Oriana López-Godino, David Valcarcel, Raquel Saldaña, Rocío Parody, Fermín Sánchez-Guijo, Isabel Montero, and Teresa Caballero-Velázquez
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Immune recovery after allo-stem cell transplantation. Mean and standard error of the mean (SEM)of different subpobpopulation of immune system are summarized in this table.
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- 2023
26. Supplementary Data 6 from Vitamin D Modifies the Incidence of Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation Depending on the Vitamin D Receptor (VDR) Polymorphisms
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José A. Pérez-Simón, Teresa Lopes Ramos, José A. Bejarano-García, Alfonso Rodríguez-Gil, Teresa Caballero-Velázquez, Miguel Alcoceba, Lucía López-Corral, Rocío Parody, Marian Cuesta, Oriana López-Godino, David Valcárcel, Christelle Ferra i Coll, Isabel Montero Cuadrado, Fermín M. Sánchez-Guijo, Francisco J. Márquez-Malaver, José R. García-Lozano, and Estrella Carrillo-Cruz
- Abstract
Syntaxis for Cox model
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- 2023
27. Delayed administration of ixazomib modifies the immune response and prevents chronic graft-versus-host disease
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Teresa L. Ramos, Alfonso Rodríguez-Gil, José Antonio Pérez-Simón, Melanie Nufer, Teresa Caballero-Velázquez, Estefanía García-Guerrero, María Victoria Barbado, Rocío Caracuel-García, María José Robles-Frías, Universidad de Sevilla. Departamento de Medicina, Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla. Departamento de Citología e Histología Normal y Patológica, Takeda Pharmaceutical Company, Asociación Española Contra el Cáncer, Centro de Investigación Biomédica en Red Cáncer (España), [Ramos,TL, García-Guerrero,E, Caballero-Velázquez,T, Rodríguez-Gil,A, Caracuel-García,R, Nufer,M, Robles-Frías,MJ, Barbado,MV, Pérez-Simón,JA] Instituto de Biomedicina de Sevilla (IBIS/CSIC), CIBERONC, Universidad de Sevilla, Sevilla, Spain. [Ramos,TL] Division of Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA, USA. [Caballero-Velázquez,T, Pérez-Simón,JA] Department of Hematology, University Hospital Virgen del Rocio, Universidad de Sevilla, Sevilla, Spain., Takeda company (PCRS-2016-101751) partially supported the study, and This work has been partially supported by the CIBERONC (CB16/12/00480), and TerCel 16/0011/0035. Spanish Association Against Cancer (AECC-POSTD18023LOPE) fellowship (TLR).
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Graft vs Host Disease ,Phenomena and Processes::Immune System Phenomena::Immune System Processes::Transplantation Immunology::Graft vs Host Reaction [Medical Subject Headings] ,Disease ,Graft-versus-host disease ,Inhibidores de proteasoma ,Ixazomib ,Mice ,chemistry.chemical_compound ,immune system diseases ,Organisms::Eukaryota::Animals [Medical Subject Headings] ,Proteasome inhibitor ,Bone Marrow Transplantation ,Leukemia ,Effector ,Médula ósea ,Hematology ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Surgical Procedures, Operative::Transplantation::Tissue Transplantation::Bone Marrow Transplantation [Medical Subject Headings] ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Amino Acids::Glycine [Medical Subject Headings] ,surgical procedures, operative ,medicine.anatomical_structure ,Linfocitos B ,medicine.drug ,Boron Compounds ,Bone marrow transplantation ,Glycine ,Graft vs Leukemia Effect ,Enfermedad injerto contra huésped ,Article ,Immune system ,medicine ,Animals ,Bone marrow ,Leucemia ,B cells ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings] ,Transplantation ,business.industry ,Immunity ,Phenomena and Processes::Immune System Phenomena::Immunity [Medical Subject Headings] ,Translational research ,medicine.disease ,Diseases::Immune System Diseases::Graft vs Host Disease [Medical Subject Headings] ,chemistry ,Immunology ,business ,Chemicals and Drugs::Inorganic Chemicals::Boron Compounds [Medical Subject Headings] - Abstract
In this study, we aimed to modify the immune response in the long term after allogeneic bone marrow transplantation (allo-BMT) by using the proteasome inhibitor ixazomib (IXZ) at the late stages of the post-transplant period. This approach facilitated the immune reconstitution after transplantation. IXZ significantly prolonged survival and decreased the risk of chronic graft-versus-host disease (cGvHD) in two different murine models without hampering the graft-versus-leukemia (GvL) effect, as confirmed by bioluminescence assays. Remarkably, the use of IXZ was related to an increase of regulatory T cells both in peripheral blood and in the GvHD target organs and a decrease of effector donor T cells. Regarding B cells, IXZ treated mice had faster recovery of B cells in PB and of pre-pro-B cells in the bone marrow. Mice receiving ixazomib had a lower number of neutrophils in the GvHD target organs as compared to the vehicle group. In summary, delayed administration of IXZ ameliorated cGvHD while preserving GvL and promoted a pro-tolerogenic immune response after allo-BMT., Takeda company (PCRS-2016-101751) partially supported the study; This work has been partially supported by the CIBERONC (CB16/12/00480), and TerCel 16/0011/0035. Spanish Association Against Cancer (AECC-POSTD18023LOPE) fellowship (TLR).
- Published
- 2021
28. Phase I/II Clinical Trials of Donor-Derived Purified Regulatory T Cells for the Treatment of Steroid-Refractory Chronic Graft Versus Host Disease
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Maria VD Soares, Virginia Escamilla Gomez, Rita I Azevedo, Paulo N.G. Pereira, Teresa Caballero Velázquez, Clara B. Garcia-Calderón, Kukatharmini Tharmaratnam, Inês A Cabral, Ana C Ribeiro, Laura Mendes, Clara Juncal, Susana Roncon, Ana Teresa Pais, Ana C Alho, Alfonso Rodriguez Gil, Eduardo L Espada, Anabela Rodrigues, Ana Garção, Marie-Laure Yaspo, Hans-Jörg Warnatz, Hans Lehrach, Nuno L. Barbosa-Morais, Ana Miguel Quintas, Paulo Palmela, Cecilia Caldas, Rosa Ferreira, Luis Leite, Carlos Martins, Fernanda Lourenço, Raúl Moreno, João Raposo, Fernando Campilho, Christopher Paul Cheyne, Marta Garcia-Fiñana, António Campos, Frédéric Baron, Mario Arpinati, Matthias Edinger, Jerome Ritz, Carlos Pinho Vaz, Jose A. Perez-Simon, and Joao F Lacerda
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
- Full Text
- View/download PDF
29. The shape of cancer relapse: Topological data analysis predicts recurrence in paediatric acute lymphoblastic leukaemia
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Salvador Chulián, Bernadette J. Stolz, Álvaro Martínez-Rubio, Cristina Blázquez Goñi, Juan F. Rodríguez Gutiérrez, Teresa Caballero Velázquez, Águeda Molinos Quintana, Manuel Ramírez Orellana, Ana Castillo Robleda, José Luis Fuster Soler, Alfredo Minguela Puras, María V. Martínez Sánchez, María Rosa, Víctor M. Pérez-García, and Helen M. Byrne
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hemic and lymphatic diseases - Abstract
Although children and adolescents with acute lymphoblastic leukaemia (ALL) have high survival rates, approximately 15-20% of patients relapse. Risk of relapse is routinely estimated at diagnosis by biological factors, including flow cytometry data. This high-dimensional data is typically manually assessed by projecting it onto a subset of biomarkers. Cell density and “empty spaces” in 2D projections of the data, i.e. regions devoid of cells, are then used for qualitative assessment. Here, we use topological data analysis (TDA), which quantifies shapes, including empty spaces, in data, to analyse pre-treatment ALL datasets with known patient outcomes. We combine these fully unsupervised analyses with Machine Learning (ML) to identify significant shape characteristics and demonstrate that they accurately predict risk of relapse, particularly for patients previously classified as ‘low risk’. We independently confirm the predictive power of CD10, CD20, CD38, and CD45 as biomarkers for ALL diagnosis. Based on our analyses, we propose three increasingly detailed prognostic pipelines for analysing flow cytometry data from ALL patients depending on technical and technological availability: 1. Visual inspection of specific biological features in biparametric projections of the data; 2. Computation of quantitative topological descriptors of such projections; 3. A combined analysis, using TDA and ML, in the four-parameter space defined by CD10, CD20, CD38 and CD45. Our analyses readily extend to other haematological malignancies.Author summaryAcute lymphoblastic leukaemia (ALL) is a blood cancer which affects predominantly children and adolescents. Therapy typically fails in approximately 20 % of patients, who suffer from relapse. To determine disease status, clinicians assess cell types, their interactions, as well as deviations from normal behaviour. Flow cytometry (FC) is a method that quantifies the intensity of specific cell markers, giving rise to high-dimensional data. This routinely collected information is then reduced to obtain human-interpretable visualisation for prognosis. Topological Data Analysis (TDA) is a field of mathematics that studies shapes in data, considering isolated data islands and empty spaces between them. We showcase how to use TDA to extract shape characteristics in FC data of relapsing patients. We propose three pipelines, of increasing methodological complexity, to aid clinical decisions for risk stratification in ALL. In combination with Machine Learning, TDA enables high-accuracy predictions of relapse to be made at the time of diagnosis.
