86 results on '"Fuster, JL"'
Search Results
2. Neuroblastoma in Spain: Linking the national clinical database and epidemiological registries – A study by the Joint Action on Rare Cancers
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Cañete, Adela, primary, Peris-Bonet, Rafael, additional, Capocaccia, Riccardo, additional, Pardo-Romaguera, Elena, additional, Segura, Vanessa, additional, Muñoz-López, Ana, additional, Fernández-Teijeiro, Ana, additional, Galceran-Padros, Jaume, additional, Gatta, Gemma, additional, Almazán, F, additional, Benito, AI, additional, Buedo, MI, additional, Calvo, C, additional, Cañete, A, additional, Cruz, O, additional, Esquembre, C, additional, Fernández, M, additional, Fernández-Teijeiro Álvarez, A, additional, Fuster, JL, additional, García, M, additional, Gil López, C, additional, Gómez, J, additional, Gondra, A, additional, González, M, additional, González, H, additional, Herrero, B, additional, Lassaletta, A, additional, López, R, additional, López-Ibor Aliño, B, additional, Madero, L, additional, Maldonado, S, additional, Mares, FJ, additional, Márquez, C, additional, Mateos, ME, additional, Melwani, K, additional, Mendoza, MC, additional, Moreno, L, additional, Moreno, ML, additional, Muñoz, GM, additional, Ortega, MJ, additional, Panizo, E, additional, Pisa Gatell, S, additional, Portugal, R, additional, Sagaseta, M, additional, Salinas, JA, additional, Sastre, A, additional, Tallón, M, additional, Torrent, M, additional, Uriz, JJ, additional, Varo, A, additional, Vázquez, MA, additional, Vílchez, JS, additional, Villegas, JA, additional, Vivanco, JL, additional, Zamora, M, additional, Alamo, R, additional, Alemán, A, additional, Chico, M, additional, Chirlaque, MD, additional, Galceran, J, additional, Marcos, R, additional, Mateos, A, additional, Quirós, JR, additional, Sanchez-Contador, C, additional, and Sabater, C, additional
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- 2022
- Full Text
- View/download PDF
3. Matched sibling donor stem cell transplantation for sickle cell disease: Results from the Spanish group for bone marrow transplantation in children
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Benitez-Carabante, MI, Belendez, C, Gonzalez-Vicent, M, Alonso, L, Uria-Oficialdegui, ML, Torrent, M, Perez-Hurtado, JM, Fuster, JL, Cela, E, and Diaz-de-Heredia, C
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surgical procedures, operative ,children ,sickle cell disease (SCD) ,hematopoietic stem cell transplantation (HSCT) - Abstract
Objectives The prevalence of sickle cell disease (SCD) in Spain is markedly inferior compared with other European and Mediterranean countries. However, the diagnosis of new patients with SCD is expected to increase. In this multicenter retrospective study, we analyze the hematopoietic stem cell transplantation (HSCT) results obtained in Spain. Methods Forty-five patients who underwent a matched sibling donor (MSD) HSCT between 1999 and 2018 were included. Primary endpoint was event-free survival (EFS), and secondary endpoints included acute and chronic graft-versus-host disease (GvHD) and overall survival (OS). Results Bone marrow was the most frequent stem cell source (93.3%). Most patients received a conditioning regimen based on busulfan and cyclophosphamide (69%). Cumulative incidence of grade III-IV acute GvHD and chronic GvHD was 6.8% (95% CI: 2.3%-20.1%) and 5.4% (95% CI: 1.38%-19.9%), respectively. EFS and overall survival (OS) at 3 years post-HSCT were 89.4% (95% CI: 73.9%-95.9%) and 92.1% (95% CI: 77.2%-97.4%), respectively. All patients aged
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- 2021
4. Near-Haploidy and Low-Hypodiploidy in B-Cell Acute Lymphoblastic Leukemia: When Less Is Too Much
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Molina O, Bataller A, Thampi N, Ribera J, Granada I, Velasco P, Fuster JL, and Menéndez P
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near-haploidy ,clinical biomarkers ,hypodiploidy ,patient stratification ,B-cell acute lymphoblastic leukemia - Abstract
Hypodiploidy with less than 40 chromosomes is a rare genetic abnormality in B-cell acute lymphoblastic leukemia (B-ALL). This condition can be classified based on modal chromosome number as low-hypodiploidy (30-39 chromosomes) and near-haploidy (24-29 chromosomes), with unique cytogenetic and mutational landscapes. Hypodiploid B-ALL with
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- 2021
5. Bone marrow MSC from pediatric patients with B-ALL highly immunosuppress T-cell responses but do not compromise CD19-CAR T-cell activity
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Zanetti SR, Romecin PA, Vinyoles M, Manel Juan Otero, Fuster JL, Camós-Guijosa M, Querol S, Delgado M, and Menendez P
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tumor microenvironment ,inflammation ,cell engineering ,immunotherapy ,immunomodulation - Abstract
BACKGROUND: Although adoptive transfer of CD19-directed chimeric antigen receptor (CAR) T-cells (CD19-CAR T-cells) achieves high rates of complete response in patients with B-cell acute lymphoblastic leukemia (B-ALL), relapse is common. Bone marrow (BM) mesenchymal stem/stromal cells (BM-MSC) are key components of the hematopoietic niche and are implicated in B-ALL pathogenesis and therapy resistance. MSC exert an immunosuppressive effect on T-cells; however, their impact on CD19-CAR T-cell activity is understudied. METHODS: We performed a detailed characterization of BM-MSC from pediatric patients with B-ALL (B-ALL BM-MSC), evaluated their immunomodulatory properties and their impact on CD19-CAR T-cell activity in vitro using microscopy, qRT-PCR, ELISA, flow cytometry analysis and in vivo using a preclinical model of severe colitis and a B-ALL xenograft model. RESULTS: While B-ALL BM-MSC were less proliferative than those from age-matched healthy donors (HD), the morphology, immunophenotype, differentiation potential and chemoprotection was very similar. Likewise, both BM-MSC populations were equally immunosuppressive in vitro and anti-inflammatory in an in vivo model of severe colitis. Interestingly, BM-MSC failed to impair CD19-CAR T-cell cytotoxicity or cytokine production in vitro using B-ALL cell lines and primary B-ALL cells. Finally, the growth of NALM6 cells was controlled in vivo by CD19-CAR T-cells irrespective of the absence/presence of BM-MSC. CONCLUSIONS: Collectively, our data demonstrate that pediatric B-ALL and HD BM-MSC equally immunosuppress T-cell responses but do not compromise CD19-CAR T-cell activity.
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- 2020
6. APPLICATION OF A NGS DIAGNOSTIC PANEL TO IMPROVE AND REFINE THE STRATIFICATION OF PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA B
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Montano, A, Matorra-Miguel, M, Forero-Castro, M, Lumbreras, E, Santos, S, Miguel, C, Fuster, JL, De las Heras, N, Garcia-de Coca, A, Sierra, M, Davila, J, De la Fuente, I, Olivier, C, Olazabal, J, Martinez, J, Vega-García N, Camós-Guijosa M, Gonzalez, T, Hernandez-Rivas, JM, and Benito, R
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- 2020
7. Efficient elimination of primary B-ALL cells in vitro and in vivo using a novel 4-1BB-based CAR targeting a membrane-distal CD22 epitope
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Velasco-Hernandez T, Zanetti SR, Roca-Ho H, Gutierrez-Aguera F, Petazzi P, Sánchez-Martínez D, Molina O, Baroni ML, Fuster JL, Ballerini P, Bueno C, Fernandez-Fuentes N, Engel P, and Menendez P
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hematologic neoplasms ,T-lymphocytes ,receptors, chimeric antigen ,cell engineering ,immunotherapy - Abstract
BACKGROUND: There are few therapeutic options available for patients with B-cell acute lymphoblastic leukemia (B-ALL) relapsing as CD19(-) either after chemotherapy or CD19-targeted immunotherapies. CD22-chimeric antigen receptor (CAR) T cells represent an attractive addition to CD19-CAR T cell therapy because they will target both CD22(+)CD19(-) B-ALL relapses and CD19(-) preleukemic cells. However, the immune escape mechanisms from CD22-CAR T cells, and the potential contribution of the epitope binding of the anti-CD22 single-chain variable fragment (scFv) remain understudied. METHODS: Here, we have developed and comprehensively characterized a novel CD22-CAR (clone hCD22.7) targeting a membrane-distal CD22 epitope and tested its cytotoxic effects against B-ALL cells both in in vitro and in vivo assays. RESULTS: Conformational epitope mapping, cross-blocking, and molecular docking assays revealed that the hCD22.7 scFv is a high-affinity binding antibody which specifically binds to the ESTKDGKVP sequence, located in the Ig-like V-type domain, the most distal domain of CD22. We observed efficient killing of B-ALL cells in vitro, although the kinetics were dependent on the level of CD22 expression. Importantly, we show an efficient in vivo control of patients with B-ALL derived xenografts with diverse aggressiveness, coupled to long-term hCD22.7-CAR T cell persistence. Remaining leukemic cells at sacrifice maintained full expression of CD22, ruling out CAR pressure-mediated antigen loss. Finally, the immunogenicity capacity of this hCD22.7-scFv was very similar to that of other CD22 scFv previously used in adoptive T cell therapy. CONCLUSIONS: We report a novel, high-affinity hCD22.7 scFv which targets a membrane-distal epitope of CD22. 4-1BB-based hCD22.7-CAR T cells efficiently eliminate clinically relevant B- CD22(high) and CD22(low) ALL primary samples in vitro and in vivo. Our study supports the clinical translation of this hCD22.7-CAR as either single or tandem CD22-CD19-CAR for both naive and anti-CD19-resistant patients with B-ALL.
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- 2020
8. Real life outcomes of patients aged >= 75 years old with acute promyelocytic leukemia: experience of the PETHEMA registry
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Salamero, O, Martinez-Cuadron, D, Sobas, M, Benavente, C, Vives, S, De la Serna, J, Perez-Encinas, M, Escoda, L, Gil, C, Brunet, S, Ramos, F, Esteve, J, Amigo, M, Krsnik, I, Manso, F, Arias, J, Gonzalez-Campos, J, Serrano, J, Oleksiuk, J, Barrios, M, Garcia-Boyero, R, Novo, A, Sanz, MA, Montesinos, P, Helbig, G, Holowiecka, A, Armatys, A, Hawrylecka, D, Golos, A, Ejduk, A, Majcherek, M, Skret, A, Czyzewska, J, Grosicki, S, Zarzycka, E, Watek, M, Piatkowska-Jakubas, B, Holojda, J, Pluta, A, Podhorecka, M, Gromek, T, Guzicka, E, Charlinski, G, Paluszewska, M, de Heredia, JMB, Hernandez, JM, Roman, A, Negri, S, Rayon, C, Fernandez-Calvo, FJ, Diaz-Mediavilla, J, Tormo, M, Olave, M, Amutio, E, Pedro, C, Gorosquieta, A, Viguria, M, Zudaire, M, Molero, T, Sayas, MJ, Guardia, R, Rivas, C, Esquembre, C, Garcia, R, Alcala, A, Lopez, JA, Rubio, V, Linares, M, Ribera, JM, San Miguel, JDG, Deben, G, de la C?mara, R, Molines, A, Loureiro, C, Allegue, MJ, Amador, L, Marti, JM, Madero, L, Lassaletta, A, Cabezudo, M, Garcia-Larana, J, Rojas, R, Ortega, F, Penarrubia, MJ, Puente, F, Lopez-Ibor, B, Bergua, JM, Ibanez, J, Sanchez, P, Font, LL, Guinea, JM, Montero, A, Gonzalez, M, Martin, G, Martinez, J, Verdeguer, A, Garcia, P, Conde, E, Garcia, J, Capote, FJ, Bueno, J, Bastida, P, Rubio, A, Fuster, JL, Perez, I, Molina, J, Mateos, MC, Ardaiz, MA, Rodriguez-calvillo, M, Poderos, C, Arnan, M, Duarte, R, Hernandez, JA, Diaz-Morfa, M, Martin-Chacon, E, Calvo-Villas, JM, Garcia-Belmonte, D, Hernandez-Maraver, D, and Miskiewicz, W
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induction mortality in APL ,APL real life outcomes ,Elderly APL ,APL prognostic factors ,neoplasms - Abstract
Acute promyelocytic leukemia is infrequent among patients aged >= 75 years old, a population that is rarely eligible for clinical protocols. This study aims to analyze the treatment strategies and clinical outcomes of very old APL patients reported to the international PETHEMA registry. Between 1997 and 2017, among 2501 APL cases registered 120 were >= 75 years old. Treatment approaches were: AIDA regimen, 79 patients; ATRA alone, 23; 16, supportive care (SC) and 2, other strategies. Patients treated with AIDA were younger, had better ECOG and lower leukocytes. Complete remission (CR) was achieved in 65% of AIDA-group vs. 45% in the ATRA-group, being infections followed by bleeding the most frequent causes of induction death. Patients in CR after AIDA showed 3-year DFS of 73%. Our real-life series of very old APL patients provides a reference basis for future treatment strategies aiming to improve clinical outcomes in this challenging population.
