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Other skin manifestations.</p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">2A: Purpura in cryoglobulinemia type I; 2B: Ulcers in cryoglobulinemia type I; 2C: Ulcers in the healing phase in type I cryoglobulinemia; 2D: Coexistence of urticarial vasculitis; 2E: Raynaud's phenomenon</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Panel 3. Systemic manifestations of particular severity.</p> <p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">3A: Digital necrosis; 3B: Deep skin ulcer; 3C: Bilateral alveolar haemorrhage; 3D: Intestinal ischemia; 3E: Membranoproliferative glomerulonephritis.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Soledad Retamozo, Luca Quartuccio, Manuel Ramos-Casals" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Soledad" "apellidos" => "Retamozo" ] 1 => array:2 [ "nombre" => "Luca" "apellidos" => "Quartuccio" ] 2 => array:2 [ "nombre" => "Manuel" "apellidos" => "Ramos-Casals" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775321007351" "doi" => "10.1016/j.medcli.2021.11.017" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775321007351?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S238702062200198X?idApp=UINPBA00004N" "url" => "/23870206/0000015800000010/v1_202206100851/S238702062200198X/v1_202206100851/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2387020622001929" "issn" => "23870206" "doi" => "10.1016/j.medcle.2021.04.033" "estado" => "S300" "fechaPublicacion" => "2022-05-27" "aid" => "5752" "copyright" => "Elsevier España, S.L.U." "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "crp" "cita" => "Med Clin. 2022;158:472-5" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Brief report</span>" "titulo" => "The clinical relevance of inhalation technique in chronic obstructive pulmonary disease patients" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "472" "paginaFinal" => "475" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Relevancia clínica de la técnica de utilización de inhaladores en pacientes con enfermedad pulmonar obstructiva crónica" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Pilar Barnestein-Fonseca, Noemí Vázquez-González, Elisa Martín-Montañez, José Leiva-Fernández, Víctor Cotta-Luque, Francisca Leiva-Fernández" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Pilar" "apellidos" => "Barnestein-Fonseca" ] 1 => array:2 [ "nombre" => "Noemí" "apellidos" => "Vázquez-González" ] 2 => array:2 [ "nombre" => "Elisa" "apellidos" => "Martín-Montañez" ] 3 => array:2 [ "nombre" => "José" "apellidos" => "Leiva-Fernández" ] 4 => array:2 [ "nombre" => "Víctor" "apellidos" => "Cotta-Luque" ] 5 => array:2 [ "nombre" => "Francisca" "apellidos" => "Leiva-Fernández" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S002577532100395X" "doi" => "10.1016/j.medcli.2021.04.034" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S002577532100395X?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020622001929?idApp=UINPBA00004N" "url" => "/23870206/0000015800000010/v1_202206100851/S2387020622001929/v1_202206100851/en/main.assets" ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial article</span>" "titulo" => "Monoclonal antibodies in frontline therapy of adult acute lymphoblastic leukemia: A step ahead" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "476" "paginaFinal" => "477" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Josep-Maria Ribera, Anna Torrent" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Josep-Maria" "apellidos" => "Ribera" "email" => array:1 [ 0 => "jribera@iconcologia.net" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Anna" "apellidos" => "Torrent" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Hematología Clínica, ICO-Hospital Germans Trias i Pujol, Institut de Recerca Josep Carreras, Universitat Autònoma de Barcelona, Barcelona, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Anticuerpos monoclonales en el tratamiento de primera línea de la leucemia aguda linfoblástica en adultos: un paso adelante" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Despite significant advances in the treatment of acute lymphoblastic leukaemia (ALL), 15–20% of paediatric and 50% of adult patients relapse. Salvage chemotherapy strategies followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) yield poor results, with a 30% complete remission rate and 10% long-term survival.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The emergence of immunotherapy strategies, currently restricted to B-precursor ALL and under active investigation in T-ALL, has meant a great step forward in the treatment of patients with relapsed or refractory ALL (R/R). These include monoclonal antibodies (mAbs) and cell therapy. Among the former, the most effective and currently approved for clinical use are the immunoconjugates (specifically inotuzumab ozogamicin, anti-CD22-calecheamicin conjugate)<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> and bispecifics (blinatumomab, anti-CD19/CD3),<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> while, in addition to allo-HSCT, the most successful cell therapy used is CAR-T cell therapy, targeting the CD19 receptor on the surface of blasts.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Firstly, it is worth mentioning rituximab, an unconjugated anti-CD20 mAb which, in association with standard first-line chemotherapy, showed a significant increase in event-free survival in adults with B-precursor ALL and CD20 expression of more than 20% in blasts in a randomised study.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In turn, the encouraging results (and superior to salvage chemotherapy) obtained with the use of blinatumomab and inotuzumab as single drugs in patients in a situation of R/R<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a> or with measurable residual disease (MRD)<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> have led to the evaluation of its use in adults with de novo ALL, in combination with chemotherapy. The theoretical advantages of such an association would be, on the one hand, the more thorough elimination of MRD and, on the other hand, the possibility of reducing the intensity of chemotherapy, which means less toxicity and greater applicability to older patients. It was precisely in the group of patients over 55–60 years of age that the combination of attenuated chemotherapy and mAbs began to be evaluated, first in R/R<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> and currently as first-line treatment, with various strategies.