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- 2021
30. Combined treatment of graft versus host disease using donor regulatory T cells and ruxolitinib
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Alfonso Rodríguez-Gil, Virginia Escamilla-Gómez, Melanie Nufer, Félix Andújar-Sánchez, Teresa Lopes-Ramos, José Antonio Bejarano-García, Estefanía García-Guerrero, Cristina Calderón-Cabrera, Teresa Caballero-Velázquez, Clara Beatriz García-Calderón, Paola Hernández-Díaz, Juan Luis Reguera-Ortega, Nancy Rodríguez-Torres, Nuria Martínez-Cibrián, José Ignacio Rodríguez-Barbosa, Javier Villadiego, José Antonio Pérez-Simón, Junta de Andalucía, Centro de Investigación Biomédica en Red Cáncer (España), Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Universidad de Sevilla, and European Commission
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Disease Models, Animal ,Mice ,Multidisciplinary ,Pyrimidines ,Nitriles ,Animals ,Graft vs Host Disease ,Pyrazoles ,T-Lymphocytes, Regulatory - Abstract
Donor derived regulatory T lymphocytes and the JAK1/2 kinase inhibitor ruxolitinib are currently being evaluated as therapeutic options in the treatment of chronic graft versus host disease (cGvHD). In this work, we aimed to determine if the combined use of both agents can exert a synergistic effect in the treatment of GvHD. For this purpose, we studied the effect of this combination both in vitro and in a GvHD mouse model. Our results show that ruxolitinib favors the ratio of thymic regulatory T cells to conventional T cells in culture, without affecting the suppressive capacity of these Treg. The combination of ruxolitinib with Treg showed a higher efficacy as compared to each single treatment alone in our GvHD mouse model in terms of GvHD incidence, severity and survival without hampering graft versus leukemia effect. This beneficial effect correlated with the detection in the bone marrow of recipient mice of the infused donor allogeneic Treg after the adoptive transfer., This work was supported by grants from Novartis and the Andalusian Regional Government (P18-RT-4047, PI-0052-2018). A.R.G. and J.A.P.S. are members of CIBERONC (CB16/12/00480) and TerCel (16/0011/0035). J.V. is member of CIBERNED (CB06/05/0027). A.R.G. is funded by a Grant of the University of Seville (US-1380874) co-funded by the European Regional Development Fund (ERDF). This study is partially funded by Novartis.
- Published
- 2021
31. Multiple erythrophagocytosis by erythroid blasts in acute myeloid leukemia with BCR-ABL1
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África Mellado-Gázquez, M. Remedios Gómez-Núñez, Sergio Jurado-Herrera, Concepción Prats-Martín, Teresa Caballero-Velázquez, and Rosario M. Morales-Camacho
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Leukemia, Myeloid, Acute ,Fusion Proteins, bcr-abl ,Humans ,Hematology ,General Medicine - Published
- 2021
32. Impact of Measurable Residual Disease (MRD) By Multiparameter Flow Cytometry (MFC): A Real-World Study in 1,076 Patients with Acute Myeloid Leukemia (AML)
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Joaquin Martinez-Lopez, Sofía Grille, Josefina Serrano, Pau Montesinos, Jesús F. San-Miguel, Bruno Paiva, C. Rodriguez, Maria Luz Amigo, Fabián Tarín, Joaquin Sanchez, Teresa Bernal del Castillo, María Belén Vidriales, Enrique Colado, Miguel A. Sanz, Juan Manuel Alonso Dominguez, Marcos González, Teresa Caballero-Velázquez, Mercedes Colorado, Maria Desamparados Sampere Talens, Raimundo García-Boyero, Jaime Pérez de Oteyza, Lourdes Cordón, Maria Jose Sayas, Manuel Perez Encinas, Olga Pérez-López, Lissette Del Pilar Costilla, Celina Benavente, Alberto Orfao, Claudia Sossa, David Martínez-Cuadrón, José A. Pérez-Simón, María Teresa Cedena, Manuel Barrios Garcia, Jesús Lorenzo Algarra, and Carmen Botella
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business.industry ,hemic and lymphatic diseases ,Immunology ,Cancer research ,Medicine ,Myeloid leukemia ,Cell Biology ,Hematology ,Disease ,Multiparameter flow cytometry ,business ,Residual ,Biochemistry - Abstract
Background: Evaluation of MRD is standard in patients with AML. However, the role of decentralized MRD assessment for risk stratification in AML remains largely unknown, and so it does which methodological aspects are critical to empower the evaluation of MRD with prognostic significance, particularly if using MFC. Aim: To evaluate the role of decentralized MRD assessment using MFC for risk stratification and putative treatment individualization of patients with AML. Methods: This study was performed on 1,076 AML patients in complete remission (CR) after 7+3 induction chemotherapy, in whom MRD was evaluated by MFC in local laboratories over a period of 20 years in the PETHEMA group. We conducted a survey of technical aspects of MFC based MRD testing in the laboratories of the 60 participating Hospitals, to determine the impact of methodological heterogeneity in the prognostic value of MFC. Results: We first investigated the most effective MRD cutoff to stratify patients' risk at first remission. Patients were segmented into progressively higher cutoffs, starting at 0.01% followed by 0.05%, 0.1%, 0.5% and 1%. Our results showed that 0.1% reached higher statistical significance to discriminate patients with different relapse-free survival (RFS, HR: 0.77; P = .001) and overall survival (OS, HR: 0.73; P = .001). In multivariate analyses together with patients' age, WBC, genetic risk and post-consolidation therapy, MRD status was selected as an independent prognostic factor for OS. To further define the utility of "real-world" MRD assessment using MFC in risk stratification of AML, recursive partitioning was performed using the prognostic and treatment related factors selected in the multivariate Cox model for OS. Of the four variables evaluated, hematopoietic stem cell transplantation (HSCT, regardless of autologous or allogeneic source) vs no transplant emerged as the best single discriminator for OS, followed by genetic risk, age and MRD status. There were two branching points defined by MRD status; the first in patients ≤60 years with intermediate genetic risk who were not transplanted and the second in patients with adverse genetics who were not transplanted, in whom Forty-nine of the 60 hospitals (82%) responded to the survey on questions regarding the measurement of MRD using MFC in the PETHEMA LMA 1999, 2007 and 2010 protocols, providing information corresponding to 966 of the 1,076 (90%) patients regarding the number of markers, preparation of samples, instruments, approach (ie, LAIP, DfN or LAIP+DfN), number of cells to define a cluster, etc. The survey revealed significant heterogeneity intra- and inter-protocols that reflected improvement in MFC assessment of MRD over time, in the absence of harmonization nor standardization at the national level. Accordingly, we investigated if the heterogeneity in methodological, interpretation and reporting aspects of MFC based MRD testing were hampering its ability to predict outcome independently of other patient and treatment related factors. Strikingly, our results showed that except for the denominator used to calculate MRD burden (ie, total nucleated cells vs leukocytes), lack of standardization in all other parameters had an impact on the ability of MFC to predict outcomes in AML (Figure). Namely, panels with ≤4 markers or ≤2 combinations failed to identify patients with significantly different RFS according to MRD status, and MFC-based MRD monitoring was prognostic only when >500,000 cells were measured. Only MRD assessment using patient-specific panels was predictive of outcome. Conclusions: We report here one of the largest studies investigating the role of MRD monitoring using MFC. Our results confirmed that detection of MRD identifies patients in CR/CRi with inferior survival, but uncovered that decentralized MRD testing lacks significance when compared to other baseline risk factors and in the context of risk-adapted post-consolidation strategies. Thus, while this study demonstrated that "real-world" decentralized assessment of MRD using MFC does provide