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- 2019
9. Clinical significance of complex karyotype at diagnosis in pediatric and adult patients with de novo acute promyelocytic leukemia treated with ATRA and chemotherapy
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Labrador, J, Luno, E, Vellenga, E, Brunet, S, Gonzalez-Campose, J, Chillon, MC, Holowiecka, A, Esteve, J, Bergua, J, Gonzalez-Sanmiguel, JD, Gil, C, Tormo, M, Salamero, O, Manso, F, Fernandez, I, de laSerna, J, Moreno, MJ, Perez-Encinas, M, Krsnik, I, Ribera, JM, Cervera, J, Calasanz, MJ, Boluda, B, Sobas, M, Lowenberg, B, Sanz, MA, Montesinos, P, Palmer, L, Ciarlo, S, Bezares, F, Rojas, F, Longoni, H, Gelemur, M, Fazio, P, Canepa, C, Saba, S, Balladares, G, Negri, P, Giunta, M, Milone, J, Prates, MV, Lafalse, D, Sossa, C, Jaramillo, F, Mayer, J, Protivankova, M, Scwarz, J, Holowiecka-Goral, A, Jakubas, B, Skret-Norwicz, A, Bizgalska-Skrzypek, P, Pluta, A, Becht, R, Kielbinski, M, Watek, M, Paluszewska, M, Gadomska, A, Rzenno, E, Piszcz, J, Ejduk, A, Dobrzanska, J, Calbecka, M, Kostyra, A, Malek, M, Grosicki, S, Knopinska, W, de Heredia, JMB, Hernandez, JM, Arias, J, Ramos, F, Roman, A, de la Serna, J, Negri, S, Rayon, C, Fernandez-Calvo, FJ, Diaz-Mediavilla, J, Olave, M, Amutio, E, Pedro, C, Gorosquieta, A, Viguria, M, Zudaire, M, Molero, T, Sayas, MJ, Guardia, R, Rivas, C, Esquembre, C, Garcia, R, Alcala, A, Lopez, JA, Rubio, V, Amigo, ML, Linares, M, San Miguel, JDG, Deben, G, Escoda, L, de la Camara, R, Molines, A, Loureiro, C, Allegue, MJ, Amador, L, Marti, JM, Madero, L, Lassaletta, A, Cabezudo, M, Garcia-Larana, J, Rojas, R, Ortega, F, Penarrubia, MJ, Puente, F, Lopez-Ibor, B, Bergua, JM, Ibanez, J, Sanchez, P, Novo, A, Font, LL, Guinea, JM, Montero, A, Gonzalez, M, Martin, G, Martinez, J, Verdeguer, A, Garcia, P, Conde, E, Garcia, J, Capote, FJ, Bueno, J, Bastida, P, Rubio, A, Fuster, JL, Gonzalez, J, Perez, I, Molina, J, Mateos, MC, Ardaiz, MA, Rodriguez-calvillo, M, Poderos, C, Arnan, M, Duarte, R, Hernandez, JA, Diaz-Morfa, M, Martin-Chacon, E, Calvo-Villas, JM, Garcia-Belmonte, D, Hernandez-Maraver, D, Ossenkoppele, GJ, van der Lelie, J, Sonneveld, P, Zijlmans, M, Maertens, J, de Valk, B, Wijermans, PW, de Groot, MR, Schouten, HC, Biesma, DH, Kooy, MV, and de Lisa, E
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relapse ,complex karyotype ,Acute promyelocytic leukemia ,ATRA ,chemotherapy ,prognostic - Abstract
Although additional cytogenetic abnormalities (ACA) do not affect the prognosis of patients with t(15;17) acute promyelocytic leukemia (APL), the role of a complex karyotype (CK) is yet to be clarified. We aimed to investigate the relationship of CK with relapse incidence in 1559 consecutive APL patients enrolled in three consecutive trials. Treatment consisted of AIDA induction followed by risk-adapted consolidation. A CK (CK) was defined as the presence of >= 2 ACA, and a very CK (CK+) as >= 3 ACA. Eighty-nine patients (8%) had a CK, of whom 41 (4%) had CK+. The 5-year cumulative incidence of relapse (CIR) in patients with CK was 18%, and 12% in those with
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- 2019
10. An analysis of the impact of CD56 expression in de novo acute promyelocytic leukemia patients treated with upfront all-trans retinoic acid and anthracycline-based regimens
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Sobas, M, Montesinos, P, Boluda, B, Bernal, T, Vellenga, E, Nomdedeu, J, Gonzalez-Campos, J, Chillon, M, Holowiecka, A, Esteve, J, Bergua, J, Gonzalez-Sanmiguel, JD, Gil-Cortes, C, Tormo, M, Salamero, O, Manso, F, Fernandez, I, de la Serna, J, Moreno, MJ, Perez-Encinas, M, Krsnik, I, Ribera, JM, Escoda, L, Lowenberg, B, Sanz, MA, de Heredia, JMB, Hernandez, JM, Arias, J, Ramos, F, Roman, A, Negri, S, Rayon, C, Fernandez-Calvo, FJ, Diaz-Mediavilla, J, Gil, C, Olave, M, Amutio, E, Pedro, C, Gorosquieta, A, Viguria, M, Zudaire, M, Molero, T, Sayas, MJ, Guardia, R, Esquembre, C, Garcia, R, Alcala, A, Lopez, JA, Rubio, V, Amigo, ML, Linares, M, San Miguel, JDG, Coruna, A, Deben, G, de la Camara, R, Molines, A, Loureiro, C, Allegue, MJ, Amador, L, Marti, JM, Madero, L, Lassaletta, A, Cabezudo, M, Garcia-Larana, J, Rojas, R, Ortega, F, Penarrubia, MJ, Puente, F, Lopez-Ibor, B, Brunet, S, Ibanez, J, Sanchez, P, Novo, A, Guinea, JM, Montero, A, Gonzalez, M, Martin, G, Martinez, J, Verdeguer, A, Garcia, P, Conde, E, Garcia, J, Capote, FJ, Bueno, J, Bastida, P, Rubio, A, Fuster, JL, Gonzalez, J, Perez, I, Molina, J, Mateos, MC, Ardaiz, MA, Rodriguez-calvillo, M, Poderos, C, Arnan, M, Duarte, R, Diaz-Morfa, M, Martin-Chacon, E, Calvo-Villas, JM, Garcia-Belmonte, D, Hernandez-Maraver, D, Ossenkoppele, GJ, van der Lelie, J, Sonneveld, P, Zijlmans, M, Maertens, J, de Valk, B, Wijermans, PW, de Groot, MR, Schouten, HC, Biesma, DH, van Marwijk, M, de Lisa, E, Golos, A, Ejduk, A, Armatys, A, Zarzycka, E, Knopinska, W, Miskiewicz, W, Jastrzab, B, Pluta, A, Paluszewska, M, Podhorecka, M, Gromek, T, Jakubas, B, Majcherek, M, Skret, A, Watek, M, Charlinski, G, Calbecka, M, Becht, R, Gadomska, A, Rzenno, E, Piszcz, J, Grosicki, S, Palmer, L, Ciarlo, S, Bezares, F, Rojas, F, Longoni, H, Gelemur, M, Fazio, P, Canepa, C, Saba, S, Balladares, G, Negri, P, Giunta, M, Milone, J, Lafalse, D, Sossa, C, Jaramillo, F, Mayer, J, Protivankova, M, and Scwarz, J
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relapse ,Acute promyelocytic leukemia ,CD56 ,ATRA ,chemotherapy ,prognostic - Abstract
Out of 956, there were 95 (10%) CD56+ APL patients treated with PETHEMA ATRA and chemotherapy. CD56+ expression was associated with high WBC, BCR3 isoform, and co-expression of CD2, CD34, CD7, HLA-DR, CD15, and CD117 antigens. CD56+ vs CD56- APL presented higher induction death rate (16% vs 8%, p = .02) and 5-years cumulative incidence of relapse (33% versus 10%, p = .006), irrespectively of the Sanz score (low-risk 47% versus 5%, p < .001; intermediate 23% versus 7%, p < .001; and high-risk 42% versus 21%, p = .007). In the multivariate analysis, CD56 + (p < .0001), higher relapse-risk score (p = .001), and male gender (p = .05) retained the independent predictive value. CD56+ APL also showed a greater risk of CNS relapse (6% versus 1%, p < .001) and lower 5-year OS (75% versus 83%, p = .003). The AIDA-based LPA2012 trial, with an intensified consolidation schedule for CD56+ APL, will elucidate whether an intensified consolidation schedule could mitigate the relapse rate in this setting.
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- 2019
11. Autoimmune hemolytic anemia (AIHA) following allogeneic hematopoietic stem cell transplantation (HSCT): A retrospective analysis and a proposal of treatment on behalf of the Grupo Espanol De Trasplante de Medula Osea en Nimos (GETMON) and the Grupo Espanol de Trasplante Hematopoyetico (GETH)
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Gonzalez-Vicent, M, Sanz, J, Fuster, JL, Cid, J, de Heredia, CD, Morillo, D, Fernandez, JM, Pascual, A, Badell, I, Serrano, D, Fox, L, de la Serna, J, Benito, A, Couselo, JM, Molina, B, Diaz, MA, and Sanz, MA
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Pediatric ,Hematopoietic stem cell transplantation ,Rituximab ,Autoinmune hemolytic anemia - Abstract
Autoimmune hemolytic anemia (AIHA) is a complication of allogeneic hematopoietic stem cell transplantation (HSCT) associated with poor outcome. However, an optimal therapeutic approach is lacking. Between 2000 and 2015, 4099 allogeneic HSCT were performed in eight pediatric centers of the Grupo Espanol De Trasplante de Medula Osea en Ninos (GETMON) and six adult centers of the Grupo Espanol de Trasplante Hematopoyetico (GETH). Sixty cases of All-IA were registered with a cumulative incidence of 1.5% occurring at a median of 6 months after HSCT. Patients aged less than 15 years (P = .005), and patients using cord blood (P = .005) or an HLA mismatch donor (P =.005) were more likely to develop AIHA. Most patients were lymphopenic at the time of diagnosis of AIHA, including a low number of regulatory T lymphocytes (median 3/mu L). Median lines of treatment received for All-IA was 3 (range, 1-7). Almost all patients received corticosteroids (88%) and more than half received immunoglobulins or rituximab (63% and 67%, respectively). Complete resolution of AIHA was achieved in 33 of 60 cases (55%). Cumulative incidence of AIHA-related mortality was 17 +/- 6%. We found a correlation of AIHA outcome with age (better outcome in younger than 15 years, RR = 1.87, P = .01) and rituximab response (higher rate of complete remission in patients responding to rituximab, RR = 1.72, P = .025). We analyzed the factors involved in the response to rituximab and found a better response when there was ABO donor/receptor disparity (P = .014) and in those patients with B lymphocytes count above the median (38/mu L) (P = .05).Thirty-six of 60 patients survived yielding a disease free survival of 52 +/- 8% at 40 months. In Cox analysis, age (children vs adults, HR: 8.19, CI 95%: 2.39-28.12, P = .001) and AIHA outcome (complete remission vs partial remission/non-response, HR: 4.18, CI 95%: 1.55-11.22, P =.005) were associated with a better survival. Our data suggest that patients who developed AIHA after HSCT are severely lymphopenic and have a high risk of mortality. Outcome is better in children and in patients treated with rituximab. We also propose an algorithm for treatment of AIHA after HSCT. (C) 2018 Elsevier Inc. All rights reserved.
- Published
- 2018
12. Últimos avances en el tratamiento de la leucemia linfoblástica aguda. ¿Estamos progresando haciaun tratamiento personalizado?
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Rives-Sola S and Fuster JL
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- 2018
13. CD19 and CD22-directed biespecific CAR for B-cell Acute Lymphoblastic Leukemia
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Zanetti, SR, additional, Velazco-Hernandez, T, additional, Gutierrez-Agüera, F, additional, Roca-Ho, H, additional, Sánchez-Martínez, D, additional, Petazzi, P, additional, Torres, R, additional, Molina, O, additional, Torrebadell-Burriel, M, additional, Vidriales-Vicente, MB, additional, Hrusak, O, additional, Fuster, JL, additional, Juan, M, additional, Bueno, C, additional, and Menéndez, P, additional
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- 2019
- Full Text
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14. DIAGNOSTICS IN HEREDITARY HEMATOLOGICAL DISEASES USING GENE PANELS OF NEXT GENERATION SEQUENCING (NGS)
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Fernandez, MS, Torro, JF, Sevilla, BC, Jurado, CE, Pastor, DB, Dapena, JL, Alvarez, AB, Betes, VM, Fuster, JL, Cortes, MB, Arenillas, L, Montesdeoca, S, Martinez, L, Pedro, C, Montero, SP, Rodriguez, IH, and Antolin, CT
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- 2017
15. Adoptive Cellular Immunotherapy using CD1a CART-cells for Treatment of Cortical Pediatric T-Cell Acute Lymphoblastic Leukemia
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Sanchez-Martinez, D, additional, Baroni, ML, additional, Castella, M, additional, Anguita, E, additional, Toribio, ML, additional, Pflumio, F, additional, Fuster, JL, additional, Campos, M, additional, Bueno, C, additional, and Menendez, P, additional
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- 2018
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16. Liposomal cytarabine for the treatment of leptomeningeal dissemination of central nervous system tumours in children and adolescents
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Moreno L, García Ariza MA, Cruz-Martínez O, Calvo C, Fuster JL, Salinas JA, Moscardo C, Portugal R, Merino JM, and Madero L
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Central nervous system tumours, Citarabina liposomal, Diseminación leptomeníngea, Ependimoma, Ependymoma, Intratecal, Intrathecal, Leptomeningeal dissemination, Liposomal cytarabine, Medulloblastoma, Meduloblastoma, Tumores del sistema nervioso central - Abstract
Leptomeningeal dissemination in paediatric central nervous system (CNS) tumours is associated with a poor outcome, and new therapeutic strategies are desperately needed. One of the main difficulties in the treatment of CNS tumours is blood brain barrier penetration. Intrathecal therapy has shown to be effective in several paediatric tumours. The aim of this article is to review the data available on the use of liposomal cytarabine for paediatric patients with leptomeningeal dissemination of CNS tumours, including the pharmacology, administration route, safety and efficacy data.
