Asparaginase use for the treatment of acute lymphoblastic leukemia

Barba, Pere; Dapena, José Luis; Montesinos, Pau; Rives, Susana
doi:10.1016/j.medcle.2017.03.002
 array:24 [
  "pii" => "S2387020617301705"
  "issn" => "23870206"
  "doi" => "10.1016/j.medcle.2017.03.002"
  "estado" => "S300"
  "fechaPublicacion" => "2017-03-08"
  "aid" => "3888"
  "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46;U&#46;. All rights reserved"
  "copyrightAnyo" => "2016"
  "documento" => "article"
  "crossmark" => 1
  "subdocumento" => "sco"
  "cita" => "Med Clin. 2017;148:225-31"
  "abierto" => array:3 [
    "ES" => false
    "ES2" => false
    "LATM" => false
  ]
  "gratuito" => false
  "lecturas" => array:1 [
    "total" => 0
  ]
  "Traduccion" => array:1 [
    "es" => array:19 [
      "pii" => "S002577531630673X"
      "issn" => "00257753"
      "doi" => "10.1016/j.medcli.2016.12.006"
      "estado" => "S300"
      "fechaPublicacion" => "2017-03-03"
      "aid" => "3888"
      "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46;U&#46;"
      "documento" => "article"
      "crossmark" => 1
      "subdocumento" => "sco"
      "cita" => "Med Clin. 2017;148:225-31"
      "abierto" => array:3 [
        "ES" => false
        "ES2" => false
        "LATM" => false
      ]
      "gratuito" => false
      "lecturas" => array:2 [
        "total" => 19
        "formatos" => array:2 [
          "HTML" => 15
          "PDF" => 4
        ]
      ]
      "es" => array:11 [
        "idiomaDefecto" => true
        "cabecera" => "<span class="elsevierStyleTextfn">Art&#237;culo especial</span>"
        "titulo" => "Asparaginasas en el tratamiento de la leucemia linfobl&#225;stica aguda"
        "tienePdf" => "es"
        "tieneTextoCompleto" => "es"
        "paginas" => array:1 [
          0 => array:2 [
            "paginaInicial" => "225"
            "paginaFinal" => "231"
          ]
        ]
        "titulosAlternativos" => array:1 [
          "en" => array:1 [
            "titulo" => "Asparaginase use for the treatment of acute lymphoblastic leukemia"
          ]
        ]
        "contieneTextoCompleto" => array:1 [
          "es" => true
        ]
        "contienePdf" => array:1 [
          "es" => true
        ]
        "resumenGrafico" => array:2 [
          "original" => 0
          "multimedia" => array:7 [
            "identificador" => "fig0010"
            "etiqueta" => "Figura 2"
            "tipo" => "MULTIMEDIAFIGURA"
            "mostrarFloat" => true
            "mostrarDisplay" => false
            "figura" => array:1 [
              0 => array:4 [
                "imagen" => "gr2.jpeg"
                "Alto" => 2035
                "Ancho" => 2968
                "Tamanyo" => 353122
              ]
            ]
            "descripcion" => array:1 [
              "es" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Algoritmo de actuaci&#243;n en caso de pancreatitis&#46;</p>"
            ]
          ]
        ]
        "autores" => array:1 [
          0 => array:2 [
            "autoresLista" => "Pere Barba, Jos&#233; Luis Dapena, Pau Montesinos, Susana Rives"
            "autores" => array:4 [
              0 => array:2 [
                "nombre" => "Pere"
                "apellidos" => "Barba"
              ]
              1 => array:2 [
                "nombre" => "Jos&#233; Luis"
                "apellidos" => "Dapena"
              ]
              2 => array:2 [
                "nombre" => "Pau"
                "apellidos" => "Montesinos"
              ]
              3 => array:2 [
                "nombre" => "Susana"
                "apellidos" => "Rives"
              ]
            ]
          ]
        ]
      ]
      "idiomaDefecto" => "es"
      "Traduccion" => array:1 [
        "en" => array:9 [
          "pii" => "S2387020617301705"
          "doi" => "10.1016/j.medcle.2017.03.002"
          "estado" => "S300"
          "subdocumento" => ""
          "abierto" => array:3 [
            "ES" => false
            "ES2" => false
            "LATM" => false
          ]
          "gratuito" => false
          "lecturas" => array:1 [
            "total" => 0
          ]
          "idiomaDefecto" => "en"
          "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020617301705?idApp=UINPBA00004N"
        ]
      ]
      "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S002577531630673X?idApp=UINPBA00004N"
      "url" => "/00257753/0000014800000005/v1_201702231707/S002577531630673X/v1_201702231707/es/main.assets"
    ]
  ]
  "itemSiguiente" => array:19 [
    "pii" => "S2387020617301730"
    "issn" => "23870206"
    "doi" => "10.1016/j.medcle.2016.10.054"
    "estado" => "S300"
    "fechaPublicacion" => "2017-03-08"
    "aid" => "3830"
    "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46;U&#46;"
    "documento" => "simple-article"
    "crossmark" => 1
    "subdocumento" => "crp"
    "cita" => "Med Clin. 2017;148:232-7"
    "abierto" => array:3 [
      "ES" => false
      "ES2" => false
      "LATM" => false