prognostic information in AML patients at first remission, our results question its readiness for risk stratification towards clinical decisions outside trials, at least until adequate standardization of this technique is achieved. Figure Disclosures Paiva: SkylineDx: Consultancy; Takeda: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Adaptive: Honoraria; Amgen: Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Kite: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding. Alonso Dominguez:Celgene: Research Funding; Incyte: Research Funding; Pfizer: Research Funding. Martinez-Lopez:Janssen: Speakers Bureau; Altum: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Hosea: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Roche: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Vivia Biotech: Honoraria; Novartis: Research Funding; BMS: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau. Sossa:Astellas: Honoraria; Roche: Honoraria; Takeda: Honoraria; Novo: Honoraria. San-Miguel:Roche, AbbVie, GlaxoSmithKline, and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb, Celgene, Novartis, Takeda, Amgen, MSD, Janssen, and Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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- 2020
33. Auer rod-like inclusions in cerebrospinal fluid in accelerated phase chronic lymphocytic leukaemia
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Emilio Franco-Macías, Rosario M. Morales-Camacho, Teresa Caballero-Velázquez, Javier Alberto Rojas-Martínez, Concepción Prats-Martín, and Patricia Alcalde-Mellado
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Inclusion Bodies ,Pathology ,medicine.medical_specialty ,Lymphocytic leukaemia ,Chemistry ,Auer rod ,Hematology ,Leukemia, Lymphocytic, Chronic, B-Cell ,Cerebrospinal fluid ,medicine ,Disease Progression ,Humans ,Female ,Lymph Nodes ,Accelerated phase ,Aged - Published
- 2021
34. Efficacy of bortezomib to intensify the conditioning regimen and the graft-versus-host disease prophylaxis for high-risk myeloma patients undergoing transplantation
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M.V. Mateos, Cristina Calderón-Cabrera, Caballero Barrigón D, Teresa Caballero-Velázquez, San Miguel J, Jesús Martín, Francisco J. Márquez-Malaver, N. Puig, Lucía López-Corral, José A. Pérez-Simón, Clara M Rosso-Fernández, Estefania Perez-Lopez, Clara B. García-Calderón, and Ministerio de Sanidad y Política Social (España)
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Melphalan ,medicine.medical_specialty ,Myeloma ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Phase I trials ,immune system diseases ,Internal medicine ,medicine ,Cumulative incidence ,Multiple myeloma ,Transplantation ,Bortezomib ,business.industry ,Hematology ,medicine.disease ,Tacrolimus ,Fludarabine ,surgical procedures, operative ,Graft-versus-host disease ,030220 oncology & carcinogenesis ,business ,030215 immunology ,medicine.drug - Abstract
This multicenter phase I trial was designed to evaluate the safety and efficacy of bortezomib (Bz) as part of both the conditioning regimen and the graft-versus-host disease (GvHD) prophylaxis. Patients received fludarabine, melphalan and Bz (days −9 and −2). GVHD prophylaxis consisted of Bz (days +1, +4, and +7), sirolimus (Siro) from day −5 and tacrolimus (Tk) from −3 (except the first five patients that did not receive Tk). Twenty-five patients with poor prognostic multiple myeloma were included. Eleven out of the 19 patients had high-risk features. Out of the 21 patients evaluable at day +100, 14 were in CR (67%) and 7 (33%) in PR. Cumulative incidence (CI) of nonrelapse mortality at 1 year was 24%. CI of grades 2–4 and 3–4 acute GvHD was 35% and 10%, respectively; CI of chronic GvHD was 35% and 55% at 1 and 2 years, respectively. Overall and event free survival at 2 years were 64% and 31%, respectively. Bz as part of the conditioning regimen and in the combination with Siro/tacrolimus for GvHD prophylaxis is safe and effective allowing an optimal disease control early after transplant and reducing the risk of GvHD., This trial was supported by Janssen and Celgene and the Ministerio de Sanidad y Política Social, convocatoria de concesión de ayudas para el fomento de la investigación clínica independiente 2010 (EC10–289); this study was partially supported by two grants from the Ministry of Health CIBER ONC, code CB16/12/00480. TCV was supported by a grant from Ministerio de Sanidad y Política Social (CM10/00161).
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- 2019
35. Impact of measurable residual disease by decentralized flow cytometry: a PETHEMA real-world study in 1076 patients with acute myeloid leukemia
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Lourdes Cordón, Teresa Bernal, David Martínez-Cuadrón, Raimundo García-Boyero, Jaime Pérez-Oteyza, Joaquin Martinez-Lopez, Mercedes Colorado, Olga Pérez, Fabián Tarín, Alberto Orfao, Sofia Grille, Juan José Garcés, Pau Montesinos, Maria-Teresa Cedena, Marcos González-Díaz, Manuel Pérez-Encinas, Carmen Botella, Miguel-Angel Sanz, Lisette Costilla-Barriga, Joaquín Sánchez, Teresa Caballero-Velázquez, Catia Patricia Simoes, María-Belén Vidriales, Juan-Manuel Alonso-Domínguez, José Antonio Pérez-Simón, María-José Sayas, Celina Benavente, Manuel Barrios, Bruno Paiva, Carlos Rodríguez-Medina, Amparo Sempere, María-Luz Amigo, Claudia Sossa, Jesús F. San Miguel, Josefina Serrano, Enrique Colado, Lorenzo Algarra, Centro de Investigación Biomédica en Red Cáncer (España), Instituto de Salud Carlos III, Junta de Castilla y León, Universidad de Navarra, Cancer Research UK, Fondazione Italiana per la Ricerca sul Cancro, and Asociación Española Contra el Cáncer
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0301 basic medicine ,Oncology ,Male ,Cancer Research ,Neoplasm, Residual ,RELAPSE RISK ,Disease ,0302 clinical medicine ,AML ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Registries ,medicine.diagnostic_test ,First remission ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Hematology ,Induction Chemotherapy ,Middle Aged ,Flow Cytometry ,Prognosis ,INDUCTION THERAPY ,Combined Modality Therapy ,Survival Rate ,Leukemia, Myeloid, Acute ,030220 oncology & carcinogenesis ,Disease Progression ,Female ,REDUCED-INTENSITY ,medicine.medical_specialty ,PROGNOSTIC IMPACT ,Recursive partitioning ,DIAGNOSIS ,1ST ,Acute myeloid leukaemia ,Flow cytometry ,HEMATOPOIETIC-CELL TRANSPLANTATION ,03 medical and health sciences ,Internal medicine ,medicine ,Overall survival ,Humans ,Transplantation, Homologous ,TREATMENT RESPONSE ,Aged ,Related factors ,business.industry ,Induction chemotherapy ,REMISSION ,030104 developmental biology ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies - Abstract
The role of decentralized assessment of measurable residual disease (MRD) for risk stratification in acute myeloid leukemia (AML) remains largely unknown, and so it does which methodological aspects are critical to empower the evaluation of MRD with prognostic significance, particularly if using multiparameter flow cytometry (MFC). We analyzed 1076 AML patients in first remission after induction chemotherapy, in whom MRD was evaluated by MFC in local laboratories of 60 Hospitals participating in the PETHEMA registry. We also conducted a survey on technical aspects of MRD testing to determine the impact of methodological heterogeneity in the prognostic value of MFC. Our results confirmed the recommended cutoff of 0.1% to discriminate patients with significantly different cumulative-incidence of relapse (-CIR- HR:0.71, P, This study was supported by the Centro de Investigación Biomédica en Red – Área de Oncología - del Instituto de Salud Carlos III (CIBERONC; CB16/12/00369, CB16/12/00233, CB16/12/00284 and CB16/12/00400), Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS No. PI16/01661, PI16/00517 and PI18/01946), Gerencia Regional de Salud de CyL (GRS 1346/A/16) and the Plan de Investigación de la Universidad de Navarra (PIUNA 2014-18). This study was supported internationally by the Cancer Research UK, FCAECC and AIRC under the Accelerator Award Program EDITOR.