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- 2016
17. Toxicity to topical dimethyl sulfoxide in a pediatric patient with anthracycline extravasation
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Gonzalez Cm, Llinares Me, Diaz Ms, Bermúdez M, and Fuster Jl
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medicine.medical_specialty ,Anthracycline ,medicine.medical_treatment ,Leukemia, Myelomonocytic, Acute ,chemistry.chemical_compound ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Severe pain ,Humans ,Dimethyl Sulfoxide ,Antidote ,Chemotherapy ,Antibiotics, Antineoplastic ,business.industry ,Dimethyl sulfoxide ,Hematology ,Extravasation ,Surgery ,Pediatric patient ,Oncology ,chemistry ,Anesthesia ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Toxicity ,Female ,business ,Extravasation of Diagnostic and Therapeutic Materials - Abstract
Accidental extravasation of vesicant chemotherapy may cause important tissue injuries. Nowadays, the majority of authors propose topical dimethyl sulfoxide (DMSO), with or without local cooling, as the treatment of choise efor anthracyclines extravasation. No significant toxicity has been reported when DMSO is used as topical treatment. This report describes a case of local toxicity consisting of severe pain after its use in a pediatric patient. An illustration shows the extravasation area.
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- 2005
18. Haploidentical versus Cord Blood Transplantation in Pediatric AML. A Retrospective Outcome Analysis on Behalf of the Pediatric Subcommittee of GETH (Grupo Español de Trasplante Hematopoyético).
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Sisinni L, Monserrate GXA, Hurtado JMP, Panesso M, Molina B, Fuentes C, Fuster JL, Verdu-Amoros J, Regueiro A, Palomo P, Beléndez C, Pascual A, Badell I, Mozo Y, Bueno D, Pérez-Martínez A, Fernández JM, Vicent MG, and de Heredia CD
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- Humans, Child, Retrospective Studies, Male, Female, Child, Preschool, Adolescent, Infant, Hematopoietic Stem Cell Transplantation methods, Young Adult, Treatment Outcome, Neoplasm, Residual, Cord Blood Stem Cell Transplantation, Leukemia, Myeloid, Acute therapy, Transplantation, Haploidentical, Graft vs Host Disease
- Abstract
Haploidentical stem cell transplantation (Haplo-SCT) and cord blood transplantation (CBT) are both effective alternative treatments in patients suffering from acute myeloid leukemia (AML) and lacking a matched HLA donor. In the last years, many centers have abandoned CBT procedures mostly due to concern about poorer immune recovery compared with Haplo-SCT. We conducted a retrospective multicenter study comparing the outcomes using both alternative approaches in AML. A total of 122 transplants (86 Haplo-SCTs and 36 CBTs) from 12 Spanish centers were collected from 2007 to 2021. Median age at hematopoietic stem cell transplantation (HSCT) was 7 years (0.4-20). Thirty-nine patients (31.9%) showed positive minimal residual disease (MRD) at HSCT and a previous HSCT was performed in 37 patients (30.3%). The median infused cellularity was 14.4 × 10
6 /kg CD34+ cells (6.0-22.07) for Haplo-SCT and 4.74 × 105 /kg CD34+ cells (0.8-9.4) for CBT. Median time to neutrophil engraftment was 14 days (7-44) for Haplo-SCT and 17 days (8-29) for CBT (P = .03). The median time to platelet engraftment was 14 days (6-70) for Haplo-SCT and 43 days (10-151) for CBT (P < .001). Graft rejection was observed in 13 Haplo-SCTs (15%) and in 6 CBTs (16%). The cumulative incidence of acute graft versus host disease (GvHD) grades II-IV was 54% and 51% for Haplo-SCT and CBT, respectively (P = .50). The cumulative incidence of severe acute GvHD (grades III-IV) was 22% for Haplo-SCT and 25% for CBT (P = .90). There was a tendency to a higher risk of chronic GvHD in the Haplo-SCT group being the cumulative incidence of 30% for Haplo-SCT and 12% for CBT (P = .09). The cumulative incidence of relapse was 28% and 20% for Haplo-SCT and CBT, respectively (P = .60). We did not observe statistically significant differences in outcome measures between Haplo-SCT and CBT procedures: 5-year overall survival (OS) was 64% versus 57% (P = .50), 5-year disease-free survival (DFS) 58% versus 57% (P = .80), GvHD-free and relapse-free survival (GFRFS) 41% versus 54% (P = .30), and cumulative incidence of transplant-related mortality (TRM) 14% versus 15% (P = .80), respectively. In the multivariate analysis, MRD positivity and a disease status >CR1 at the time of HSCT were significantly associated with poorer outcomes (P < .05). In conclusion, our study supports that both haploidentical and cord blood transplantation show comparable outcomes in pediatric AML patients. We obtained comparable survival rates, although CBT showed a trend to lower rates of chronic GvHD and higher GFRFS, demonstrating that it should still be considered a valuable option, particularly for pediatric patients., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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19. ECLIM-SEHOP: how to develop a platform to conduct academic trials for childhood cancer.
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Juan-Ribelles A, Bautista F, Cañete A, Rubio-San-Simón A, Alonso-Saladrigues A, Hladun R, Rives S, Dapena JL, Fernández JM, Lassaletta Á, Cruz O, Ramírez-Villar G, Fuster JL, de Heredia CD, García-Ariza M, Quiroga E, Del Mar Andrés M, Verdú-Amorós J, Molinés A, Herrero B, López M, Márquez C, Toboso M, Lendínez F, Sirvent JG, Tallón M, Rodríguez G, Acha T, Moreno L, and Fernández-Teijeiro A
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- Humans, Child, Spain, Medical Oncology, Observational Studies as Topic, International Cooperation, Patient Selection, Clinical Trials as Topic, Neoplasms therapy, Registries
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Introduction: ECLIM-SEHOP platform was created in 2017. Its main objective is to establish the infrastructure to allow Spanish participation into international academic collaborative clinical trials, observational studies, and registries in pediatric oncology. The aim of this manuscript is to describe the activity conducted by ECLIM-SEHOP since its creation., Methods: The platform's database was queried to provide an overview of the studies integrally and partially supported by the organization. Data on trial recruitment and set-up/conduct metrics since its creation until November 2023 were extracted., Results: ECLIM-SEHOP has supported 47 studies: 29 clinical trials and 18 observational studies/registries that have recruited a total of 5250 patients. Integral support has been given to 25 studies: 16 trials recruiting 584 patients and nine observational studies/registries recruiting 278 patients. The trials include front-line studies for leukemia, lymphoma, brain and solid extracranial tumors, and other key transversal topics such as off-label use of targeted therapies and survivorship. The mean time from regulatory authority submission to first patient recruited was 12.2 months and from first international site open to first Spanish site open was 31.3 months., Discussion: ECLIM-SEHOP platform has remarkably improved the availability and accessibility of international academic clinical trials and has facilitated the centralization of resources in childhood cancer treatment. Despite the progressive improvement on clinical trial set-up metrics, timings should still be improved. The program has contributed to leveling survival rates in Spain with those of other European countries that presented major differences in the past., (© 2024. The Author(s).)
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- 2024
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20. Integrative single-cell expression and functional studies unravels a sensitization to cytarabine-based chemotherapy through HIF pathway inhibition in AML leukemia stem cells.
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Velasco-Hernandez T, Trincado JL, Vinyoles M, Closa A, Martínez-Moreno A, Gutiérrez-Agüera F, Molina O, Rodríguez-Cortez VC, Ximeno-Parpal P, Fernández-Fuentes N, Petazzi P, Beneyto-Calabuig S, Velten L, Romecin P, Casquero R, Abollo-Jiménez F, de la Guardia RD, Lorden P, Bataller A, Lapillonne H, Stam RW, Vives S, Torrebadell M, Fuster JL, Bueno C, Sarry JE, Eyras E, Heyn H, and Menéndez P
- Abstract
Relapse remains a major challenge in the clinical management of acute myeloid leukemia (AML) and is driven by rare therapy-resistant leukemia stem cells (LSCs) that reside in specific bone marrow niches. Hypoxia signaling maintains cells in a quiescent and metabolically relaxed state, desensitizing them to chemotherapy. This suggests the hypothesis that hypoxia contributes to the chemoresistance of AML-LSCs and may represent a therapeutic target to sensitize AML-LSCs to chemotherapy. Here, we identify HIF
high and HIFlow specific AML subgroups (inv(16)/ t (8;21) and MLLr, respectively) and provide a comprehensive single-cell expression atlas of 119,000 AML cells and AML-LSCs in paired diagnostic-relapse samples from these molecular subgroups. The HIF/hypoxia pathway signature is attenuated in AML-LSCs compared with more differentiated AML cells but is more expressed than in healthy hematopoietic cells. Importantly, chemical inhibition of HIF cooperates with standard-of-care chemotherapy to impair AML growth and to substantially eliminate AML-LSCs in vitro and in vivo. These findings support the HIF pathway in the stem cell-driven drug resistance of AML and unravel avenues for combinatorial targeted and chemotherapy-based approaches to specifically eliminate AML-LSCs., Competing Interests: Pablo Menéndez is the founder of the spin‐off OneChain Immunotherapeutics, which has no connection with the present research. The other authors declare no conflict of interest., (© 2024 The Authors. HemaSphere published by John Wiley & Sons Ltd. on behalf of European Hematology Association.)- Published
- 2024
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21. Measurable residual disease study through three different methods can anticipate relapse and guide early interventions in childhood acute lymphoblastic leukemia.
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Ramos Elbal E, Fuster JL, Campillo JA, Galera AM, Cortés MB, Llinares ME, Jiménez I, Plaza M, Martínez Banaclocha H, Galián JA, Blanquer Blanquer M, Martínez Sánchez MV, Muro M, and Minguela A
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- Child, Humans, Neoplasm, Residual genetics, Recurrence, Flow Cytometry methods, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy
- Abstract
Introduction: Acute lymphoblastic leukemia (ALL) is the most common cancer among children. Measurable residual disease (MRD, previously named minimal residual disease) study can guide therapy adjustments or preemptive interventions that might avoid hematological relapse., Methods: Clinical decision making and patient outcome were evaluated in 80 real-life childhood ALL patients, according to the results observed in 544 bone marrow samples analyzed with three MRD methods: multiparametric flow cytometry (MFC), fluorescent in-situ hybridization (FISH) on B or T-purified lymphocytes and patient-specific nested reverse transcription polymerase chain reaction (RT-PCR)., Results: Estimated 5 year overall survival and event-free survival were 94% and 84.1%, respectively. A total of 12 relapses in 7 patients were associated with positive MRD detection with at least one of the three methods: MFC (p < 0.00001), FISH (p < 0.00001) and RT-PCR (p = 0.013). MRD assessment allowed the anticipation of relapse and adapted early interventions with different approaches including chemotherapy intensification, blinatumomab, HSCT and targeted therapy to halt relapse in five patients, although two of them relapsed afterwards., Conclusion: MFC, FISH and RT-PCR are complementary methods for MRD monitoring in pediatric ALL. Although, our data clearly show that MDR positive detection is associated with relapse, continuation of standard treatment, intensification or other early interventions were able to halt relapse in patients with different risks and genetic background. More sensitive and specific methods are warranted to enhance this approach. However, whether early treatment of MRD can improve overall survival in patients with childhood ALL needs to be evaluated in adequately controlled clinical trials., (© 2023. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)
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- 2024
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22. Chromosomal instability in aneuploid acute lymphoblastic leukemia associates with disease progression.