    ]
    "gratuito" => false
    "lecturas" => array:1 [
      "total" => 0
    ]
    "en" => array:10 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Diagnosis and treatment</span>"
      "titulo" => "Treatment of cognitive impairment in Parkinson disease"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "232"
          "paginaFinal" => "237"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "Tratamiento del deterioro cognitivo en la enfermedad de Parkinson"
        ]
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Carmen Gasca-Salas"
          "autores" => array:1 [
            0 => array:2 [
              "nombre" => "Carmen"
              "apellidos" => "Gasca-Salas"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "Traduccion" => array:1 [
      "es" => array:9 [
        "pii" => "S002577531630553X"
        "doi" => "10.1016/j.medcli.2016.10.027"
        "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/S002577531630553X?idApp=UINPBA00004N"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020617301730?idApp=UINPBA00004N"
    "url" => "/23870206/0000014800000005/v1_201704020027/S2387020617301730/v1_201704020027/en/main.assets"
  ]
  "itemAnterior" => array:19 [
    "pii" => "S2387020617301675"
    "issn" => "23870206"
    "doi" => "10.1016/j.medcle.2017.03.001"
    "estado" => "S300"
    "fechaPublicacion" => "2017-03-08"
    "aid" => "3879"
    "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46;U&#46;"
    "documento" => "article"
    "crossmark" => 1
    "subdocumento" => "rev"
    "cita" => "Med Clin. 2017;148:218-24"
    "abierto" => array:3 [
      "ES" => false
      "ES2" => false
      "LATM" => false
    ]
    "gratuito" => false
    "lecturas" => array:1 [
      "total" => 0
    ]
    "en" => array:13 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Review</span>"
      "titulo" => "Current status of iron metabolism&#58; Clinical and therapeutic implications"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "es"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "218"
          "paginaFinal" => "224"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "Estado actual del metabolismo del hierro&#58; implicaciones cl&#237;nicas y terap&#233;uticas"
        ]
      ]
      "contieneResumen" => array:2 [
        "en" => true
        "es" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:7 [
          "identificador" => "fig0005"
          "etiqueta" => "Fig&#46; 1"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr1.jpeg"
              "Alto" => 1041
              "Ancho" => 1734
              "Tamanyo" => 124041
            ]
          ]
          "descripcion" => array:1 [
            "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Body iron homeostasis&#46; The interaction of hepcidin with ferroportin &#40;FPN&#41; controls the main efflux of iron into plasma&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Susana Conde Diez, Ricardo de las Cuevas Allende, Eulogio Conde Garc&#237;a"
          "autores" => array:3 [
            0 => array:2 [
              "nombre" => "Susana"
              "apellidos" => "Conde Diez"
            ]
            1 => array:2 [
              "nombre" => "Ricardo"
              "apellidos" => "de las Cuevas Allende"
            ]
            2 => array:2 [
              "nombre" => "Eulogio"
              "apellidos" => "Conde Garc&#237;a"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "Traduccion" => array:1 [
      "es" => array:9 [
        "pii" => "S0025775316306649"
        "doi" => "10.1016/j.medcli.2016.10.047"
        "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/S0025775316306649?idApp=UINPBA00004N"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020617301675?idApp=UINPBA00004N"
    "url" => "/23870206/0000014800000005/v1_201704020027/S2387020617301675/v1_201704020027/en/main.assets"
  ]
  "en" => array:18 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">Special article</span>"
    "titulo" => "Asparaginase use for the treatment of acute lymphoblastic leukemia"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "225"
        "paginaFinal" => "231"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "Pere Barba, Jos&#233; Luis Dapena, Pau Montesinos, Susana Rives"
        "autores" => array:4 [
          0 => array:4 [
            "nombre" => "Pere"
            "apellidos" => "Barba"
            "email" => array:1 [
              0 => "pebarba&#64;vhebron&#46;net"
            ]
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;</span>"
                "identificador" => "cor0005"
              ]
            ]
          ]
          1 => array:3 [
            "nombre" => "Jos&#233; Luis"
            "apellidos" => "Dapena"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff0010"
              ]
            ]
          ]
          2 => array:3 [
            "nombre" => "Pau"
            "apellidos" => "Montesinos"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">c</span>"