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- 2021
36. High-dimensional analysis of single-cell flow cytometry data predicts relapse in childhood acute lymphoblastic leukaemia
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Águeda Molinos Quintana, Víctor M. Pérez-García, Manuel Ramírez-Orellana, Teresa Caballero-Velázquez, Juan Francisco Rodríguez Gutiérrez, Ana Castillo Robleda, María Rosa, Lourdes Hermosín-Ramos, Juan Luis Fernández-Martínez, Álvaro Martínez-Rubio, Cristina Blázquez Goñi, Salvador Chulián, and Matemáticas
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Fisher's Ratio ,Fisher’s Ratio ,Cell ,Disease ,High dimensional ,mathematical oncology ,lcsh:RC254-282 ,flow cytometry data ,Article ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,hemic and lymphatic diseases ,medicine ,medicine.diagnostic_test ,business.industry ,allergology ,Acute Lymphoblastic Leukaemia ,personalised medicine ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Lymphoblastic leukaemia ,response biomarkers ,business ,CD38 - Abstract
Artificial intelligence methods may help in unveiling information that is hidden in high-dimensional oncological data. Flow cytometry studies of haematological malignancies provide quantitative data with the potential to be used for the construction of response biomarkers. Many computational methods from the bioinformatics toolbox can be applied to these data, but they have not been exploited in their full potential in leukaemias, specifically for the case of childhood B-cell Acute Lymphoblastic Leukaemia. In this paper, we analysed flow cytometry data that were obtained at diagnosis from 56 paediatric B-cell Acute Lymphoblastic Leukaemia patients from two local institutions. Our aim was to assess the prognostic potential of immunophenotypical marker expression intensity. We constructed classifiers that are based on the Fisher&rsquo, s Ratio to quantify differences between patients with relapsing and non-relapsing disease. We also correlated this with genetic information. The main result that arises from the data was the association between subexpression of marker CD38 and the probability of relapse.
- Published
- 2021
37. The incidental detection of clonal haemopoiesis of indeterminate potential with del(5q)
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Concepción Prats‐Martín, Maria Teresa Vargas, Marta Reinoso‐Segura, Teresa Caballero‐Velázquez, Eusebio Martín‐Chacón, and Rosario M. Morales‐Camacho
- Subjects
Myelodysplastic Syndromes ,Chromosomes, Human, Pair 5 ,Humans ,Hematology ,Chromosome Deletion ,Hematopoiesis - Published
- 2022
38. ASXL1 mutation as a surrogate marker in acute myeloid leukemia with myelodysplasia-related changes and normal karyotype
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Milagros Suito, José A. González, José Antonio Pérez-Simón, Olga Pérez‐López, Maria T. Vargas, Rosario M. Morales-Camacho, Teresa Caballero-Velázquez, Ricardo Bernal, Concepción Prats-Martín, Sergio Burillo-Sanz, and Estrella Carrillo-Cruz
- Subjects
0301 basic medicine ,Oncology ,Male ,Cancer Research ,ASXL1 ,myeloid leukemia ,0302 clinical medicine ,Bone Marrow ,hemic and lymphatic diseases ,AML-MRC ,Leukocytosis ,Mutation frequency ,Original Research ,Aged, 80 and over ,Myeloid leukemia ,Karyotype ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Prognosis ,Survival Rate ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,medicine.symptom ,Adult ,medicine.medical_specialty ,Myelodysplasia ,AML‐MRC ,lcsh:RC254-282 ,03 medical and health sciences ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Radiology, Nuclear Medicine and imaging ,Aged ,Chromosome Aberrations ,business.industry ,Surrogate endpoint ,Clinical Cancer Research ,medicine.disease ,Repressor Proteins ,030104 developmental biology ,Dysplasia ,Case-Control Studies ,Myelodysplastic Syndromes ,Mutation ,Bone marrow ,business ,myelodysplasia ,Follow-Up Studies - Abstract
Acute myeloid leukemia with myelodysplasia‐related changes (AML‐MRC) are poor outcome leukemias. Its diagnosis is based on clinical, cytogenetic, and cytomorphologic criteria, last criterion being sometimes difficult to assess. A high frequency of ASXL1 mutations have been described in this leukemia. We sequenced ASXL1 gene mutations in 61 patients with AML‐MRC and 46 controls with acute myeloid leukemia without other specifications (AML‐NOS) to identify clinical, cytomorphologic, and cytogenetic characteristics associated with ASXL1 mutational status. Mutated ASXL1 (ASXL1+) was observed in 31% of patients with AML‐MRC compared to 4.3% in AML‐NOS. Its presence in AML‐MRC was associated with older age, a previous history of myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN), leukocytosis, presence of micromegakaryocytes in bone marrow, lower number of blasts in bone marrow, myelomonocytic/monocytic morphological features and normal karyotype. ASXL1 mutation was not observed in patients with myelodysplastic syndrome‐related cytogenetic abnormalities or TP53 mutations. Differences in terms of overall survival were found only in AML‐MRC patients without prior MDS or MDS/MPN and with intermediate‐risk karyotype, having ASXL1+ patients a worst outcome than ASXL1−. We conclude that the ASXL1 mutation frequency is high in AML‐MRC patients being its presence associated with specific characteristics including morphological signs of dysplasia. This association raises the possible role of ASXL1 as a surrogate marker in AML‐MRC, which could facilitate the diagnosis of patients within this group when the karyotype is normal, and especially when the assessment of multilineage dysplasia morphologically is difficult. This mutation could be used as a worst outcome marker in de novo AML‐MRC with intermediate‐risk karyotype., The ASXL1 mutation frequency is high in AML‐MRC patients being its presence associated with specific characteristics, including morphological signs of dysplasia. This association raises the possible role of ASXL1 as a surrogate marker in AML‐MRC, which could facilitate the diagnosis of patients within this group when the karyotype is normal, and especially when the assessment of multilineage dysplasia morphologically is difficult. This mutation could be used as a worst outcome marker in de novo AML‐MRC with intermediate‐risk karyotype.
- Published
- 2020
39. Eosinophils engulfing platelets and with ring‐shaped nuclei in nivolumab‐associated eosinophilia
- Author
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Teresa Caballero-Velázquez, Concepción Prats-Martín, M. Teresa Vargas, Silvia García‐Canale, Rosario M. Morales-Camacho, and Javier Delgado‐Serrano
- Subjects
Blood Platelets ,Male ,Cell Nucleus Shape ,Pathology ,medicine.medical_specialty ,Chemistry ,Hematology ,Middle Aged ,Ring (chemistry) ,Eosinophils ,Nivolumab ,Eosinophilia ,medicine ,Humans ,Platelet ,medicine.symptom - Abstract
Images in Haematology.