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8–11</span></a> Among them, it is worth mentioning those that apply such a combination during the remission induction phase and those that use mAbs during the consolidation period. Most studies are phase II clinical trials and use one of the two mAbs, blinatumomab or inotuzumab, in combination with attenuated-intensity chemotherapy, but there is at least one study where these two mAbs are administered sequentially (first, inotuzumab, for rapid cytoreduction and blinatumomab to effectively eliminate MRD).<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> The results of these studies, still with little follow-up, have shown complete remission rates of around 80–85%, very low mortality in induction (1–3%) and a 1-year overall survival (OS) probability of 60–70%, something that had not been achieved with conventional chemotherapy in elderly patients. Obviously, there is a lack of randomised studies comparing this strategy with conventional chemotherapy. To date, only one study with a historical comparison has demonstrated the superiority of attenuated chemotherapy and mAb compared to conventional chemotherapy.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The next logical step was to introduce these mAbs in the treatment of young adult patients, either during induction and/or during consolidation, in this case without attenuating the intensity of chemotherapy, or by substituting some of its components, which would be followed by allo-HSCT in patients with high-risk criteria. There are also phase II clinical trials that have demonstrated several facts: the applicability and tolerability of this combination, the significant reduction in MRD after administration of mAbs, and the promising OS (around 80% at 1-year), although the follow-up is still scarce.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14–16</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The combination of mAb immunotherapy and molecular targeted therapy is a major step forward in some subgroups of B-precursor ALL, such as Philadelphia chromosome-positive ALL (Ph+ ALL). Since blinatumomab was shown to be effective in the R/R context,<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> the next step has been to incorporate it into first-line treatment, in combination with tyrosine kinase inhibitors (dasatinib or ponatinib).<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18–20</span></a> This has made possible, on the one hand, to eliminate chemotherapy in the initial treatment of the disease and, on the other hand, to increase the frequency of complete molecular response, which has led to a reduction in the need for allo-HSCT in these patients. The probability of OS greater than 90% at 1–2 years supports the efficacy of such an association.</p><p id="par0025" class="elsevierStylePara elsevierViewall">We are still far from achieving a cure for all adult patients with ALL. Strategies employed so far include the optimisation of chemotherapy (with the introduction of effective drugs such as asparaginase combined with polyethylene glycol at various stages of treatment), post-consolidation treatment (chemotherapy or allo-HCT) targeted according to the level of MRD, and the introduction of molecular targeted drugs, among others. However, with the caution implied by the still short follow-up of the clinical trials mentioned above, it is very likely that the introduction of mAb immunotherapy in the first-line treatment of ALL (in induction and/or consolidation) constitutes a step forward that allows to overcome the 40–50% of cures achieved with chemotherapy followed or not by allo-HSCT in young adults and the 10% that is achieved in elderly patients. Two facts are certain at the present time: such an association is tolerable and, secondly, it allows to reduce the level of MRD. It is well known that the amount of MRD is the main prognostic factor in ALL and correlates with the probability of relapse and OS. It is very likely that, with the increased follow-up of the above-mentioned clinical trials and with the results of phase III trials currently under development and ongoing, the use of mAbs in the initial treatment of B-precursor ALL in adults will be approved and funded within the National Health System in the near future. This would allow the use of CAR-T cell therapy, another highly effective immunotherapy strategy in ALL, to be brought forward to the first relapse (or even to the initial phases in very high-risk patients with ALL).</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0030" class="elsevierStylePara elsevierViewall">Research funded in part by the grant <span class="elsevierStyleGrantNumber" refid="gs0005">2017 SGR288</span> (GRC) <span class="elsevierStyleGrantSponsor" id="gs0005">Generalitat de Catalunya and "la Caixa" Foundation</span>.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflict of interests</span><p id="par0035" class="elsevierStylePara elsevierViewall">Josep-María Ribera participated as an investigator in the studies that led to the approval of blinatumomab and inotuzumab, sponsored by AMGEN and Pfizer, respectively, and has received research grants from both pharmaceutical companies.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflict of interests" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Ribera J-M, Torrent A. Anticuerpos monoclonales en el tratamiento de primera línea de la leucemia aguda linfoblástica en adultos: un paso adelante. Med Clin (Barc). 2022;158:476–477.</p>" ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Research partially funded by the grant 2017 SGR288 (GRC) Generalitat de Catalunya and “la Caixa” Foundation.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:20 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:5 [ 0 => "N. Gökbuget" 1 => "H. Dombret" 2 => "J.M. Ribera" 3 => "A.K. Fielding" 4 => "A. 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Journal Information
Vol. 158. Issue 10.
Pages 476-477 (May 2022)
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Vol. 158. Issue 10.
Pages 476-477 (May 2022)
Editorial article
Monoclonal antibodies in frontline therapy of adult acute lymphoblastic leukemia: A step ahead
Anticuerpos monoclonales en el tratamiento de primera línea de la leucemia aguda linfoblástica en adultos: un paso adelante
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Servicio de Hematología Clínica, ICO-Hospital Germans Trias i Pujol, Institut de Recerca Josep Carreras, Universitat Autònoma de Barcelona, Barcelona, Spain
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