                "identificador" => "aff0015"
              ]
            ]
          ]
          3 => array:3 [
            "nombre" => "Susana"
            "apellidos" => "Rives"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">d</span>"
                "identificador" => "aff0020"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:4 [
          0 => array:3 [
            "entidad" => "Servicio de Hematolog&#237;a&#44; Hospital Universitari Vall d&#8217;Hebr&#243;n&#44; Universidad Aut&#242;noma de Barcelona&#44; Barcelona&#44; Spain"
            "etiqueta" => "a"
            "identificador" => "aff0005"
          ]
          1 => array:3 [
            "entidad" => "Servicio de Oncolog&#237;a y Hematolog&#237;a pedi&#225;tricas&#44; Hospital Universitari Vall d&#8217;Hebr&#243;n&#44; Barcelona&#44; Spain"
            "etiqueta" => "b"
            "identificador" => "aff0010"
          ]
          2 => array:3 [
            "entidad" => "Hospital Universitari i Polit&#232;cnic la Fe&#44; Val&#232;ncia&#44; Spain"
            "etiqueta" => "c"
            "identificador" => "aff0015"
          ]
          3 => array:3 [
            "entidad" => "Hospital Universitari Sant Joan de D&#233;u&#44; Barcelona&#44; Spain"
            "etiqueta" => "d"
            "identificador" => "aff0020"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor0005"
            "etiqueta" => "&#8270;"
            "correspondencia" => "Corresponding author&#46;"
          ]
        ]
      ]
    ]
    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "Asparaginasas en el tratamiento de la leucemia linfobl&#225;stica aguda"
      ]
    ]
    "resumenGrafico" => array:2 [
      "original" => 0
      "multimedia" => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1802
            "Ancho" => 2841
            "Tamanyo" => 151029
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Management algorithm for asparaginase hypersensitivity reactions&#46; <span class="elsevierStyleSup">a</span>If an asparaginase activity test cannot be performed&#44; and differentiation between an infusional or a hypersensitivity reaction is not possible&#44; a formulation change is recommended&#44; either to PEG-asparaginase or to <span class="elsevierStyleItalic">Erwinia</span> asparaginase&#46; <span class="elsevierStyleSup">b</span>Mainly&#44; a change to <span class="elsevierStyleItalic">Erwinia</span> L-ASA to avoid cross-reactivity&#46; <span class="elsevierStyleSup">c</span>Not recommended&#46; It can be considered in cases of very severe reaction and if the formulation cannot be changed and&#47;or if the planned treatment has been almost completed&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Acute lymphoblastic leukaemia &#40;ALL&#41; is a rare neoplastic disease whose peak of incidence ranges between 2 and 5 years of age&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a> Asparaginase &#40;L-ASA&#41; is considered an essential drug in its treatment&#46; It is an enzyme from cultures of <span class="elsevierStyleItalic">Escherichia coli &#40;E&#46; coli&#41;</span> and of <span class="elsevierStyleItalic">Chrysantemii Erwinia &#40;E&#46; chrysantemii&#41;</span> with the ability to hydrolyse L-asparagine converting it into aspartic acid and ammonium&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a> Normal cells are able to synthesize this amino acid <span class="elsevierStyleItalic">de novo</span>&#44; but in leukemic cells&#44; L-asparagine extracellular depletion causes cell cycle arrest and inhibition of protein synthesis by inducing cell apoptosis&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a> Depletion of L-asparagine is also associated with decreased synthesis of other proteins as albumin&#44; insulin&#44; fibrinogen and clotting factors&#44; resulting in L-ASA-specific homeostatic abnormalities&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">4&#44;5</span></a> Despite its strong anti-leukemic efficacy&#44; especially demonstrated in childhood ALL&#44;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">6&#44;7</span></a> this drug has been used less frequently in adult ALL protocols&#44; because its specific toxic effects increase with age&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">8&#44;9</span></a> The use of L-ASA in adults is also limited by the lower tolerability of conventional multidrug therapy regimens&#44; especially in older patients&#46; Therefore&#44; L-ASA is a little-known drug&#44; especially in among haematologists who treat adult patients&#44; in whom the disease is less prevalent&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Methodology and objectives</span><p id="par0010" class="elsevierStylePara elsevierViewall">Four Spanish doctors with extensive experience in the treatment of ALL in paediatric patients &#40;JLD and SR&#41; and adults &#40;PB and PM&#41; participated in the design and development of this article&#46; A comprehensive literature search of the most relevant aspects of asparaginase