- Published
- 2020
40. Polyphenolic Extract (PE) from Olive Oil Exerts a Potent Immunomodulatory Effect and Prevents Graft-versus-Host Disease in a Mouse Model
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Teresa L. Ramos, Marina Sánchez-Hidalgo, Mayte Medrano, José I. Piruat, Catalina Alarcón-de-la-Lastra, José A. Pérez-Simón, Francisco J. Hidalgo, María Victoria Barbado, Rosario Zamora, Rocío Caracuel-García, Isabel Álvarez-Laderas, Teresa Caballero-Velázquez, and Universidad de Sevilla. Departamento de Farmacología
- Subjects
Graft vs Host Disease ,Butyrate ,Pharmacology ,Lower risk ,Graft-versus-host disease ,Proinflammatory cytokine ,Mouse model ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Western blot ,Virgin olive oil ,medicine ,Animals ,Survival rate ,Olive Oil ,Transplantation ,medicine.diagnostic_test ,business.industry ,Plant Extracts ,NF-kappa B ,Hematology ,medicine.disease ,Disease Models, Animal ,Polyphenol ,030220 oncology & carcinogenesis ,Polyphenolic extract ,business ,030215 immunology - Abstract
9 Figuras, Polyphenols are a group of chemical substances found in plants, with immunomodulatory, antiproliferative, and anti-inflammatory properties that might be useful in the prophylaxis and treatment of graft-versus-host disease (GVHD). Polyphenolic extract (PE) obtained from extra virgin olive oil (EVOO) decreased the activation and proliferation of activated T cells. In addition, a decreased production of proinflammatory cytokines was observed upon exposure to PE. Western blot assays showed a marked inhibition of Akt phosphorylation and nuclear translocation of NF-κB in activated T cells. In a murine model of acute GVHD, we observed that mice that received a diet supplemented in PE (600 ppm) presented a higher survival rate and lower risk of developing GVHD when compared with the group that received a control diet. Histopathologic examination showed a significantly lower gut involvement in mice receiving PE, with a decrease in proinflammatory cytokines (IL-2, IL-17, and TNF-α) in serum and the reestablishment of butyrate concentration in the gut. In conclusion, PE obtained from EVOO exerted a potent immunomodulatory effect, reducing the activation and proliferation of activated T cells and the production of proinflammatory cytokines. In a murine model of acute GVHD, a PE-supplemented diet reduced the incidence and severity of the disease and increased survival after transplantation.
- Published
- 2020
41. Ruxolitinib in refractory acute and chronic graft-versus-host disease: a multicenter survey study
- Author
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Virginia Escamilla Gomez, Kyra Velázquez-Kennedy, Estefania Perez, Jorge Sierra, A. Martínez, José Antonio Pérez-Simón, Rodrigo Martino Bofarull, Christelle Ferra i Coll, Ingrid Parra Salinas, María João Mende, Marc Poch, Lucía López Corral, Silvanna Daniela Saavedra Gerosa, Guillermo Ortí, Marta González Vicent, Francisco J Márquez Malaver, Teresa Caballero-Velázquez, Rocio Parody Porras, Pedro Antonio González Sierra, Nancy Rodríguez Torres, Isabel Sanchez Ortega, Paula Moles, Maria Teresa Zudaire Ripa, Irene García Cadenas, Rafael De la Cámara LLanzá, Grupo Español de Trasplante Hematopoyético, Miguel Pérez, Ildefonso Espigado Tocino, Juan Montoro Gómez, Maria De La Cruz Viguria Alegria, Jaime Sanz Caballer, Valentín García-Gutiérrez, Dolores Caballero Barrigón, David Valcárcel Ferreiras, Blanca Molina Angulo, Cristina Calderón Cabrera, and Instituto de Salud Carlos III
- Subjects
0301 basic medicine ,Ruxolitinib ,medicine.medical_specialty ,medicine.medical_treatment ,Graft vs Host Disease ,Drug development ,Stem cells ,Disease ,Hematopoietic stem cell transplantation ,RESISTANT ,Gastroenterology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,AVAILABLE THERAPY ,Internal medicine ,Nitriles ,Mortalitat ,CRITERIA ,Humans ,Medicine ,Mortality ,IBRUTINIB ,Retrospective Studies ,Transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Retrospective cohort study ,Hematology ,CONSENSUS DEVELOPMENT PROJECT ,medicine.disease ,Pyrimidines ,Morbiditat ,030104 developmental biology ,Graft-versus-host disease ,Multicenter study ,Molecularly targeted therapy ,030220 oncology & carcinogenesis ,Acute Disease ,Chronic Disease ,Multicenter survey ,Pyrazoles ,Morbidity ,RAPAMYCIN ,Cèl·lules mare ,business ,CLINICAL-TRIALS ,medicine.drug - Abstract
On behalf of the Grupo Español de Trasplante Hematopoyético (GETH): et al., Graft-versus-host disease is the main cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. First-line treatment is based on the use of high doses of corticosteroids. Unfortunately, second-line treatment for both acute and chronic graft-versus-host disease, remains a challenge. Ruxolitinib has been shown as an effective and safe treatment option for these patients. Seventy-nine patients received ruxolitinib and were evaluated in this retrospective and multicenter study. Twenty-three patients received ruxolitinib for refractory acute graft-versus-host disease after a median of 3 (range 1–5) previous lines of therapy. Overall response rate was 69.5% (16/23) which was obtained after a median of 2 weeks of treatment, and 21.7% (5/23) reached complete remission. Fifty-six patients were evaluated for refractory chronic graft-versus-host disease. The median number of previous lines of therapy was 3 (range 1–10). Overall response rate was 57.1% (32/56) with 3.5% (2/56) obtaining complete remission after a median of 4 weeks. Tapering of corticosteroids was possible in both acute (17/23, 73%) and chronic graft-versus-host disease (32/56, 57.1%) groups. Overall survival was 47% (CI: 23–67%) at 6 months for patients with aGVHD (62 vs 28% in responders vs non-responders) and 81% (CI: 63–89%) at 1 year for patients with cGVHD (83 vs 76% in responders vs non-responders). Ruxolitinib in the real life setting is an effective and safe treatment option for GVHD, with an ORR of 69.5% and 57.1% for refractory acute and chronic graft-versus-host disease, respectively, in heavily pretreated patients., This study has been performed in collaboration with the Spanish Group of Hematopoietic Transplant and Cell Therapy (GETH). To the CIBERONC (CB16/12/00480).
- Published
- 2020
42. Genotoxicity of tetrahydrofolic acid to hematopoietic stem and progenitor cells
- Author
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María José Castro, José A. Pérez-Simón, Teresa Caballero-Velázquez, José I. Piruat, Iván V. Rosado, Paula Moreno-Gordillo, Clara B. García-Calderón, Jose Antonio Bejarano-García, and Isabel Tinoco-Gago
- Subjects
0301 basic medicine ,Genome instability ,DNA Repair ,DNA repair ,DNA damage ,Apoptosis ,Article ,Genomic Instability ,Cell Line ,Histones ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Fanconi anemia ,medicine ,Animals ,Phosphorylation ,Progenitor cell ,Tetrahydrofolic acid ,Molecular Biology ,Tetrahydrofolates ,Mice, Knockout ,Chemistry ,Alcohol Dehydrogenase ,Hematopoietic stem cell ,Thymidylate Synthase ,Cell Biology ,Hematopoietic Stem Cells ,medicine.disease ,Fanconi Anemia Complementation Group Proteins ,Hematopoiesis ,Cell biology ,Mice, Inbred C57BL ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,Chickens ,DNA Damage - Abstract
Metabolically reactive formaldehyde is a genotoxin and a carcinogen. Mice lacking the main formaldehyde-detoxifying gene Adh5 combined with the loss of the Fanconi anemia (FA) DNA repair pathway rapidly succumbed to bone marrow failure (BMF) primarily due to the extensive ablation of the hematopoietic stem cell (HSC) pool. However, the mechanism by which formaldehyde mediates these toxic effects is still unknown. We uncover a detrimental role of tetrahydrofolic acid (THF) in cells lacking Adh5 or the FA repair pathway. We show that Adh5- or FA-deficient cells are hypersensitive to formaldehyde and to THF, presenting DNA damage and genome instability. THF cytotoxicity involved imbalance of the nucleotide pool by deregulation of the thymidylate synthase (TYMS) enzyme, which stalled replication forks. In mice, THF exposure had widespread effects on hematopoiesis, affecting the frequency and the viability of myeloid- and lymphoid-committed precursor cells. Moreover, the hematopoietic stem and progenitor cells (HSPC) showed genomic instability, reduced colony-forming capacity and increased frequency of cycling and apoptotic HSCs upon THF exposure. Overall, our data reveal that the physiological pool of THF and formaldehyde challenge the stability of the genome of HSPCs that might lead to blood disorders.