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Molina O, Ortega-Sabater C, Thampi N, Fernández-Fuentes N, Guerrero-Murillo M, Martínez-Moreno A, Vinyoles M, Velasco-Hernández T, Bueno C, Trincado JL, Granada I, Campos D, Giménez C, Boer JM, den Boer ML, Calvo GF, Camós M, Fuster JL, Velasco P, Ballerini P, Locatelli F, Mullighan CG, Spierings DCJ, Foijer F, Pérez-García VM, and Menéndez P
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- Child, Humans, Animals, Mice, Chromosomal Instability, Disease Progression, Aneuploidy, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
Chromosomal instability (CIN) lies at the core of cancer development leading to aneuploidy, chromosomal copy-number heterogeneity (chr-CNH) and ultimately, unfavorable clinical outcomes. Despite its ubiquity in cancer, the presence of CIN in childhood B-cell acute lymphoblastic leukemia (cB-ALL), the most frequent pediatric cancer showing high frequencies of aneuploidy, remains unknown. Here, we elucidate the presence of CIN in aneuploid cB-ALL subtypes using single-cell whole-genome sequencing of primary cB-ALL samples and by generating and functionally characterizing patient-derived xenograft models (cB-ALL-PDX). We report higher rates of CIN across aneuploid than in euploid cB-ALL that strongly correlate with intraclonal chr-CNH and overall survival in mice. This association was further supported by in silico mathematical modeling. Moreover, mass-spectrometry analyses of cB-ALL-PDX revealed a "CIN signature" enriched in mitotic-spindle regulatory pathways, which was confirmed by RNA-sequencing of a large cohort of cB-ALL samples. The link between the presence of CIN in aneuploid cB-ALL and disease progression opens new possibilities for patient stratification and offers a promising new avenue as a therapeutic target in cB-ALL treatment., (© 2023. The Author(s).)
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- 2024
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23. Treosulfan-Based Conditioning Regimen In Pediatric Hematopoietic Stem Cell Transplantation: A Retrospective Analysis on Behalf of the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC).
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Galán V, Beléndez C, Echecopar C, Estival P, Sissini L, Olivas R, Bueno D, Molina B, Fuentes C, Regueiro A, Benítez I, Plaza M, Margarit A, Rifón J, Pascual A, Palomo P, Urtasun A, Fuster JL, Díaz de Heredia C, Fernández Navarro JM, González-Vicent M, Ruz B, and Pérez-Martínez A
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- Adolescent, Child, Humans, Child, Preschool, Retrospective Studies, Transplantation Conditioning methods, Hematopoietic Stem Cell Transplantation adverse effects, Graft vs Host Disease epidemiology, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control, Neoplasms
- Abstract
Increasing data on treosulfan-based conditioning regimens before hematopoietic stem cell transplantation (HSCT) demonstrate the consistent benefits of this approach, particularly regarding acute toxicity. This study aimed to describe the results of treosulfan-based conditioning regimens in children, focusing on toxicity and outcomes when used to treat both malignant and nonmalignant diseases. This retrospective observational study of pediatric patients treated in Spain with treosulfan-based conditioning regimens before HSCT was based on data collection from electronic clinical records. We studied a total of 160 treosulfan-based conditioning HSCTs to treat nonmalignant diseases (n = 117) or malignant diseases (n = 43) in 158 children and adolescents. The median patient age at HSCT was 5.1 years (interquartile range, 2 to 10 years). The most frequent diagnoses were primary immunodeficiency (n = 42; 36%) and sickle cell disease (n = 42; 36%) in the nonmalignant disease cohort and acute lymphoblastic leukemia (n = 15; 35%) in the malignant disease cohort. Engraftment occurred in 97% of the patients. The median times to neutrophil engraftment (17 days versus 14 days; P = .008) and platelet engraftment (20 days versus 15 days; P = .002) were linger in the nonmalignant cohort. The 1-year cumulative incidence of veno-occlusive disease was 7.98% (95% confidence interval [CI], 4.6% to 13.6%), with no significant differences between cohorts. The 1-year cumulative incidence of grade III-IV acute graft-versus-host disease (GVHD) was higher in the malignant disease cohort (18% versus 3.2%; P = .011). Overall, the malignant cohort had both a higher total incidence (9% versus 3%; P < .001) and a higher 2-year cumulative incidence (16% versus 1.9%; P < .001) of total chronic GVHD. The 2-year cumulative transplantation-related mortality was 15%, with no difference between the 2 cohorts. The 5-year overall survival was 80% (95% CI, 72% to 86%) and was higher in the nonmalignant cohort (87% versus 61%; P = .01). The 2-year cumulative incidence of relapse was 25% in the malignant cohort. The 5-year cumulative GVHD-free, relapse-free survival rate was 60% (95% CI, 51% to 70%) and was higher in the nonmalignant cohort (72% versus 22%; P < .001). A treosulfan-based radiation-free conditioning regimen is feasible, achieving a high engraftment rate and 5-year overall survival, and is an emerging option for the first HSCT in nonmalignant diseases., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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24. Haploidentical Hematopoietic Stem Cell Transplantation in Pediatric Patients with Acquired Hypocellular Bone Marrow Failure.
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Quintero V, Bueno-Sánchez D, Mozo-Del-Castillo Y, Urtasun-Erburu A, Sisinni L, López-Duarte M, Pérez-Hurtado JM, Fuster JL, González-Vicent M, Pérez-Martínez A, and Diaz-de-Heredia C
- Abstract
Children with acquired hypocellular bone marrow failure of unknown cause (AHBMF) are usually diagnosed either with severe aplastic anemia (SAA) or refractory cytopenia of childhood (RCC). Patients with AHBMF who lack a matched donor and who failed or relapsed after immunosuppressive therapy (IST) need alternative therapies. Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) offers a curative treatment for these patients. We report a multicenter Spanish experience with haplo-HSCT in pediatric patients with AHBMF. Eleven pediatric patients (SAA, n = 9; RCC, n = 2) underwent haplo-HSCT with different lymphodepletion strategies. Most patients (10 of 11) had previously failed to respond or relapsed after IST. The conditioning regimen was reduced intensity in SAA and myeloablative in RCC. Patients with SAA received low-dose radiotherapy as part of their conditioning regimen. All patients engrafted. Viral reactivation was common (8 of 11). Acute GVHD grade ≥II was seen in 5 patients. Chronic GVHD was diagnosed in 4 of the long-term survivors. Transplantation-associated microangiopathy was a frequent complication in SAA patients and was related to worse outcome. Two patients died of transplantation-related complications. Overall survival was 81%, with a median follow-up of 36 months. Haplo-HSCT can be a successful salvage curative treatment for pediatric patients with AHBMF, but with significant toxicities that must be addressed. Transplantation-associated microangiopathy was the most critical complication., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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25. The relapsed acute lymphoblastic leukemia network (ReALLNet): a multidisciplinary project from the spanish society of pediatric hematology and oncology (SEHOP).
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Velasco P, Bautista F, Rubio A, Aguilar Y, Rives S, Dapena JL, Pérez A, Ramirez M, Saiz-Ladera C, Izquierdo E, Escudero A, Camós M, Vega-García N, Ortega M, Hidalgo-Gómez G, Palacio C, Menéndez P, Bueno C, Montero J, Romecín PA, Zazo S, Alvarez F, Parras J, Ortega-Sabater C, Chulián S, Rosa M, Cirillo D, García E, García J, Manzano-Muñoz A, Minguela A, and Fuster JL
- Abstract
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, with survival rates exceeding 85%. However, 15% of patients will relapse; consequently, their survival rates decrease to below 50%. Therefore, several research and innovation studies are focusing on pediatric relapsed or refractory ALL (R/R ALL). Driven by this context and following the European strategic plan to implement precision medicine equitably, the Relapsed ALL Network (ReALLNet) was launched under the umbrella of SEHOP in 2021, aiming to connect bedside patient care with expert groups in R/R ALL in an interdisciplinary and multicentric network. To achieve this objective, a board consisting of experts in diagnosis, management, preclinical research, and clinical trials has been established. The requirements of treatment centers have been evaluated, and the available oncogenomic and functional study resources have been assessed and organized. A shipping platform has been developed to process samples requiring study derivation, and an integrated diagnostic committee has been established to report results. These biological data, as well as patient outcomes, are collected in a national registry. Additionally, samples from all patients are stored in a biobank. This comprehensive repository of data and samples is expected to foster an environment where preclinical researchers and data scientists can seek to meet the complex needs of this challenging population. This proof of concept aims to demonstrate that a network-based organization, such as that embodied by ReALLNet, provides the ideal niche for the equitable and efficient implementation of "what's next" in the management of children with R/R ALL., Competing Interests: The project has received funding from the pharmaceutical companies Amgen, Servier, and Pfizer. The authors’; relationships with these companies are as follows: PV received honoraria for speaking at a symposia from Servier. JF is a consultant/advisory member and receives honoraria for speaking at symposia from Amgen, Servier and Pfizer, and support for attending symposia from Servier. FB had a consulting or advisory role for Amgen and received honoraria for speaking at a symposium from Servier. SR: receives honoraria from Pfizer, Amgen and Servier as a advisory member and support for attending medical congresses. AR: receives support for attending symposia from Amgen. JM is co-inventor of dynamic BH3 profiling (patented by Dana-Farber Cancer Institute, US10393733B2). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Velasco, Bautista, Rubio, Aguilar, Rives, Dapena, Pérez, Ramirez, Saiz-Ladera, Izquierdo, Escudero, Camós, Vega-Garcia, Ortega, Hidalgo-Gómez, Palacio, Menéndez, Bueno, Montero, Romecín, Zazo, Alvarez, Parras, Ortega-Sabater, Chulián, Rosa, Cirillo, García, García, Manzano-Muñoz, Minguela and Fuster.)
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- 2023
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26. TIM3, a human acute myeloid leukemia stem cell marker, does not enrich for leukemia-initiating stem cells in B-cell acute lymphoblastic leukemia.
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Bueno C, Martínez A, Romecin PA, Zanetti SR, Tirtakusuma R, Genesca E, Camós M, Ramírez-Orellana M, Anguita E, Ballerini P, Locatelli F, Fuster JL, and Menéndez P
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- Humans, Hepatitis A Virus Cellular Receptor 2, Stem Cells, Leukemia, Myeloid, Acute, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma diagnosis
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- 2023
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27. Measurable residual disease study through three different methods can anticipate relapse and guide pre-emptive therapy in childhood acute myeloid leukemia.
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Ramos Elbal E, Fuster JL, Campillo JA, Galera AM, Cortés MB, Llinares ME, Jiménez I, Plaza M, Banaclocha HM, Galián JA, Blanquer Blanquer M, Martínez Sánchez MV, Muro M, and Minguela A
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- Humans, Flow Cytometry methods, In Situ Hybridization, Fluorescence, Neoplasm, Residual genetics, Polymerase Chain Reaction, Progression-Free Survival, Recurrence, Retrospective Studies, Leukemia, Myeloid, Acute pathology
- Abstract
Purpose: Although outcomes of children with acute myeloid leukemia (AML) have improved over the last decades, around one-third of patients relapse. Measurable (or minimal) residual disease (MRD) monitoring may guide therapy adjustments or pre-emptive treatments before overt hematological relapse., Methods: In this study, we review 297 bone marrow samples from 20 real-life pediatric AML patients using three MRD monitoring methods: multiparametric flow cytometry (MFC), fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR)., Results: Patients showed a 3-year overall survival of 73% and a 3-year event-free survival of 68%. Global relapse rate was of 25%. All relapses were preceded by the reappearance of MRD detection by: (1) MFC (p = 0.001), (2) PCR and/or FISH in patients with an identifiable chromosomal translocation (p = 0.03) and/or (3) one log increase of Wilms tumor gene 1 (WT1) expression in two consecutive samples (p = 0.02). The median times from MRD detection to relapse were 26, 111, and 140 days for MFC, specific PCR and FISH, and a one log increment of WT1, respectively., Conclusions: MFC, FISH and PCR are complementary methods that can anticipate relapse of childhood AML by weeks to several months. However, in our series, pre-emptive therapies were not able to prevent disease progression. Therefore, more sensitive MRD monitoring methods that further anticipate relapse and more effective pre-emptive therapies are needed., (© 2023. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)
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- 2023
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28. Haploidentical vs. HLA-matched donor hematopoietic stem-cell transplantation for pediatric patients with acute lymphoblastic leukemia in second remission: A collaborative retrospective study of the Spanish Group for Bone Marrow Transplantation in Children (GETMON/GETH) and the Spanish Childhood Relapsed ALL Board (ReALLNet).