in the treatment of ALL was performed&#46; The authors shared their clinical experience and therapeutic approaches&#44; discussed algorithms and recommendations and participated in drafting and revising the manuscript in various face-to-face and virtual meetings&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Types of asparaginase</span><p id="par0015" class="elsevierStylePara elsevierViewall">L-ASA is marketed in 3 forms &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0020" class="elsevierStylePara elsevierViewall">Derived from native <span class="elsevierStyleItalic">E&#46; coli&#46;</span> It is the most commonly used formulation&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0025" class="elsevierStylePara elsevierViewall">Derived from the <span class="elsevierStyleItalic">E&#46; chrysanthemi bacteria&#46;</span> It is used in patients who have developed hypersensitivity to native <span class="elsevierStyleItalic">E&#46; coli</span> L-ASA and Peg-asparaginase &#40;PEG-ASP&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0030" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">E&#46; coli</span> asparaginase conjugated with polyethylene glycol &#40;PEG-ASP&#41;&#46; Indicated as part of the ALL combined cytostatic treatment in paediatric and adult patients&#46;</p></li></ul></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Dose&#44; dose equivalence&#44; frequency and route of administration</span><p id="par0035" class="elsevierStylePara elsevierViewall">L-ASA can be used intravenously &#40;IV&#41; or intramuscularly &#40;IM&#41;&#46; The plasma concentration of L-ASA depends on the dose administered&#44; obtaining the peak plasma concentration with IM&#44; half of what is obtained IV&#46; Abbott et al&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a> allergic reactions evaluated PEG-ASP according to the route used&#44; observing an increased frequency of allergic reactions in patients using the IV route&#46; Petersen et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a> in a similar study&#44; showed that intravenous administration was associated with a higher incidence of reactions and an earlier onset of the same&#44; although with a similar severity profile&#46; In another study with PEG-ASP&#44; more local reactions were observed using the IM route&#44; while with IV these were more systemic&#44; although less severe&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Regarding PEG-ASP&#39;s action duration&#44; it has a longer half-life&#44; providing a longer asparagine depletion period after a single dose&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a> L-ASA of native <span class="elsevierStyleItalic">E&#46; coli</span> and <span class="elsevierStyleItalic">Erwinia</span> have a much shorter half-life and must be administered more frequently to maintain asparagine depletion &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The recommended doses for native <span class="elsevierStyleItalic">E&#46; coli</span> L-ASA are 5000&#8211;10&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span>&#47;48&#8211;72<span class="elsevierStyleHsp" style=""></span>h&#44; for <span class="elsevierStyleItalic">Erwinia</span> L-ASA 20&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span>&#47;48<span class="elsevierStyleHsp" style=""></span>h &#40;3 times&#47;week&#41;&#44; and PEG-ASP 1000&#8211;2500<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> every 2 weeks&#46; In general&#44; each dose of 10&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> of native <span class="elsevierStyleItalic">E&#46; coli</span> L-ASA should be replaced by 20&#44;000&#8211;25&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> of <span class="elsevierStyleItalic">Erwinia L-ASA&#46;</span> The replacement dose of <span class="elsevierStyleItalic">Erwinia</span> L-ASA in patients suffering from hypersensitivity to PEG-ASP would be 25&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> administered IV or IM &#40;mon-wed-fri&#41; for 2 weeks&#44; per dose of PEG-ASP&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Using asparaginase according to current protocols</span><p id="par0050" class="elsevierStylePara elsevierViewall">The Spanish protocol for childhood ALL &#40;LAL&#47;SEHOP-PETHEMA 2013&#41; differentiates 3 risk groups&#44; each with a different adapted treatment&#46; The treatment is less intensive in low risk patients&#44; with 2 inductions&#44; one consolidation&#44; one re-induction and a prolonged maintenance&#46; Both phases of induction and re-induction contain native L-ASA &#40;12 doses of 10&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> IM&#41;&#46; In the cases of intermediate-risk children&#44; their maintenance also contains 10 doses of 1000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> of PEG-ASP IM&#46; In those with high risk&#44; an additional dose of 1000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> of PEG-ASP IM is administered in