- Published
- 2018
43. MLL-rearranged acute myeloid leukemia: Influence of the genetic partner in allo-HSCT response and prognostic factor of MLL 3′ region mRNA expression
- Author
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Jose Gonzalez Campos, Ricardo Bernal, Rosario M. Morales-Camacho, Javier Sánchez, Estrella Carrillo, Olga Pérez-López, María Teresa Vargas, Inmaculada Soto, Concepción Prats-Martín, Sergio Burillo-Sanz, and Teresa Caballero-Velázquez
- Subjects
Male ,0301 basic medicine ,Oncology ,Oncogene Proteins, Fusion ,Kaplan-Meier Estimate ,Translocation, Genetic ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,Gene expression ,Medicine ,Child ,3' Untranslated Regions ,In Situ Hybridization, Fluorescence ,Gene Rearrangement ,Acute leukemia ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Hematology ,General Medicine ,Middle Aged ,Prognosis ,Gene Expression Regulation, Neoplastic ,Leukemia, Myeloid, Acute ,Leukemia ,Treatment Outcome ,RUNX1 ,Child, Preschool ,030220 oncology & carcinogenesis ,Cohort ,Female ,Myeloid-Lymphoid Leukemia Protein ,Adult ,medicine.medical_specialty ,Adolescent ,Karyotype ,Context (language use) ,Young Adult ,03 medical and health sciences ,Internal medicine ,Biomarkers, Tumor ,Humans ,Transplantation, Homologous ,RNA, Messenger ,neoplasms ,Gene ,Aged ,Proportional Hazards Models ,business.industry ,Infant ,Histone-Lysine N-Methyltransferase ,medicine.disease ,MDS1 and EVI1 Complex Locus Protein ,030104 developmental biology ,fms-Like Tyrosine Kinase 3 ,chemistry ,business - Abstract
Objective MLL gene is involved in more than 80 known genetic fusions in acute leukemia. To study the relevance of MLL partner gene and selected gene's expression, in this work, we have studied a cohort of 20 MLL-rearranged acute myeloid leukemia (AML). Methods Twenty MLL-rearranged AML patients along with a control cohort of 138 AML patients are included in this work. By RT-PCR and sequencing, MLL genetic fusion was characterized, and relative gene expression quantification was carried out for EVI1, MEIS1, MLL-3', RUNX1, SETBP1, HOXA5, and FLT3 genes. Risk stratification and association of MLL genetic partner and gene expression to overall survival, in the context of received therapy, were performed. Results MLLr cohort showed to have an OS more similar to intermediate-risk AML. Type of MLL genetic partner showed to be relevant in allo-HSCT response; having MLLT1 and MLLT3, a better benefit from it. Expression of MLL-3' region, EVI1 and FLT3, showed association with OS in patients undergoing allo-HSCT. Conclusion We show that the MLL genetic partner could have implications in allo-HSCT response, and we propose three genes whose expression could be useful for the prognosis of this leukemia in patients undergoing allo-HSCT: 3' region of MLL, EVI1, and FLT3.
- Published
- 2018
44. Cannabinoid derivatives exert a potent anti-myeloma activity bothin vitroandin vivo
- Author
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Iván V. Rosado, José Antonio Pérez-Simón, Teresa Caballero-Velázquez, Pedro González-Naranjo, M. Victoria Barbado, Luis Ignacio Sánchez-Abarca, Mayte Medrano, Jesús Martín-Sánchez, Estefania Garcia-Guerrero, Isabel Álvarez-Laderas, Juan A. Páez, Nuria E. Campillo, and José I. Piruat
- Subjects
0301 basic medicine ,Cancer Research ,Ceramide ,medicine.medical_treatment ,Biology ,Pharmacology ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Oncology ,chemistry ,Cell culture ,In vivo ,Apoptosis ,030220 oncology & carcinogenesis ,Immunology ,Cannabinoid receptor type 2 ,medicine ,lipids (amino acids, peptides, and proteins) ,Cannabinoid ,Stem cell ,Protein kinase B - Abstract
Although hematopoietic and immune system show high levels of the cannabinoid receptor CB2, the potential effect of cannabinoids on hematologic malignancies has been poorly determined. Here we have investigated their anti-tumor effect in multiple myeloma (MM). We demonstrate that cannabinoids induce a selective apoptosis in MM cell lines and in primary plasma cells of MM patients, while sparing normal cells from healthy donors, including hematopoietic stem cells. This effect was mediated by caspase activation, mainly caspase-2, and was partially prevented by a pan-caspase inhibitor. Their pro-apoptotic effect was correlated with an increased expression of Bax and Bak, a decrease of Bcl-xL and Mcl-1, a biphasic response of Akt/PKB and an increase in the levels of ceramide in MM cells. Inhibition of ceramide synthesis partially prevented apoptosis, indicating that these sphingolipids play a key role in the pro-apoptotic effect of cannabinoids in MM cells. Remarkably, blockage of the CB2 receptor also inhibited cannabinoid-induced apoptosis. Cannabinoid derivative WIN-55 enhanced the anti-myeloma activity of dexamethasone and melphalan overcoming resistance to melphalan in vitro. Finally, administration of cannabinoid WIN-55 to plasmacytoma-bearing mice significantly suppressed tumor growth in vivo. Together, our data suggest that cannabinoids may be considered as potential therapeutic agents in the treatment of MM.
- Published
- 2016
45. Vitamin D Modifies the Incidence of Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation Depending on the Vitamin D Receptor (VDR) Polymorphisms
- Author
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David Valcárcel, Alfonso Rodríguez-Gil, Christelle Ferra i Coll, José A. Pérez-Simón, Fermín Sánchez-Guijo, Teresa L. Ramos, José R. García-Lozano, Lucía López-Corral, Estrella Carrillo-Cruz, Teresa Caballero-Velázquez, Francisco J. Márquez-Malaver, Oriana López-Godino, Rocío Parody, Isabel Montero Cuadrado, Marian Cuesta, Jose Antonio Bejarano-García, and Miguel Alcoceba
- Subjects
Vitamin ,Cancer Research ,medicine.medical_specialty ,TaqI ,Graft vs Host Disease ,Gastroenterology ,Calcitriol receptor ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Vitamin D and neurology ,Medicine ,Humans ,Prospective Studies ,Prospective cohort study ,Cholecalciferol ,biology ,business.industry ,Incidence ,Case-control study ,Hematopoietic Stem Cell Transplantation ,Vitamins ,FokI ,Transplantation ,Treatment Outcome ,Oncology ,chemistry ,Haplotypes ,Spain ,030220 oncology & carcinogenesis ,Case-Control Studies ,biology.protein ,Receptors, Calcitriol ,business ,030215 immunology - Abstract
Purpose: The biologically active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 (vit D), has immunoregulatory properties via binding vitamin D receptor (VDR). In a prospective trial, we previously reported a reduction in the incidence of chronic GvHD (cGvHD) among patients who received vit D after allogeneic stem cell transplantation (allo-HSCT; Clinical Trials.gov: NCT02600988). Here we analyze the role of patients and donors' VDR SNPs on the immunomodulatory effect of vit D. Patients and Methods: Patients undergoing allo-HSCT were included in a prospective phase I/II clinical trial (Alovita) in three consecutive cohorts: control (without vit D), low-dose (1,000 IU/day), and high-dose (5,000 IU/day) groups. Vit D was given from day −5 until +100 after transplant. Genotyping of four SNPs of the VDR gene, FokI, BsmI, ApaI, and TaqI, were performed using TaqMan SNP genotyping assays. Results: We observed a decrease in the incidence of overall cGvHD at 1 year after allo-HSCT depending on the use or not of vit D among patients with FokI CT genotype (22.5% vs 80%, P = 0.0004) and among those patients without BsmI/ApaI/TaqI ATC haplotype (22.2% vs 68.8%, P = 0.0005). In a multivariate analysis, FokI CT genotype significantly influenced the risk of cGvHD in patients treated with vit D as compared with the control group (HR 0.143, Pinteraction < 0.001). Conclusions: Our results show that the immunomodulatory effect of vit D depends on the VDR SNPs, and patients carrying the FokI CT genotype display the highest benefit from receiving vit D after allo-HSCT.