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Moreno C, Ramos-Elbal E, Velasco P, Aguilar Y, Gonzáález Martínez B, Fuentes C, Molinos Á, Guerra-García P, Palomo P, Verdu J, Adán Pedroso RM, Vagace JM, López-Duarte M, Regueiro A, Tasso M, Dapena JL, Salinas JA, Navarro S, Bautista F, Lassaletta Á, Lendínez F, Rives S, Pascual A, Rodríguez A, Pérez-Hurtado JM, Fernández JM, Pérez-Martínez A, González-Vicent M, Díaz de Heredia C, and Fuster JL
- Abstract
Introduction: Studies addressing the role of haploidentical as alternative to HLA-matched donors for stem cell transplantation (SCT) often include patients with diverse hematological malignancies in different remission statuses., Methods: We compared outcomes of children with acute lymphoblastic leukemia (ALL) undergoing SCT in second complete remission (CR2) from haploidentical (n = 25) versus HLA-matched donor (n = 51)., Results: Patients were equally distributed across both groups according to age, immunophenotype, time to and site of relapse, relapse risk-group allocation, and minimal residual disease (MRD) before SCT. Incidence of graft failure, acute graft versus host disease (GVHD), and other early complications did not differ between both groups. We found no differences in overall survival (58.7% versus 59.5%; p = .8), leukemia free survival (LFS) (48% versus 36.4%; p = .5), event free survival (40% versus 34.4%; p = .69), cumulative incidence (CI) of subsequent relapse (28% versus 40.9%; p = .69), treatment related mortality (24% versus 23.6%; p = .83), CI of cGVHD (4.5% versus 18.7%; p = .2), and chronic GVHD-free and leukemia-free survival (44% versus 26.3%; p = .3) after haploidentical donor SCT. Chronic GVHD (HR = 0.09; p =.02) had protective impact, and MRD ≥ 0.01% before SCT (HR = 2.59; p =.01) had unfavorable impact on LFS., Discussion: These results support the role of haploidentical donor SCT in children with ALL in CR2., Competing Interests: PV took up an advisory role for Servier and Janssen and received honoraria for speaking at symposia from Novartis, Vi&; and Servier. BG played the role of a consultant or advisor for Servier and Jazz Pharmaceuticals and received honoraria from Servier for speaking at symposia. PG-G was a consultant or advisor for Bayer and Servier. FB is a member of a data monitoring committee for a clinical trial sponsored by Sanofi, was a consultant or advisor for Bayer, Amgen, Roche Genentech, and EusaPharma, and received honoraria from Roche Genentech for speaking at symposia. RA received honoraria from Servier and Jazz Pharmaceutical for speaking. JMV received honoraria from Servier for the same purpose. AR was a consultant or advisor for Servier and Jazz Pharmaceuticals. ÁL was a consultant or advisor for Servier and Jazz Pharmaceuticals. SR was a member of a data monitoring committee and of a steering committee for two clinical trials sponsored by Novartis, was a consultant or advisor for Novartis, Kite/Gilead, Celgene/Bristol-Myers, Servier, Amgen, and Jazz-Pharmaceuticals, and received honoraria from Novartis, Servier, Amgen, and Jazz-Pharmaceuticals for speaking at symposia and for attending symposia. JV received honoraria from Servier for speaking at symposia. JMF was a consultant/advisor for Servier, Jazz Pharmaceuticals, Gilead, and Pfizer and received honoraria from Servier, Pfizer, Gilead, and Jazz Pharmaceuticals for speaking at and/or attending symposia. JLF was a consultant/advisory member for Amgen, Jazz Pharmaceuticals, and Novartis, received honoraria from Amgen, Servier, Jazz Pharmaceuticals, Pfizer, and Novartis for speaking at symposia and support from Servier and Jazz Pharmaceuticals for attending symposia. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Moreno, Ramos-Elbal, Velasco, Aguilar, González, Fuentes, Molinos, Guerra-García, Palomo, Verdu, Adán, Vagace, Duarte, Regueiro, Tasso, Dapena, Salinas, Navarro, Bautista, Lassaletta, Lendínez, Rives, Pascual, Rodríguez, Pérez-Hurtado, Fernández, Pérez-Martínez, González-Vicent, de Heredia and Fuster.)
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- 2023
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29. Haploidentical hematopoietic stem cell transplantation in pediatric and adolescent patients: A study of the Spanish hematopoietic stem cell transplantation group (GETH).
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Ochoa-Fernández B, Galán-Gómez V, Mestre C, González-Vicent M, Pascual A, Alonso L, Regueiro A, Plaza M, Pérez Hurtado JM, Benito A, Fuster JL, Bueno D, Mozo Y, Vicario JL, Balas A, Sisinni L, Díaz de Heredia C, and Pérez-Martínez A
- Subjects
- Humans, Child, Adolescent, Retrospective Studies, Cyclophosphamide therapeutic use, T-Lymphocytes, Tissue Donors, Transplantation Conditioning methods, Hematopoietic Stem Cell Transplantation, Graft vs Host Disease drug therapy
- Abstract
Introduction: The main advantages of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) are the immediate availability of donors, the possibility of developing cell therapy approaches with different novel transplant platforms, and the procedure's cost savings., Methodology: We retrospectively analyzed the pediatric haplo-HSCT activity of the Spanish hematopoietic stem-cell transplantation group (GETH) between 1999 and 2016, aiming to study clinical characteristics and outcomes by describing patient groups with non-malignant disease (NMD) or malignant disease (MD) and the impact of 2 different periods (1999-2009 and 2010-2016) on long-term outcomes., Results: Twelve centers performed 232 haplo-HSCTs in 227 children, representing 10% of all pediatric allogeneic HSCT activity in Spain from 1999 to 2016, with a notable increase since 2013. Most haplo-HSCTs (86.7%) were performed in patients with MD; 95% received peripheral blood stem cells from donors, and 78.9% received ex vivo T-cell depleted grafts. Non-manipulated grafts using post-transplantation cyclophosphamide have been incorporated since 2012. We observed a higher percentage of graft failure in NMD versus MD (32% vs. 15.6%; p=0.029). Relapse and transplant-related mortality were the procedure's main limitations in MD and NMD, respectively. Five-year overall survival was 48.5% (SE 3.9), with no statistically significant difference when comparing the MD and NMD cohorts. Patients who received previously a HSCT the overall survival was significantly decreased. We observed no survival improvement over time., Conclusions: Although haplo-HSCT is an increasingly employed treatment option, our patients' results need improvement. We need to develop reference centers, especially for NMD whose rarity makes it difficult to gain experience., (Copyright © 2022 Elsevier España, S.L.U. All rights reserved.)
- Published
- 2022
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30. Src-related thrombocytopenia: a fine line between a megakaryocyte dysfunction and an immune-mediated disease.
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Palma-Barqueros V, Revilla N, Zaninetti C, Galera AM, Sánchez-Fuentes A, Zámora-Cánovas A, Bohdan N, Padilla J, Marín-Quilez A, Rodriguez-Alen A, Fuster JL, Greinacher A, Vicente V, Bastida JM, Rivera J, and Lozano ML
- Subjects
- Adult, Blood Platelets, Humans, Megakaryocytes, Thrombopoiesis, Purpura, Thrombocytopenic, Idiopathic diagnosis, Purpura, Thrombocytopenic, Idiopathic genetics, Thrombocytopenia genetics
- Abstract
Src-related thrombocytopenia (SRC-RT) is a rare autosomal dominant, inherited platelet disorder resulting from the p.E527K heterozygous germline gain-of-function variant of Src. To date, genetic diagnosis of the disease has only been reported in 7 patients from 3 unrelated families. The clinical features ranged from isolated thrombocytopenia to complex syndromic manifestations characterized by thrombocytopenia, bleeding, myelofibrosis, splenomegaly, and bone disease. We report a new 3-generation kindred with the Src p.E527K variant. Patients presented with rather variable platelet counts (38-139 × 109/L), mildly impaired platelet function, >15% immature platelet fraction, and with a significant proportion of large-giant platelets. Four adults from the family were diagnosed with immune thrombocytopenia (ITP) and underwent splenectomy, achieving sustained platelet counts >75 × 109/L for several years; increases in platelet counts were also observed after corticosteroid therapy. Four of 7 Src p.E527K variant carriers showed immune defects and recurrent infections. In addition, a range of neurological symptoms, from specific language impairment to epilepsy, was seen in some family members. Patient platelets exhibited constitutive Src, Bruton tyrosine kinase, and phospholipase Cγ2 activation, and after stimulating CD19 cells by crosslinking surface immunoglobulin M, phosphorylated extracellular signal-regulated kinase (ERK) was significantly increased in B cells from individuals carrying the Src p.E527K substitution. In summary, in addition to causing impaired platelet production, SRC-RT may associate immune dysregulation and increased platelet consumption. In families in whom several members are responsive to ITP-directed therapies, an underlying Src p.E527K variant should be excluded., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2022
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31. Clonal heterogeneity and rates of specific chromosome gains are risk predictors in childhood high-hyperdiploid B-cell acute lymphoblastic leukemia.
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Ramos-Muntada M, Trincado JL, Blanco J, Bueno C, Rodríguez-Cortez VC, Bataller A, López-Millán B, Schwab C, Ortega M, Velasco P, Blanco ML, Nomdedeu J, Ramírez-Orellana M, Minguela A, Fuster JL, Cuatrecasas E, Camós M, Ballerini P, Escherich G, Boer J, DenBoer M, Hernández-Rivas JM, Calasanz MJ, Cazzaniga G, Harrison CJ, Menéndez P, and Molina O
- Subjects
- Child, Chromosomal Instability, Chromosomes, Humans, Risk Factors, Chromosome Aberrations, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
B-cell acute lymphoblastic leukemia (B-ALL) is the commonest childhood cancer. High hyperdiploidy (HHD) identifies the most frequent cytogenetic subgroup in childhood B-ALL. Although hyperdiploidy represents an important prognostic factor in childhood B-ALL, the specific chromosome gains with prognostic value in HHD-B-ALL remain controversial, and the current knowledge about the hierarchy of chromosome gains, clonal heterogeneity and chromosomal instability in HHD-B-ALL remains very limited. We applied automated sequential-iFISH coupled with single-cell computational modeling to identify the specific chromosomal gains of the eight typically gained chromosomes in a large cohort of 72 primary diagnostic (DX, n = 62) and matched relapse (REL, n = 10) samples from HHD-B-ALL patients with either favorable or unfavorable clinical outcome in order to characterize the clonal heterogeneity, specific chromosome gains and clonal evolution. Our data show a high degree of clonal heterogeneity and a hierarchical order of chromosome gains in DX samples of HHD-B-ALL. The rates of specific chromosome gains and clonal heterogeneity found in DX samples differ between HHD-B-ALL patients with favorable or unfavorable clinical outcome. In fact, our comprehensive analyses at DX using a computationally defined risk predictor revealed low levels of trisomies +18+10 and low levels of clonal heterogeneity as robust relapse risk factors in minimal residual disease (MRD)-negative childhood HHD-B-ALL patients: relapse-free survival beyond 5 years: 22.1% versus 87.9%, P < 0.0001 and 33.3% versus 80%, P < 0.0001, respectively. Moreover, longitudinal analysis of matched DX-REL HHD-B-ALL samples revealed distinct patterns of clonal evolution at relapse. Our study offers a reliable prognostic sub-stratification of pediatric MRD-negative HHD-B-ALL patients., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
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- 2022
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32. New Cases of Hypochromic Microcytic Anemia Due to Mutations in the SLC11A2 Gene and Functional Characterization of the G75R Mutation.
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Romero-Cortadellas L, Hernández G, Ferrer-Cortès X, Zalba-Jadraque L, Fuster JL, Bermúdez-Cortés M, Galera-Miñarro AM, Pérez-Montero S, Tornador C, and Sánchez M
- Subjects
- Animals, Humans, Iron metabolism, Mammals metabolism, Mutation, Anemia genetics, Anemia, Hypochromic genetics, Iron Overload metabolism
- Abstract
Divalent metal-iron transporter 1 (DMT1) is a mammalian iron transporter encoded by the SLC11A2 gene. DMT1 has a vital role in iron homeostasis by mediating iron uptake in the intestine and kidneys and by recovering iron from recycling endosomes after transferrin endocytosis. Mutations in SLC11A2 cause an ultra-rare hypochromic microcytic anemia with iron overload (AHMIO1), which has been described in eight patients so far. Here, we report two novel cases of this disease. The first proband is homozygous for a new SLC11A2 splicing variant (c.762 + 35A > G), becoming the first ever patient reported with a SLC11A2 splicing mutation in homozygosity. Splicing studies performed in this work confirm its pathogenicity. The second proband harbors the previously reported DMT1 G75R mutation in homozygosis. Functional studies with the G75R mutation in HuTu 80 cells demonstrate that this mutation results in improper DMT1 accumulation in lysosomes, which correlates with a significant decrease in DMT1 levels in patient-derived lymphoblast cell lines (LCLs). We also suggest that recombinant erythropoietin would be an adequate therapeutic approach for AHMIO1 patients as it improves their anemic state and may possibly contribute to mobilizing excessive hepatic iron.
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- 2022
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33. A novel and efficient tandem CD19- and CD22-directed CAR for B cell ALL.