each of the three intensifications and 2 equal doses of PEG-ASP in each of the three re-inductions&#44; without PEG-ASP during maintenance&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Regarding adult ALL&#44; the PETHEMA group offers protocols adapted to the risk of relapse&#44; age and ALL subtype&#46; Teenagers and young adults &#40;up to 30 years&#41; receive a protocol based on paediatric regimens &#40;ALL-RI-2008&#41;&#46; This protocol contains 8 doses of 10&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> of native IV L-ASA for induction and consolidation&#44; and up to 6 doses of 20&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> during re-inductions&#46; For patients with very high risk&#44; generally over 30 years of age&#44; the ALL-AR-2011 protocol contains IV native L-ASA &#40;4 doses of 10&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> in induction and 6 doses of 20&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> in consolidation&#44; it is omitted at re-induction and maintenance&#41; or IV PEG-ASP &#40;a dose of 2000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> in induction and up to 6 doses 2000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> in consolidation&#41;&#46; It is recommended to administer 50&#37; of the native L-ASA and PEG-ASP doses in patients over 50 years of age&#46; The protocol for those over 55 years of age &#40;ALL-Old-2007&#41; only contains 6 doses of 10&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> native L-ASA&#44; all in consolidation&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">One of the features in the PETHEMA and SEHOP protocols is the role of <span class="elsevierStyleItalic">E&#46; chrysantemii</span>&#44; L-ASA which would be indicated as the first alternative to native L-ASA and PEG-ASP in case of allergic reaction or prior hypersensitivity&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Drug interactions</span><p id="par0065" class="elsevierStylePara elsevierViewall">Because of its effect on liver function&#44; L-ASA can cause increased toxicity of hepatotoxic drugs with hepatic metabolism or attached to plasma proteins&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a> Therefore&#44; these recommendations should be observed when using the following drugs commonly used in ALL&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0070" class="elsevierStylePara elsevierViewall">Vincristine&#58; should not be administered together with L-ASA&#44; as it may increase its toxicity &#40;neurotoxicity&#41; and the risk of allergic reactions &#40;administer it 3&#8211;24<span class="elsevierStyleHsp" style=""></span>h before L-ASA&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0075" class="elsevierStylePara elsevierViewall">Glucocorticoids and&#47;or anticoagulants&#58; its concomitant use increases the risk of clotting disorders&#44; favouring a tendency to bleed &#40;anticoagulants&#41; or to develop thrombotic disorders &#40;glucocorticoids&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">-</span><p id="par0080" class="elsevierStylePara elsevierViewall">Methotrexate &#40;MTX&#41;&#58; inhibition of protein synthesis secondary to L-ASA-induced asparagine concentration decrease attenuates the cytotoxic effect of MTX&#44; as cell replication is necessary for the antineoplastic activity of this drug&#46; This antagonism occurs if L-ASA is administered prior to or in combination with MTX&#46; In contrast&#44; the antitumor effects of MTX increase when L-ASA is administered 24<span class="elsevierStyleHsp" style=""></span>h after treatment with MTX&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">-</span><p id="par0085" class="elsevierStylePara elsevierViewall">Cytarabine&#58; <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span> data indicate that the efficacy of cytarabine at high-doses decreases when administered before L-ASA&#46; However&#44; a synergistic effect was observed when L-ASA was administered after cytarabine&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">-</span><p id="par0090" class="elsevierStylePara elsevierViewall">Oral contraceptives are not recommended to be used as L-ASA hepatotoxicity can affect the hepatic clearance of these&#46;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">-</span><p id="par0095" class="elsevierStylePara elsevierViewall">Avoid concomitant administration of PEG-ASP with live virus vaccines&#44; BCG&#44; belimumab&#44; natalizumab&#44; pimecrolimus or tacrolimus &#40;topical&#41;&#46; Patients should be carefully monitored if PEG-ASP is administered concomitantly with attenuated virus vaccines&#44; denosumab or trastuzumab&#46;</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">-</span><p id="par0100" class="elsevierStylePara elsevierViewall">Thyroxine&#58; L-ASA produces a decrease in serum thyroxine&#46;</p></li></ul></p><p id="par0105" class="elsevierStylePara elsevierViewall">However&#44; many of these drugs are commonly used