- Published
- 2019
46. Selection of Tumor-Specific Cytotoxic T Lymphocytes in Acute Myeloid Leukemia Patients Through the Identification of T-Cells Capable to Establish Stable Interactions With the Leukemic Cells: 'Doublet Technology'
- Author
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José González-Campos, Jose Antonio Bejarano-García, Esther Domingo, Luis Ignacio Sánchez-Abarca, Teresa L. Ramos, Teresa Caballero-Velázquez, Estefanía García-Guerrero, José A. Pérez-Simón, Universidad de Sevilla. Departamento de Medicina, Instituto de Salud Carlos III, European Commission, Sociedad Española de Hematología y Hemoterapia, European Science Foundation, and Centros de Investigación Biomédica en Red (España)
- Subjects
Cytotoxicity, Immunologic ,medicine.medical_treatment ,Cell Separation ,Lymphocyte Activation ,Immunotherapy, Adoptive ,0302 clinical medicine ,Cell selection ,Tumor Microenvironment ,Immunology and Allergy ,Cytotoxic T cell ,Immunologic Surveillance ,Cells, Cultured ,Antigen Presentation ,Myeloid leukemia ,Flow Cytometry ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Tumor-specific T cells ,030220 oncology & carcinogenesis ,Immunotherapy ,immunotherapy ,lcsh:Immunologic diseases. Allergy ,T cell ,Immunology ,Receptors, Antigen, T-Cell ,chemical and pharmacologic phenomena ,acute myeloid leukemia ,cell selection ,Cancer Vaccines ,03 medical and health sciences ,Immune system ,Lymphocytes, Tumor-Infiltrating ,Antigens, Neoplasm ,medicine ,Immune Tolerance ,Humans ,tumor-specific T cells ,Antigen-presenting cell ,T cell-tumor cell synapse ,Acute myeloid leukemia ,Tumor-infiltrating lymphocytes ,business.industry ,Cancer research ,Tumor Escape ,Bone marrow ,business ,lcsh:RC581-607 ,030215 immunology ,T-Lymphocytes, Cytotoxic - Abstract
The relevance of the immune system in cancer has long been studied. Autologous adoptive T cell therapies, based on the use of tumor infiltrating lymphocytes (TILs), have made great progress in recent years for the treatment of solid tumors, especially melanoma. However, further work is needed to isolate tumor-reactive T cells among patients diagnosed with hematologic malignancies. The dynamics of the interaction between T cells and antigen presenting cells (APC) dictate the quality of the immune responses. While stable joints between target cells and T lymphocytes lead to the induction of T cell activation and immune response, brief contacts contribute to the induction of immune-tolerance. Taking advantage of the strong interaction between target cell and activated T-cells, we show the feasibility to identify and isolate tumor-specific cytotoxic T lymphocytes (CTLs) from acute myeloid leukemia (AML) patients by flow cytometry. Using this technology, CTLs bound through T cell receptor (TCR) to tumor cells can be identified in peripheral blood and bone marrow and subsequently selected and isolated by FACS-based cell sorting. These CTLs display higher percentage of effector cells and marked cytotoxic activity against AML blasts. In conclusion, we have developed a new procedure to identify and select specific cytotoxic T cells in patients diagnosed with acute myeloid leukemia., EG-G was supported by Instituto de Salud Carlos III (PFIS- FI12/00189). JB-G was supported by the SEHH. This work was supported by the Instituto de Salud Carlos III (ISCIII PI14/02074, PI11/02366, and PI17/02177), integrated in the national I+D+i 2013–2016 and co-funded by European Union (ERDF/ESF, Investing in your future) and the CIBER (CB16/12/00480).
- Published
- 2018
47. KIT D816V− chronic myelomonocytic leukemia progressing to KIT D816V+ associated to mast cell leukemia responding to allogeneic hematopoietic cell transplantation
- Author
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M. Teresa Vargas, Estrella Carrillo, Ricardo Bernal, Teresa Caballero-Velázquez, Rosario M. Morales-Camacho, Sergio Burillo-Sanz, Patricia Jiménez-Guerrero, Olga Pérez, Concepción Prats-Martín, José A. Pérez-Simón, Isabel Montero, Jose F Falantes, and Juan J. Borrero
- Subjects
medicine.medical_specialty ,Hematology ,Hematopoietic cell ,business.industry ,medicine.medical_treatment ,education ,Chronic myelomonocytic leukemia ,General Medicine ,Hematopoietic stem cell transplantation ,medicine.disease ,Mast cell leukemia ,Kit d816v ,Transplantation ,03 medical and health sciences ,Leukemia ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Cancer research ,business ,030215 immunology - Published
- 2018
48. Reduced intensity conditioning increases risk of severe cGVHD : identification of risk factors for cGVHD in a multicenter setting
- Author
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José Luis Piñana, Olle Ringdén, Jose Antonio Pérez Simón, Gabriel Afram, Teresa Caballero-Velázquez, Dolores Caballero, Lucía López-Corral, Lourdes Vázquez, Oriana López-Godino, Jordi Sierra, Mats Remberger, Hans Hägglund, Albert Esquirol, Irene Garcia, Per Ljungman, and Rodrigo Martino
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Transplantation Conditioning ,Adolescent ,medicine.medical_treatment ,Graft vs Host Disease ,Disease ,Hematopoietic stem cell transplantation ,Gastroenterology ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Patient age ,Risk Factors ,immune system diseases ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Transplantation, Homologous ,In patient ,Hematologi ,Risk factor ,Child ,Aged ,Retrospective Studies ,Original Paper ,Hematology ,business.industry ,Incidence (epidemiology) ,Hematopoietic Stem Cell Transplantation ,Infant ,General Medicine ,Middle Aged ,ATG ,Oncology ,030220 oncology & carcinogenesis ,Reduced Intensity Conditioning ,Child, Preschool ,Chronic Disease ,Graft-versus-host disease (GVHD) ,Female ,business ,030215 immunology - Abstract
Chronic graft-versus-host disease (cGVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Aim is to identify risk factors for the development of cGVHD in a multicenter setting. Patients transplanted between 2000 and 2006 were analyzed (n = 820). Donors were HLA-identical siblings (57%), matched unrelated donors (30%), and HLA-A, B or DR antigen mismatched (13%). Reduced intensity conditioning (RIC) was given to 65% of patients. Overall incidence of cGVHD was 46% for patients surviving more than 100 days after HSCT (n = 747). Older patient age [HR 1.15, p < 0.001], prior acute GVHD [1.30, p = 0.024], and RIC [1.36, p = 0.028] increased overall cGVHD. In addition, RIC [4.85, p < 0.001], prior aGVHD [2.14, p = 0.001] and female donor to male recipient [1.80, p = 0.008] increased the risk of severe cGVHD. ATG had a protective effect for both overall [0.41, p < 0.001] and severe cGVHD [0.20, p < 0.001]. Relapse-free survival (RFS) was impaired in patients with severe cGVHD. RIC, prior aGVHD, and female-to-male donation increase the risk of severe cGVHD. ATG reduces the risk of all grades of cGVHD without hampering RFS. GVHD prophylaxis may be tailored according to the risk profile of patients.