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Zanetti SR, Velasco-Hernandez T, Gutierrez-Agüera F, Díaz VM, Romecín PA, Roca-Ho H, Sánchez-Martínez D, Tirado N, Baroni ML, Petazzi P, Torres-Ruiz R, Molina O, Bataller A, Fuster JL, Ballerini P, Juan M, Jeremias I, Bueno C, and Menéndez P
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- Antigens, CD19, B-Lymphocytes, Humans, Immunotherapy, Adoptive, Sialic Acid Binding Ig-like Lectin 2 genetics, T-Lymphocytes, Receptors, Chimeric Antigen metabolism
- Abstract
CD19-directed chimeric antigen receptor (CAR) T cells have yielded impressive response rates in refractory/relapse B cell acute lymphoblastic leukemia (B-ALL); however, most patients ultimately relapse due to poor CAR T cell persistence or resistance of either CD19
+ or CD19- B-ALL clones. CD22 is a pan-B marker whose expression is maintained in both CD19+ and CD19- relapses. CD22-CAR T cells have been clinically used in B-ALL patients, although relapse also occurs. T cells engineered with a tandem CAR (Tan-CAR) containing in a single construct both CD19 and CD22 scFvs may be advantageous in achieving higher remission rates and/or preventing antigen loss. We have generated and functionally validated using cutting-edge assays a 4-1BB-based CD22/CD19 Tan-CAR using in-house-developed novel CD19 and CD22 scFvs. Tan-CAR-expressing T cells showed similar in vitro expansion to CD19-CAR T cells with no increase in tonic signaling. CRISPR-Cas9-edited B-ALL cells confirmed the bispecificity of the Tan-CAR. Tan-CAR was as efficient as CD19-CAR in vitro and in vivo using B-ALL cell lines, patient samples, and patient-derived xenografts (PDXs). Strikingly, the robust antileukemic activity of the Tan-CAR was slightly more effective in controlling the disease in long-term follow-up PDX models. This Tan-CAR construct warrants a clinical appraisal to test whether simultaneous targeting of CD19 and CD22 enhances leukemia eradication and reduces/delays relapse rates and antigen loss., Competing Interests: Declaration of interests S.R.Z., T.V.-H., F.G.-A., D.S.-M., and P.M. are inventors of a CD22scFv pending European patent (file no. 20382175.6). P.M. is the co-founder of OneChain Immunotherapeutics (OCI). V.M.D. is employed by OCI., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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34. Engraftment characterization of risk-stratified AML in NSGS mice.
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Díaz de la Guardia R, Velasco-Hernandez T, Gutiérrez-Agüera F, Roca-Ho H, Molina O, Nombela-Arrieta C, Bataller A, Fuster JL, Anguita E, Vives S, Zamora L, Nomdedeu J, Gómez-Casares MT, Ramírez-Orellana M, Lapillonne H, Ramos-Mejia V, Rodríguez-Manzaneque JC, Bueno C, Lopez-Millan B, and Menéndez P
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- Animals, Antigens, CD34, Bone Marrow, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Leukemia, Myeloid, Acute therapy
- Abstract
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Disease heterogeneity is well documented, and patient stratification determines treatment decisions. Patient-derived xenografts (PDXs) from risk-stratified AML are crucial for studying AML biology and testing novel therapeutics. Despite recent advances in PDX modeling of AML, reproducible engraftment of human AML is primarily limited to high-risk (HR) cases, with inconsistent or very protracted engraftment observed for favorable-risk (FR) and intermediate-risk (IR) patients. We used NSGS mice to characterize the engraftment robustness/kinetics of 28 AML patient samples grouped according to molecular/cytogenetic classification and assessed whether the orthotopic coadministration of patient-matched bone marrow mesenchymal stromal cells (BM MSCs) improves AML engraftment. PDX event-free survival correlated well with the predictable prognosis of risk-stratified AML patients. The majority (85-94%) of the mice were engrafted in bone marrow (BM) independently of the risk group, although HR AML patients showed engraftment levels that were significantly superior to those of FR or IR AML patients. Importantly, the engraftment levels observed in NSGS mice by week 6 remained stable over time. Serial transplantation and long-term culture-initiating cell (LTC-IC) assays revealed long-term engraftment limited to HR AML patients, fitter leukemia-initiating cells (LICs) in HR AML samples, and the presence of AML LICs in the CD34- leukemic fraction, regardless of the risk group. Finally, orthotopic coadministration of patient-matched BM MSCs and AML cells was dispensable for BM engraftment levels but favored peripheralization of engrafted AML cells. This comprehensive characterization of human AML engraftment in NSGS mice offers a valuable platform for in vivo testing of targeted therapies in risk-stratified AML patient samples., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2021
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35. CD8+ T lymphocytes are sensitive to NKG2A/HLA-E licensing interaction: role in the survival of cancer patients.
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Gimeno L, González-Lozano I, Soto-Ramírez MF, Martínez-Sánchez MV, López-Cubillana P, Fuster JL, Martínez-García J, Martínez-Escribano J, Campillo JA, Pons-Fuster E, Ferri B, López-Abad A, Muro M, and Minguela A
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- Histocompatibility Antigens Class I, Humans, Retrospective Studies, HLA-E Antigens, CD8-Positive T-Lymphocytes, Neoplasms genetics
- Abstract
NK and CD8
+ T cells are the main cytolytic effectors involved in innate and adaptive tumor immune surveillance, respectively. Although their educational pathways differ, similarities in their development and function suggest that CD8+ T lymphocytes could be sensitive to NK cell licensing signals, which might influence their antitumor response. To demonstrate this hypothesis, we retrospectively evaluated the impact that NK cell licensing interactions have on the expression of CD226 on CD8+ T lymphocytes and on the survival of patients with different hematopoietic and solid cancers (n = 1,023). Prospectively, we analyzed by multiparametric flow cytometry the anti-CD3/CD28-induced proliferation and immune-receptor expression of purified CD8+ T lymphocytes from healthy donors ( n = 17) with different combinations of NK cell licensing ligands. Results show that methionine/threonine (M/T) dimorphism at position -21 of the HLA-B leader peptide, but not other HLA class-I dimorphisms involved in the education of NK cells (HLA-C1/C2 or HLA-Bw4), is associated with greater survival and expression of CD226 in cancer patients, which was proportional to the number of methionines present in their genotype. CD8+ T lymphocytes from healthy donors with -21 M showed higher proliferation rates and lower expression of TIGIT after in vitro stimulation. Therefore, CD8+ T lymphocytes, like NK cells, appear to be sensitive to the -21 M/T dimorphism of HLA-B leader peptide, which results in the modulation of CD226 in vivo and the proliferation and expression of TIGIT after in vitro stimulation, all of which could be related to their immune-surveillance capacity and the survival of cancer patients., Competing Interests: The authors report no conflict of interest., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)- Published
- 2021
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36. Blinatumomab to improve the outcome of children with relapsed B-cell acute lymphoblastic leukemia.
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Fuster JL, Bautista F, González B, Fernández JM, Rives S, and Dapena JL
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- Child, Disease-Free Survival, Humans, Recurrence, Treatment Outcome, Antibodies, Bispecific therapeutic use, Antineoplastic Agents therapeutic use, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Published
- 2021
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37. Hereditary Hyperferritinemia Cataract Syndrome: Ferritin L Gene and Physiopathology behind the Disease-Report of New Cases.
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Celma Nos F, Hernández G, Ferrer-Cortès X, Hernandez-Rodriguez I, Navarro-Almenzar B, Fuster JL, Bermúdez Cortés M, Pérez-Montero S, Tornador C, and Sanchez M
- Subjects
- Adult, Cataract genetics, Child, Female, Humans, Iron metabolism, Iron Metabolism Disorders genetics, Iron-Regulatory Proteins genetics, Mutation genetics, Cataract congenital, Ferritins genetics, Iron Metabolism Disorders congenital
- Abstract
Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare disease characterized by high serum ferritin levels, congenital bilateral cataracts, and the absence of tissue iron overload. This disorder is produced by mutations in the iron responsive element (IRE) located in the 5' untranslated regions (UTR) of the light ferritin ( FTL ) gene. A canonical IRE is a mRNA structure that interacts with the iron regulatory proteins (IRP1 and IRP2) to post-transcriptionally regulate the expression of proteins related to iron metabolism. Ferritin L and H are the proteins responsible for iron storage and intracellular distribution. Mutations in the FTL IRE abrogate the interaction of FTL mRNA with the IRPs, and de-repress the expression of FTL protein. Subsequently, there is an overproduction of ferritin that accumulates in serum (hyperferritinemia) and excess ferritin precipitates in the lens, producing cataracts. To illustrate this disease, we report two new families affected with hereditary hyperferritinemia-cataract syndrome with previous known mutations. In the diagnosis of congenital bilateral cataracts, HHCS should be taken into consideration and, therefore, it is important to test serum ferritin levels in patients with cataracts.
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- 2021
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38. Expression of NK Cell Receptor Ligands on Leukemic Cells Is Associated with the Outcome of Childhood Acute Leukemia.
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Martínez-Sánchez MV, Fuster JL, Campillo JA, Galera AM, Bermúdez-Cortés M, Llinares ME, Ramos-Elbal E, Pascual-Gázquez JF, Fita AM, Martínez-Banaclocha H, Galián JA, Gimeno L, Muro M, and Minguela A
- Abstract
Acute leukemia is the most common malignancy in children. Most patients are cured, but refractory/relapsed AML and ALL are the first cause of death from malignancy in children. Maintenance chemotherapy in ALL has improved survival by inducing leukemic cell apoptosis, but immune surveillance effectors such as NK cells might also contribute. The outcome of B-ALL ( n = 70), T-ALL ( n = 16), and AML ( n = 16) pediatric patients was evaluated according to leukemic cell expression of ligands for activating and inhibiting receptors that regulate NK cell functioning. Increased expression of ULBP-1, a ligand for NKG2D, but not that of CD112 or CD155, ligands for DNAM-1, was associated with poorer 5-year event-free survival (5y-EFS, 77.6% vs. 94.9%, p < 0.03). Reduced expression of HLA-C on leukemic cells in patients with the KIR2DL1/HLA-C*04 interaction was associated with a higher rate of relapse (17.6% vs. 4.4%, p = 0.035) and lower 5y-EFS (70.6% vs. 92.6%, p < 0.002). KIR2DL1/HLA-C*04 interaction was an independent predictive factor of events (HR = 4.795, p < 0.005) or death (HR = 6.731, p < 0.005) and might provide additional information to the current risk stratification. Children who carry the KIR2DL1/HLA-C*04 interaction were refractory to current chemotherapy treatments, including allogeneic stem cell transplantation; therefore, they should be considered as candidates for alternative biological therapies that might offer better results.
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- 2021
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39. Matched sibling donor stem cell transplantation for sickle cell disease: Results from the Spanish group for bone marrow transplantation in children.
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Benítez-Carabante MI, Beléndez C, González-Vicent M, Alonso L, Uría-Oficialdegui ML, Torrent M, Pérez-Hurtado JM, Fuster JL, Cela E, and Díaz-de-Heredia C
- Subjects
- Anemia, Sickle Cell epidemiology, Child, Female, Graft vs Host Disease diagnosis, Graft vs Host Disease epidemiology, Graft vs Host Disease etiology, Humans, Incidence, Male, Retrospective Studies, Severity of Illness Index, Spain, Transplantation Conditioning, Transplantation, Homologous, Anemia, Sickle Cell therapy, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Siblings
- Abstract
Objectives: The prevalence of sickle cell disease (SCD) in Spain is markedly inferior compared with other European and Mediterranean countries. However, the diagnosis of new patients with SCD is expected to increase. In this multicenter retrospective study, we analyze the hematopoietic stem cell transplantation (HSCT) results obtained in Spain., Methods: Forty-five patients who underwent a matched sibling donor (MSD) HSCT between 1999 and 2018 were included. Primary endpoint was event-free survival (EFS), and secondary endpoints included acute and chronic graft-versus-host disease (GvHD) and overall survival (OS)., Results: Bone marrow was the most frequent stem cell source (93.3%). Most patients received a conditioning regimen based on busulfan and cyclophosphamide (69%). Cumulative incidence of grade III-IV acute GvHD and chronic GvHD was 6.8% (95% CI: 2.3%-20.1%) and 5.4% (95% CI: 1.38%-19.9%), respectively. EFS and overall survival (OS) at 3 years post-HSCT were 89.4% (95% CI: 73.9%-95.9%) and 92.1% (95% CI: 77.2%-97.4%), respectively. All patients aged ≤ 5 presented 100% EFS and OS., Conclusions: An early referral to HSCT centers should be proposed early in life, before severe complications occur. MSD HSCT should be considered a curative option for all patients aged ≤ 5 years and for older pediatric patients who present complications derived from the disease., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2021
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40. Measurable Residual Disease Assessed by Flow-Cytometry Is a Stable Prognostic Factor for Pediatric T-Cell Acute Lymphoblastic Leukemia in Consecutive SEHOP Protocols Whereas the Impact of Oncogenetics Depends on Treatment.