in the treatment of ALL and co-administration may be inevitable&#46; It is therefore important to follow the directions about the drugs&#8217; order of administration and be attentive to their potential toxicities&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Adverse effects</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Hypersensitivity</span><p id="par0110" class="elsevierStylePara elsevierViewall">Hypersensitivity is one of the most common adverse reactions associated with the use of L-ASA&#46; It is one of the most important complications due to the potential severity and therapeutic and prognostic implications involved in its development&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The incidence ranges from 0 to 50&#37;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">6&#44;14</span></a> in children and around 15&#37; in adults&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a> The incidence is higher with native L-ASA&#44; while PEG-ASP and <span class="elsevierStyleItalic">Erwinia</span> L-ASA have shown a lower incidence&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">15</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Hypersensitivity reactions have been associated with the generation of antibodies against bacterial proteins&#46; Most episodes occur during re-exposure&#44; with consolidation and maintenance being the phases where these most frequently occur&#46; The IV route has been associated classically with increased risk&#44; although recent studies have not confirmed it&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">15&#44;16</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The severity of hypersensitivity reactions range from grade 1&#44; with isolated hives or hypotension that does not require fluids to grade 4&#44; with hypotension and anaphylactic shock &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; The vast majority are grade 1&#8211;2 and often appear as local reactions at the puncture site when administered intramuscularly&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">16</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">Patient monitoring during the 2<span class="elsevierStyleHsp" style=""></span>h after administration of L-ASA is recommended&#46; Most reactions occur within the first hour&#44; although IM route and the use of PEG-ASP can cause delayed reactions&#46; It is therefore advisable to instruct the patient and his&#47;her companions on delayed reaction detection&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">The use of premedication to prevent the development of hypersensitivity reactions is widespread&#44; although there is little scientific evidence to support it&#46; In addition&#44; their use could mask reactions that would highlight the presence of inactivated antibodies&#46; Since glucocorticoids are part of the treatment of ALL&#44; it seems advisable to administer L-ASA after the glucocorticoid dose&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">The treatment will vary depending on severity and presentation&#46; IV fluid therapy or fast-acting glucocorticoids &#40;hydrocortisone&#41; may be useful in most cases of grade 3&#8211;4&#46; More intensive measures and transfer to an ICU may be needed in more severe situations&#46;</p><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Prognostic implications&#44; changes and suspension of asparaginase</span><p id="par0145" class="elsevierStylePara elsevierViewall">Several studies have shown the importance of L-ASA as an essential part of the treatment of ALL&#44; and how patients that can complete treatment with L-ASA have better survival than those who have to stop treatment&#46; Two studies have shown that&#44; if after a hypersensitivity reaction to native or PEGylated L-ASA&#44; patients received <span class="elsevierStyleItalic">Erwinia</span> L-ASA&#44; these had a similar survival to those who never developed hypersensitivity&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">8&#44;17</span></a> It is therefore advisable to maintain the treatment with L-ASA&#44; either using the same or different formulation &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0150" class="elsevierStylePara elsevierViewall">Patients developing a grade 2&#8211;4 hypersensitivity should continue treatment with a different L-ASA&#46; <span class="elsevierStyleItalic">Erwinia</span> L-ASA would be recommended if the L-ASA used as first-line was the native <span class="elsevierStyleItalic">E&#46; coli</span>&#46; If <span class="elsevierStyleItalic">Erwinia</span> L-ASA is not available&#44; it could be switched to PEG-ASP&#44; but&#44; in these cases&#44; it is recommended to measure the levels of activity due to the possibility of cross-reactivity&#46; If the reaction occurs because of PEG-ASP&#44; it is advisable to use <span class="elsevierStyleItalic">Erwinia</span> L-ASA&#44; as there would be a high risk of developing a reaction of hypersensitivity with