- Published
- 2018
49. Basophil-lineage commitment in acute promyelocytic leukemia predicts for severe bleeding after starting therapy
- Author
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Aránzazu García Mateo, Oliver Gutiérrez, Carlos Fernandez, Monique Bourgeois García, Gloria García-Donas, Vincent H.J. van der Velden, Carlos Salvador Osuna, Isabel Recio, Jacques J.M. van Dongen, Teresa Caballero-Velázquez, Andrea Mayado, Ana Yeguas Bermejo, Alberto Orfao, Antonio López, María C. Chillón, Cristina De Ramón Sánchez, Mojca Jongen-Lavrencic, Javier Sánchez-Real, María Laura Gutiérrez, Marcos González, Enrique Colado, María Belén Vidriales, Daniel Rivera, Sergio Matarraz, Susana Barrena, Pilar Leoz, Luis Alonso, Paloma Bárcena, Fundación Científica Asociación Española Contra el Cáncer, Fundación Rafael del Pino, Centro de Investigación Biomédica en Red Cáncer (España), Instituto de Salud Carlos III, Immunology, and Hematology
- Subjects
Acute promyelocytic leukemia ,Adult ,Male ,medicine.medical_specialty ,Pathology ,Adolescent ,CD34 ,Hemorrhage ,Predictive markers ,Gastroenterology ,Pathology and Forensic Medicine ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Immunophenotyping ,Leukemia, Promyelocytic, Acute ,Internal medicine ,medicine ,Humans ,Cumulative incidence ,Cell Lineage ,Young adult ,Child ,Aged ,Aged, 80 and over ,Acute myeloid leukemia ,business.industry ,Hazard ratio ,Middle Aged ,medicine.disease ,Basophils ,Leukemia ,medicine.anatomical_structure ,Phenotype ,030220 oncology & carcinogenesis ,Child, Preschool ,Female ,Bone marrow ,business ,030215 immunology - Abstract
Severe hemorrhagic events occur in a significant fraction of acute promyelocytic leukemia patients, either at presentation and/or early after starting therapy, leading to treatment failure and early deaths. However, identification of independent predictors for high-risk of severe bleeding at diagnosis, remains a challenge. Here, we investigated the immunophenotype of bone marrow leukemic cells from 109 newly diagnosed acute promyelocytic leukemia patients, particularly focusing on the identification of basophil-related features, and their potential association with severe bleeding episodes and patient overall survival. From all phenotypes investigated on leukemic cells, expression of the CD203c and/or CD22 basophil-associated markers showed the strongest association with the occurrence and severity of bleeding (p ≤ 0.007); moreover, aberrant expression of CD7, coexpression of CD34+/CD7+ and lack of CD71 was also more frequently found among patients with (mild and severe) bleeding at baseline and/or after starting treatment (p ≤ 0.009). Multivariate analysis showed that CD203c expression (hazard ratio: 26.4; p = 0.003) and older age (hazard ratio: 5.4; p = 0.03) were the best independent predictors for cumulative incidence of severe bleeding after starting therapy. In addition, CD203c expression on leukemic cells (hazard ratio: 4.4; p = 0.01), low fibrinogen levels (hazard ratio: 8.8; p = 0.001), older age (hazard ratio: 9.0; p = 0.002), and high leukocyte count (hazard ratio: 5.6; p = 0.02) were the most informative independent predictors for overall survival. In summary, our results show that the presence of basophil-associated phenotypic characteristics on leukemic cells from acute promyelocytic leukemia patients at diagnosis is a powerful independent predictor for severe bleeding and overall survival, which might contribute in the future to (early) risk-adapted therapy decisions., This work was supported by the Fundación Científica de la Asociación Española Contra el Cáncer (AECC, Madrid, Spain) and the Fundación Rafael del Pino (Madrid, Spain) and both CIBERONC (CB16/12/00400, CB16/12/00233, CB16/12/00480) and grant PI16/00787 from Instituto de Salud Carlos III (Ministerio de Economía y Competitividad, Madrid, Spain).
- Published
- 2018
50. NUP98-HOXA9bearing therapy-related myeloid neoplasm involves myeloid-committed cell and inducesHOXA5,EVI1, FLT3,andMEIS1expression
- Author
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Jose F Falantes, Ricardo Bernal, Teresa Caballero-Velázquez, Jose Raul Garcia-Lozano, María Teresa Vargas, José A. Pérez-Simón, Sergio Burillo-Sanz, Concepción Prats-Martín, and Rosario M. Morales-Camacho
- Subjects
0301 basic medicine ,Myeloid ,Adolescent ,Oncogene Proteins, Fusion ,Cellular differentiation ,Clinical Biochemistry ,Gene Expression ,Translocation, Genetic ,Immunophenotyping ,Myeloid Neoplasm ,Fusion gene ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Proto-Oncogenes ,medicine ,Humans ,Myeloid Cells ,Myeloid Ecotropic Viral Integration Site 1 Protein ,In Situ Hybridization, Fluorescence ,Homeodomain Proteins ,Acute leukemia ,business.industry ,Gene Expression Profiling ,Biochemistry (medical) ,Disease Management ,Myeloid leukemia ,Neoplasms, Second Primary ,Hematology ,General Medicine ,medicine.disease ,Fusion protein ,MDS1 and EVI1 Complex Locus Protein ,Neoplasm Proteins ,DNA-Binding Proteins ,Nuclear Pore Complex Proteins ,Leukemia, Myeloid, Acute ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,fms-Like Tyrosine Kinase 3 ,030220 oncology & carcinogenesis ,Immunology ,Female ,business ,Transcription Factors - Abstract
Summary Introduction Chromosomal rearrangements involving NUP98 gene have been associated with human leukemias such as de novo AML, therapy-related AML (t-AML), myelodysplastic syndrome (MDS), and chronic myeloid leukemia (CML). Genetic fusion NUP98–HOXA9, caused by t(7;11)(p15;p15), is a recurrent cytogenetic alteration in de novo acute myeloid leukemia (AML) usually found in young Asian patients and its description in therapy-related myeloid neoplasms (t-MN) is rare. Only one Asian case with molecular demonstration of the NUP98–HOXA9 fusion has been reported in therapy-related leukemia. NUP98–HOXA9 leukemogenic mechanism is derived from the transcription factor activity of the chimeric protein, which enhances the expression of genes related to cellular differentiation arrest and proliferation. Patients and Methods We studied a Caucasian woman with a therapy-related acute myeloid leukemia after Ewing′s sarcoma. Molecular demonstration of the genetic fusion NUP98–HOXA9 was performed by RT-PCR, and gene expression was analyzed by real-time PCR, including four AML patients with MLL rearrangements for comparative analysis. Cytologic and flow cytometric analysis was also carried out. Results After cytologic and flow cytometric analysis diagnostics was therapy-related myeloid neoplasm (t-MN). The major component of blasts in the acute leukemia was with neutrophilic differentiation, but 13% erythroid lineage blasts were also found. Cytogenetic and FISH analysis revealed t(7;11)(p15;p15) and NUP98–HOXA9 fusion gene was demonstrated. Gene expression analysis showed upregulation of EVI1 and MEIS1 in the index patient, both of them previously related to a worst outcome. Conclusion In this work, we include a detailed molecular, clinical, cytological, and cytometric study of the second t-AML bearing NUP98–HOXA9 genetic fusion.
- Published
- 2015
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