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Vega-García N, Perez-Jaume S, Esperanza-Cebollada E, Vicente-Garcés C, Torrebadell M, Jiménez-Velasco A, Ortega M, Llop M, Abad L, Vagace JM, Minguela A, Pratcorona M, Sánchez-Garcia J, García-Calderón CB, Gómez-Casares MT, Martín-Clavero E, Escudero A, Riñón Martinez-Gallo M, Muñoz L, Velasco MR, García-Morin M, Català A, Pascual A, Velasco P, Fernández JM, Lassaletta A, Fuster JL, Badell I, Molinos-Quintana Á, Molinés A, Guerra-García P, Pérez-Martínez A, García-Abós M, Robles Ortiz R, Pisa S, Adán R, Díaz de Heredia C, Dapena JL, Rives S, Ramírez-Orellana M, and Camós M
- Abstract
Robust and applicable risk-stratifying genetic factors at diagnosis in pediatric T-cell acute lymphoblastic leukemia (T-ALL) are still lacking, and most protocols rely on measurable residual disease (MRD) assessment. In our study, we aimed to analyze the impact of NOTCH1, FBXW7, PTEN , and RAS mutations, the measurable residual disease (MRD) levels assessed by flow cytometry (FCM-MRD) and other reported risk factors in a Spanish cohort of pediatric T-ALL patients. We included 199 patients treated with SEHOP and PETHEMA consecutive protocols from 1998 to 2019. We observed a better outcome of patients included in the newest SEHOP-PETHEMA-2013 protocol compared to the previous SHOP-2005 cohort. FCM-MRD significantly predicted outcome in both protocols, but the impact at early and late time points differed between protocols. The impact of FCM-MRD at late time points was more evident in SEHOP-PETHEMA 2013, whereas in SHOP-2005 FCM-MRD was predictive of outcome at early time points. Genetics impact was different in SHOP-2005 and SEHOP-PETHEMA-2013 cohorts: NOTCH1 mutations impacted on overall survival only in the SEHOP-PETHEMA-2013 cohort, whereas homozygous deletions of CDKN2A / B had a significantly higher CIR in SHOP-2005 patients. We applied the clinical classification combining oncogenetics, WBC count and MRD levels at the end of induction as previously reported by the FRALLE group. Using this score, we identified different subgroups of patients with statistically different outcome in both Spanish cohorts. In SHOP-2005, the FRALLE classifier identified a subgroup of high-risk patients with poorer survival. In the newest protocol SEHOP-PETHEMA-2013, a very low-risk group of patients with excellent outcome and no relapses was detected, with borderline significance. Overall, FCM-MRD, WBC count and oncogenetics may refine the risk-stratification, helping to design tailored approaches for pediatric T-ALL patients., Competing Interests: MT reports travel and accommodation support from Novartis (outside the submitted work); travel and accommodation support from Jazz Pharma and Shire/Servier (outside the submitted work); and travel and accommodation support from Amgen (outside the submitted work). JLF is a consultant/advisory member for Amgen, Jazz Pharmaceuticals, and Novartis (outside the submitted work), receives honoraria for speaking at symposia from Amgen, Servier, Jazz Pharmaceuticals, and Pfizer (outside the submitted work) and support for attending symposia from Servier and Jazz Pharmaceuticals (outside the submitted work). AM discloses talk fees from Jazz Pharma and Shire/Servier outside the presented work and reports travel and accommodation support from Jazz Pharma, Shire/Servier, and Novartis (outside the submitted work). JD reports advisory board honorarium, speaker fees, and travel and accommodation support from Jazz Pharma and Shire/Servier; personal fees, advisory board honorarium, speaker fees, and travel and accommodation support from Novartis (outside the submitted work); advisory board honorarium, and travel and accommodation support from Amgen (outside the submitted work); advisory board honorarium, speaker fees, and travel and accommodation support from Celgene (outside the submitted work); advisory board honorarium, speaker fees, and travel and accommodation support from Sobi (outside the submitted work). SR reports advisory board honorarium, speaker fees, and travel and accommodation support from Jazz Pharma and Shire/Servier; personal fees, advisory board honorarium, speaker fees, and travel and accommodation support from Novartis (outside the submitted work); advisory board honorarium, and travel and accommodation support from Amgen (outside the submitted work); advisory board honorarium, speaker fees, and travel and accommodation support from Celgene (outside the submitted work). MC discloses talk fees from Shire/Servier outside the presented work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Vega-García, Perez-Jaume, Esperanza-Cebollada, Vicente-Garcés, Torrebadell, Jiménez-Velasco, Ortega, Llop, Abad, Vagace, Minguela, Pratcorona, Sánchez-Garcia, García-Calderón, Gómez-Casares, Martín-Clavero, Escudero, Riñón Martinez-Gallo, Muñoz, Velasco, García-Morin, Català, Pascual, Velasco, Fernández, Lassaletta, Fuster, Badell, Molinos-Quintana, Molinés, Guerra-García, Pérez-Martínez, García-Abós, Robles Ortiz, Pisa, Adán, Díaz de Heredia, Dapena, Rives, Ramírez-Orellana, Camós and on behalf of the Biological Committee of the Group of Leukaemia of the Spanish Society of Paediatric Haematology Oncology (SEHOP Group).)
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- 2021
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41. Haploidentical transplantation in pediatric non-malignant diseases: A retrospective analysis on behalf of the Spanish Group for Hematopoietic Transplantation (GETH).
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Torres Canizales J, Ferreras C, Pascual A, Alonso L, Regueiro A, Plaza M, Pérez Hurtado JM, Benito A, Couselo JM, Fuster JL, Díaz-Almirón M, Bueno D, Mozo Y, Gómez López A, Vicario JL, Balas A, Sisinni L, Díaz de Heredia C, and Pérez-Martínez A
- Subjects
- Age Factors, Child, Preschool, Disease Management, Female, Graft Survival, Graft vs Host Disease diagnosis, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Humans, Infant, Infections etiology, Infections therapy, Male, Outcome Assessment, Health Care, Pediatrics methods, Practice Patterns, Physicians', Prognosis, Retrospective Studies, Spain, Transplantation Chimera, Transplantation Conditioning, Transplantation, Haploidentical adverse effects, Transplantation, Haploidentical methods, Hematopoietic Stem Cell Transplantation statistics & numerical data, Transplantation, Haploidentical statistics & numerical data
- Abstract
Objective: Describe the GETH haploidentical stem cell transplantation (haplo-HSCT) activity in non-malignant disease (NMDs)., Methods: We retrospectively analyzed data from children with NMDs who underwent haplo-HSCT., Results: From January 2001 to December 2016, 26 pediatric patients underwent 31 haplo-HSCT through ex vivo T cell-depleted (TCD) graft platforms or post-transplantation cyclophosphamide (PT-Cy) at 7 Spanish centers. Five cases employed unmanipulated PT-Cy haplo-HSCT, 16 employed highly purified CD34
+ cells, and 10 employed ex vivo TCD grafts manipulated either with CD3+ CD19+ depletion, TCRαβ+ CD19+ selection or naive CD45RA+ T-cell depletion. Peripheral blood stem cells were the sole source for patients following TCD haplo-HSCT, and bone marrow was the source for one PT-Cy haplo-HSCT. The most common indications for transplantation were primary immunodeficiency disorders (PIDs), severe aplastic anemia, osteopetrosis, and thalassemia. The 1-year cumulative incidence of graft failure was 27.4%. The 1-year III-IV acute graft-versus-host disease (GvHD) and 1-year chronic GvHD rates were 34.6% and 16.7%, respectively. The 2-year overall survival was 44.9% for PIDs, and the 2-year graft-versus-host disease-free and relapse-free survival rate was 37.6% for the other NMDs. The transplantation-related mortality at day 100 was 30.8%., Conclusion: Although these results are discouraging, improvements will come if procedures are centralized in centers of expertise., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)- Published
- 2021
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42. Comprehensive Custom NGS Panel Validation for the Improvement of the Stratification of B-Acute Lymphoblastic Leukemia Patients.
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Montaño A, Hernández-Sánchez J, Forero-Castro M, Matorra-Miguel M, Lumbreras E, Miguel C, Santos S, Ramírez-Maldonado V, Fuster JL, de Las Heras N, García-de Coca A, Sierra M, Dávila J, de la Fuente I, Olivier C, Olazabal J, Martínez J, Vega-García N, González T, Hernández-Rivas JM, and Benito R
- Abstract
Background: B-acute lymphoblastic leukemia (B-ALL) is a hematological neoplasm of the stem lymphoid cell of the B lineage, characterized by the presence of genetic alterations closely related to the course of the disease. The number of alterations identified in these patients grows as studies of the disease progress, but in clinical practice, the conventional techniques frequently used are only capable of detecting the most common alterations. However, techniques, such as next-generation sequencing (NGS), are being implemented to detect a wide spectrum of new alterations that also include point mutations., Methods: In this study, we designed and validated a comprehensive custom NGS panel to detect the main genetic alterations present in the disease in a single step. For this purpose, 75 B-ALL diagnosis samples from patients previously characterized by standard-of-care diagnostic techniques were sequenced., Results: The use of the custom NGS panel allowed the correct detection of the main genetic alterations present in B-ALL patients, including the presence of an aneuploid clone in 14 of the samples and some of the recurrent fusion genes in 35 of the samples. The panel was also able to successfully detect a number of secondary alterations, such as single nucleotide variants (SNVs) and copy number variations (CNVs) in 66 and 46 of the samples analyzed, respectively, allowing for further refinement of the stratification of patients. The custom NGS panel could also detect alterations with a high level of sensitivity and reproducibility when the findings obtained by NGS were compared with those obtained from other conventional techniques., Conclusions: The use of this custom NGS panel allows us to quickly and efficiently detect the main genetic alterations present in B-ALL patients in a single assay (SNVs and insertions/deletions (INDELs), recurrent fusion genes, CNVs, aneuploidies, and single nucleotide polymorphisms (SNPs) associated with pharmacogenetics). The application of this panel would thus allow us to speed up and simplify the molecular diagnosis of patients, helping patient stratification and management.
- Published
- 2020
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43. Initial report on Spanish pediatric oncologic, hematologic, and post stem cell transplantation patients during SARS-CoV-2 pandemic.
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Faura A, Rives S, Lassaletta Á, Sebastián E, Madero L, Huerta J, García-Morín M, Martínez AP, Sisinni L, Astigarraga I, Velasco P, Gros L, Moreno L, Carboné A, Rodríguez-Vigil C, Riesco S, Mendoza MDC, Macias EG, Trabazo M, Torrent M, Badell I, Fuster JL, Dominguez-Pinilla N, Juan Ribelles A, Pérez-Alonso V, Fernández Sanmartín M, Baragaño M, Gorostegui M, Perez-Jaume S, Fernández-Teijeiro A, Morales La Madrid A, and Dapena JL
- Subjects
- Adolescent, COVID-19, Child, Humans, SARS-CoV-2, Betacoronavirus, Coronavirus Infections, Neoplasms, Pandemics, Pneumonia, Viral epidemiology
- Published
- 2020
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- View/download PDF
44. Blinatumomab and inotuzumab for B cell precursor acute lymphoblastic leukaemia in children: a retrospective study from the Leukemia Working Group of the Spanish Society of Pediatric Hematology and Oncology (SEHOP).
- Author
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Fuster JL, Molinos-Quintana A, Fuentes C, Fernández JM, Velasco P, Pascual T, Rives S, Dapena JL, Sisinni L, López-Godino O, Palomo P, Villa-Alcázar M, Bautista F, González-Vicent M, López-Duarte M, García-Morín M, Ramos-Elbal E, and Ramírez M
- Subjects
- Adolescent, Antibodies, Bispecific administration & dosage, Antibodies, Bispecific adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Child, Child, Preschool, Disease-Free Survival, Female, Hematology, Humans, Infant, Inotuzumab Ozogamicin administration & dosage, Inotuzumab Ozogamicin adverse effects, Male, Medical Oncology, Retrospective Studies, Societies, Medical, Spain epidemiology, Survival Rate, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma mortality
- Abstract
Blinatumomab and inotuzumab ozogamycin represent promising alternatives to conventional chemotherapy in acute lymphoblastic leukaemia (ALL). We analysed data from 29 children with ALL treated under compassionate use with blinatumomab, inotuzumab or both. The complete remission (CR) rate in a heavily pretreated population with overt relapse was 47·6%. At earlier stages (first/second CR), both antibodies represented a useful tool to reduce minimal residual disease, and/or avoid further toxic chemotherapy until stem cell transplantation. Six patients developed grade 3 reversible non-haematological toxicity. The 12-month overall survival and event-free survival rates were 50·8 ± 26·4% and 38·9 ± 25·3% with blinatumomab, 45·8 ± 26% and 27·5 ± 25% with inotuzumab., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)
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- 2020
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45. Integrated Genomic Analysis of Chromosomal Alterations and Mutations in B-Cell Acute Lymphoblastic Leukemia Reveals Distinct Genetic Profiles at Relapse.
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Forero-Castro M, Montaño A, Robledo C, García de Coca A, Fuster JL, de Las Heras N, Queizán JA, Hernández-Sánchez M, Corchete-Sánchez LA, Martín-Izquierdo M, Ribera J, Ribera JM, Benito R, and Hernández-Rivas JM
- Abstract
The clonal basis of relapse in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is complex and not fully understood. Next-generation sequencing (NGS), array comparative genomic hybridization (aCGH), and multiplex ligation-dependent probe amplification (MLPA) were carried out in matched diagnosis-relapse samples from 13 BCP-ALL patients to identify patterns of genetic evolution that could account for the phenotypic changes associated with disease relapse. The integrative genomic analysis of aCGH, MLPA and NGS revealed that 100% of the BCP-ALL patients showed at least one genetic alteration at diagnosis and relapse. In addition, there was a significant increase in the frequency of chromosomal lesions at the time of relapse ( p = 0.019). MLPA and aCGH techniques showed that IKZF1 was the most frequently deleted gene. TP53 was the most frequently mutated gene at relapse. Two TP53 mutations were detected only at relapse, whereas the three others showed an increase in their mutational burden at relapse. Clonal evolution patterns were heterogeneous, involving the acquisition, loss and maintenance of lesions at relapse. Therefore, this study provides additional evidence that BCP-ALL is a genetically dynamic disease with distinct genetic profiles at diagnosis and relapse. Integrative NGS, aCGH and MLPA analysis enables better molecular characterization of the genetic profile in BCP-ALL patients during the evolution from diagnosis to relapse.