native <span class="elsevierStyleItalic">E&#46; coli</span> L-ASA&#46; As for the time of administration of the new formulation&#44; it seems advisable to start early &#40;24&#8211;48<span class="elsevierStyleHsp" style=""></span>h after the reaction&#41;&#44; providing the patient has recovered&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">In grade 1 hypersensitivity reactions&#44; an infusion reaction must be ruled out&#46; The L-ASA activity test determination would distinguish between a hypersensitivity reaction&#44; which often leads to a decrease in the activity of L-ASA below the minimum level of activity &#40;1&#46;00<span class="elsevierStyleHsp" style=""></span>IU&#47;l&#41;&#44; and an infusion reaction that would not mean a decrease in activity and would allow us to continue with the same treatment&#46; In case of grade 2&#8211;4 hypersensitivity&#44; the L-ASA formulation should be changed&#46; If this change is not viable&#44; a method which is underused and does not solve the silent inactivation&#44; would be a desensitization with increasing doses of L-ASA&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">18</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Due to all these implications&#44; it is essential to confirm that the reaction was due to the use of L-ASA and rule out any other cause&#44; especially of infectious origin&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Recommendations&#58;</span><ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">1&#46;</span><p id="par0170" class="elsevierStylePara elsevierViewall">Monitor the patient during the first hour after administration of L-ASA in the native form and during 2<span class="elsevierStyleHsp" style=""></span>h in the case of PEG-ASP&#46;</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">2&#46;</span><p id="par0175" class="elsevierStylePara elsevierViewall">Instruct the patient and their companions on the detection of delayed reactions&#46;</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">3&#46;</span><p id="par0180" class="elsevierStylePara elsevierViewall">Perform a L-ASA activity test after the hypersensitivity episode to rule out the inactivation of the drug&#46;</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">4&#46;</span><p id="par0185" class="elsevierStylePara elsevierViewall">Schedule the administration of L-ASA following the dose of glucocorticoids&#46;</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">5&#46;</span><p id="par0190" class="elsevierStylePara elsevierViewall">Do not use additional premedication with antihistamines and glucocorticoids&#46;</p></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">6&#46;</span><p id="par0195" class="elsevierStylePara elsevierViewall">L-ASA should be maintained whenever possible&#44; either with the same formulation or a different one&#46;</p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">7&#46;</span><p id="par0200" class="elsevierStylePara elsevierViewall">Change formulation in the case of a grade 2&#8211;4 hypersensitivity reaction&#46;</p></li><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">8&#46;</span><p id="par0205" class="elsevierStylePara elsevierViewall">Switch to <span class="elsevierStyleItalic">Erwinia</span> L-ASA if the L-ASA used in first line was native or PEGylated&#44; according to equivalent doses &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; If <span class="elsevierStyleItalic">Erwinia</span> L-ASA is not available&#44; it could be changed to PEG-ASP after a hypersensitivity reaction to native <span class="elsevierStyleItalic">E&#46; coli</span> L-ASA&#46;</p></li></ul></p></span></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Silent inactivation</span><p id="par0210" class="elsevierStylePara elsevierViewall">L-ASA frequently causes the formation of antibodies that can inactivate it&#46; These antibodies are not associated with hypersensitivity reaction in 8&#8211;33&#37; of cases&#44; but cause L-ASA inactivation which is associated with reduced efficacy&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">Silent inactivation can be detected by&#58;<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">1&#41;</span><p id="par0220" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Determination of asparagine concentration in plasma</span>&#46; Technically difficult because the enzyme still acts <span class="elsevierStyleItalic">ex vivo</span> if the blood sample is not kept on ice and processed immediately&#46;</p></li><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">2&#41;</span><p id="par0225" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Detection of antibodies against L-ASA</span>&#46; Sensitive but unspecific&#44; since not all antibodies have neutralizing activity&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a></p></li><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">3&#41;</span><p id="par0230" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Measurement