- Published
- 2020
- Full Text
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46. Haploidentical transplantation in high-risk pediatric leukemia: A retrospective comparative analysis on behalf of the Spanish working Group for bone marrow transplantation in children (GETMON) and the Spanish Grupo for hematopoietic transplantation (GETH).
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Pérez-Martínez A, Ferreras C, Pascual A, Gonzalez-Vicent M, Alonso L, Badell I, Fernández Navarro JM, Regueiro A, Plaza M, Pérez Hurtado JM, Benito A, Beléndez C, Couselo JM, Fuster JL, Díaz-Almirón M, Bueno D, Mozo Y, Marsal J, Gómez López A, Sisinni L, de Heredia CD, and Díaz MÁ
- Subjects
- Bone Marrow Transplantation methods, Bone Marrow Transplantation mortality, Child, Cyclophosphamide therapeutic use, Female, Graft Survival, Graft vs Host Disease prevention & control, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation methods, Hematopoietic Stem Cell Transplantation mortality, Humans, Leukemia mortality, Lymphocyte Depletion, Male, Pediatrics methods, Recurrence, Retrospective Studies, Spain, Survival Analysis, Leukemia therapy, Transplantation, Haploidentical
- Abstract
A total of 192 pediatric patients, median age 8.6 years, with high-risk hematological malignancies, underwent haploidentical stem cell transplantation (haplo-HSCT) using post-transplantation cyclophosphamide (PT-Cy), or ex vivo T cell-depleted (TCD) graft platforms, from January 1999 to December 2016 in 10 centers in Spain. Some 41 patients received an unmanipulated graft followed by PT-Cy for graft-vs-host disease (GvHD) prophylaxis. A total of 151 patients were transplanted with CD3-depleted peripheral blood stem cells (PBSCs) by either CD34
+ selection, CD3+ CD19+ depletion, TCRαβ+ CD19+ depletion or CD45RA+ depletion, added to CD34+ selection for GvHD prophylaxis. The PBSCs were the only source in patients following ex vivo TCD haplo-HSCT; bone marrow was the source in 9 of 41 patients following PT-CY haplo-HSCT. Engraftment was achieved in 91.3% of cases. A donor younger than 30 years, and the development of chronic GvHD were positive factors influencing survival, whereas positive minimal residual disease (MRD) before transplant and lymphoid disease were negative factors. The probability of relapse increased with lymphoid malignancies, a donor killer-cell immunoglobulin-like receptor (KIR) haplotype A and positive MRD pretransplant. No difference was found in overall survival, disease-free survival or relapse incidence between the two platforms. Relapse is still of concern in both platforms, and it should be the focus of future efforts. In conclusion, both platforms for haplo-HSCT were effective and could be utilized depending on the comfort level of the center., (© 2019 Wiley Periodicals, Inc.)- Published
- 2020
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47. ECLIM-SEHOP, a new platform to set up and develop international academic clinical trials for childhood cancer and blood disorders in Spain.
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Bautista F, Cañete A, Ramírez-Villar GL, Fernández JM, Fuster JL, Diaz de Heredia C, Astigarraga I, García-Ariza M, Rives S, Dapena JL, Márquez C, Molinés A, Bermúdez MDM, Gallego S, Andrés MDM, Verdu-Amoros J, Hernández C, López M, Catalá A, Lassaletta Á, Cruz O, Ramírez M, Lendínez F, Carboné A, Gomez Sirvent J, Tallón M, Acha T, Moreno L, and Fernández-Teijeiro A
- Subjects
- Adolescent, Cancer Survivors, Child, Hematologic Neoplasms therapy, Hematology organization & administration, Humans, Medical Oncology organization & administration, Neoplasms therapy, Pediatrics organization & administration, Spain, Clinical Trials as Topic statistics & numerical data, International Cooperation, Multicenter Studies as Topic statistics & numerical data, Observational Studies as Topic statistics & numerical data, Organizational Objectives, Societies, Medical organization & administration
- Abstract
Introduction: Cancer and blood disorders in children are rare. The progressive improvement in survival over the last decades largely relies on the development of international academic clinical trials that gather the sufficient number of patients globally to elaborate solid conclusions and drive changes in clinical practice. The participation of Spain into large international academic trials has traditionally lagged behind of other European countries, mainly due to the burden of administrative tasks to open new studies, lack of financial support and limited research infrastructure in our hospitals., Methods: The objective of ECLIM-SEHOP platform (Ensayos Clínicos Internacionales Multicéntricos-SEHOP) is to overcome these difficulties and position Spain among the European countries leading the advances in cancer and blood disorders, facilitate the access of our patients to novel diagnostic and therapeutic approaches and, most importantly, continue to improve survival and reducing long-term sequelae. ECLIM-SEHOP provides to the Spanish clinical investigators with the necessary infrastructural support to open and implement academic clinical trials and registries., Results: In less than 3 years from its inception, the platform has provided support to 20 clinical trials and 8 observational studies, including 8 trials and 4 observational studies where the platform performs all trial-related tasks (integral support: trial setup, monitoring, etc.) with more than 150 patients recruited since 2017 to these studies. In this manuscript, we provide baseline metrics for academic clinical trial performance that permit future comparisons., Conclusions: ECLIM-SEHOP facilitates Spanish children and adolescents diagnosed with cancer and blood disorders to access state-of-the-art diagnostic and therapeutic strategies.
- Published
- 2019
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48. NG2 antigen is a therapeutic target for MLL-rearranged B-cell acute lymphoblastic leukemia.
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Lopez-Millan B, Sanchéz-Martínez D, Roca-Ho H, Gutiérrez-Agüera F, Molina O, Diaz de la Guardia R, Torres-Ruiz R, Fuster JL, Ballerini P, Suessbier U, Nombela-Arrieta C, Bueno C, and Menéndez P
- Subjects
- Animals, Antigens genetics, Asparaginase administration & dosage, Dexamethasone administration & dosage, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasm Invasiveness, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Proteoglycans genetics, Remission Induction, Survival Rate, Vincristine administration & dosage, Xenograft Model Antitumor Assays, Antigens metabolism, Antineoplastic Combined Chemotherapy Protocols therapeutic use, B-Lymphocytes pathology, Drug Resistance, Neoplasm, Gene Rearrangement, Histone-Lysine N-Methyltransferase genetics, Myeloid-Lymphoid Leukemia Protein genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma prevention & control, Proteoglycans metabolism
- Abstract
B cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer, with cure rates of ∼80%. MLL-rearranged (MLLr) B-ALL (MLLr-B-ALL) has, however, an unfavorable prognosis with common therapy refractoriness and early relapse, and therefore new therapeutic targets are needed for relapsed/refractory MLLr-B-ALL. MLLr leukemias are characterized by the specific expression of chondroitin sulfate proteoglycan-4, also known as neuron-glial antigen-2 (NG2). NG2 was recently shown involved in leukemia invasiveness and central nervous system infiltration in MLLr-B-ALL, and correlated with lower event-free survival (EFS). We here hypothesized that blocking NG2 may synergize with established induction therapy for B-ALL based on vincristine, glucocorticoids, and L-asparaginase (VxL). Using robust patient-derived xenograft (PDX) models, we found that NG2 is crucial for MLLr-B-ALL engraftment upon intravenous (i.v.) transplantation. In vivo blockade of NG2 using either chondroitinase-ABC or an anti-NG2-specific monoclonal antibody (MoAb) resulted in a significant mobilization of MLLr-B-ALL blasts from bone marrow (BM) to peripheral blood (PB) as demonstrated by cytometric and 3D confocal imaging analysis. When combined with either NG2 antagonist, VxL treatment achieved higher rates of complete remission, and consequently higher EFS and delayed time to relapse. Mechanistically, anti-NG2 MoAb induces neither antibody-dependent cell-mediated not complement-dependent cytotoxicity. NG2 blockade rather overrides BM stroma-mediated chemoprotection through PB mobilization of MLLr-B-ALL blasts, thus becoming more accessible to chemotherapy. We provide a proof of concept for NG2 as a therapeutic target for MLLr-B-ALL.
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- 2019
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49. Fratricide-resistant CD1a-specific CAR T cells for the treatment of cortical T-cell acute lymphoblastic leukemia.
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Sánchez-Martínez D, Baroni ML, Gutierrez-Agüera F, Roca-Ho H, Blanch-Lombarte O, González-García S, Torrebadell M, Junca J, Ramírez-Orellana M, Velasco-Hernández T, Bueno C, Fuster JL, Prado JG, Calvo J, Uzan B, Cools J, Camos M, Pflumio F, Toribio ML, and Menéndez P
- Subjects
- Animals, Humans, Jurkat Cells, Mice, Xenograft Model Antitumor Assays, Antigens, CD1 immunology, Drug Resistance, Neoplasm immunology, Immunotherapy, Adoptive, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma immunology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma therapy, Receptors, Chimeric Antigen immunology
- Abstract
Relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) has a dismal outcome, and no effective targeted immunotherapies for T-ALL exist. The extension of chimeric antigen receptor (CAR) T cells (CARTs) to T-ALL remains challenging because the shared expression of target antigens between CARTs and T-ALL blasts leads to CART fratricide. CD1a is exclusively expressed in cortical T-ALL (coT-ALL), a major subset of T-ALL, and retained at relapse. This article reports that the expression of CD1a is mainly restricted to developing cortical thymocytes, and neither CD34
+ progenitors nor T cells express CD1a during ontogeny, confining the risk of on-target/off-tumor toxicity. We thus developed and preclinically validated a CD1a-specific CAR with robust and specific cytotoxicity in vitro and antileukemic activity in vivo in xenograft models of coT-ALL, using both cell lines and coT-ALL patient-derived primary blasts. CD1a-CARTs are fratricide resistant, persist long term in vivo (retaining antileukemic activity in re-challenge experiments), and respond to viral antigens. Our data support the therapeutic and safe use of fratricide-resistant CD1a-CARTs for relapsed/refractory coT-ALL., (© 2019 by The American Society of Hematology.)- Published
- 2019
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- View/download PDF
50. [Long-term renal function in Wilms tumor survivors].
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Sánchez Sánchez A, Girón Vallejo O, Ruiz Pruneda R, Fernández Ibieta M, Villamil V, Giménez Aleixandre MC, Montoya-Rangel CA, Fuster JL, Pascual Gázquez JF, Ortega García JA, Cárceles Álvarez A, Vicente Calderón C, Zambudio Carmona G, Ruiz Jiménez JI, and Hernández Bermejo JP
- Subjects
- Child, Child, Preschool, Female, Follow-Up Studies, Glomerular Filtration Rate, Humans, Infant, Kidney Neoplasms mortality, Kidney Neoplasms pathology, Male, Prevalence, Renal Insufficiency, Chronic epidemiology, Retrospective Studies, Wilms Tumor mortality, Wilms Tumor pathology, Cancer Survivors, Kidney physiopathology, Kidney Neoplasms physiopathology, Wilms Tumor physiopathology
- Abstract
Objetive: To evaluate long-term renal function and morbimortality in non-syndromic Wilms tumor (WT) survivors., Methods: Retrospective study about WT patients treated in 1993-2017, according to SIOP protocols. Mortality, glomerular filtration rate (GFR), prevalence of hypertension and requirement of dialysis and renal transplant were evaluated. Chronic kidney disease (CKD) was defined as GFR <90 ml/min/1.73 m2., Results: Thirty-nine children were treated in the 25 analyzed years. Median time of follow-up was 6 years (0.5-21 years). 48% (19 patients) debuted with stage I or II. Four cases had high-grade histo-logy. Mortality rate was 10%. GFR data were found in 37 patients. Chronic kidney disease (grade I-II) turned up in 6 patients (16%). No patient required renal replacement therapy or renal transplant. 16% of patients developed CKD in both unilateral and bilateral WT, (p>0.05); OR 1.04 (IC 95% 0.09-10.9). Identical results were obtained comparing patients treated with or without radiotherapy (16%). Children with stage I-III had CKD in 11% vs. 40% of patients with stage IV (p=0.12); OR 5.3 (IC 95% 0.61-45). None of them presented hypertension in addition., Conclusions: In the current study the prevalence of CKD was low but not negligible, although no patients required renal replacement therapy or renal transplant. Bilateral renal involvement and radiotherapy were not associated with CKD development. Metastatic disease determines a higher risk of CKD.
- Published
- 2019
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