of the enzymatic activity of L-ASA</span>&#46; It correlates with the level of asparagine depletion and is reliable&#46; With L-ASA serum activity levels above 100<span class="elsevierStyleHsp" style=""></span>IU&#47;l&#44; asparagine depletion is achieved below the quantification levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">2&#44;20</span></a> Monitoring the activity of L-ASA allows to detect silent inactivation and individualize the dose to achieve the therapeutic range&#46;</p></li></ul></p><p id="par0235" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Recommendations</span></p><p id="par0240" class="elsevierStylePara elsevierViewall">In cases of silent inactivation&#58;<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">1&#46;</span><p id="par0245" class="elsevierStylePara elsevierViewall">Monitor L-ASA&#39;s enzymatic activity levels&#44; whenever possible&#44; which should be &#8805;100<span class="elsevierStyleHsp" style=""></span>IU&#47;l&#46;</p></li><li class="elsevierStyleListItem" id="lsti0115"><span class="elsevierStyleLabel">2&#46;</span><p id="par0250" class="elsevierStylePara elsevierViewall">Change L-ASA&#39;s formulation for another without cross reactivity&#46; There is no cross-reaction between native L-ASA or <span class="elsevierStyleItalic">E&#46; coli</span> PEG-ASP with <span class="elsevierStyleItalic">Erwinia</span> L-ASA&#44; so&#44; in these cases&#44; it would be of choice&#46;</p></li></ul></p><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Thrombosis</span><p id="par0255" class="elsevierStylePara elsevierViewall">Both thrombosis and haemorrhage associated with L-ASA occur in 90&#37; of cases during the induction phase&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a> probably due to multiple factors such as concomitant use of central venous catheter&#44; glucocorticoid treatment and the neoplastic growth itself&#46; Although the effects of L-ASA occur in procoagulant factors &#40;hypofibrinogenemia&#44; decreased factor IX&#44; X and plasminogen&#41; and anticoagulants &#40;decreased antithrombin III&#44; protein C and S&#41;&#44; clinical manifestations usually reflect a prothrombotic state&#46; Antithrombin III deficiency favours the generation of thrombin and fibrinogen and&#44; secondarily&#44; an increase of fibrinogen degradation products and factor consumption&#46; The reported incidence of thrombosis ranges between 1&#37; and 36&#37;&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">Age is a risk factor and children have a lower predisposition&#46; The presence of at least one inherited thrombophilic factor has been associated with an increased risk of thrombosis in children&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">According to a meta-analysis in the paediatric population&#44;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a> thrombotic episodes were associated more frequently with the use of low doses of L-ASA in longer periods of time&#46; Other factors were the use of prednisone &#40;instead of dexamethasone&#41; and anthracyclines&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Recommendations</span><ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0120"><span class="elsevierStyleLabel">1&#46;</span><p id="par0275" class="elsevierStylePara elsevierViewall">The use of L-ASA should be discontinued temporarily in the case of clinically significant bleeding or thrombotic episodes&#46;</p></li><li class="elsevierStyleListItem" id="lsti0125"><span class="elsevierStyleLabel">2&#46;</span><p id="par0280" class="elsevierStylePara elsevierViewall">L-ASA should be discontinued in the acute phase of venous thrombosis&#46;</p></li><li class="elsevierStyleListItem" id="lsti0130"><span class="elsevierStyleLabel">3&#46;</span><p id="par0285" class="elsevierStylePara elsevierViewall">Patients with deep venous thrombosis should receive anticoagulant therapy&#44; preferably with low molecular weight heparin &#40;LMWH&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0135"><span class="elsevierStyleLabel">4&#46;</span><p id="par0290" class="elsevierStylePara elsevierViewall">Once the symptoms and the thrombus are resolved&#44; re-exposure to L-ASA under prophylaxis with LMWH may be feasible and safe&#46; LMWH should be administered at anticoagulant doses during the first 3&#8211;6 months and if the thrombus is resolved&#44; move on to prophylactic doses each time the patient receives L-ASA from the day before until 15 days after the last dose of L-ASA&#46;</p></li><li class="elsevierStyleListItem" id="lsti0140"><span class="elsevierStyleLabel">5&#46;</span><p id="par0295" class="elsevierStylePara elsevierViewall">Primary prophylaxis with LMWH should be performed in patients with increased risk of thrombosis until the risk period is over &#40;from one day before the start of treatment with L-ASA until 15 days later&#41;&#46; Repeat every time L-ASA is administered&#46;</p></li></ul></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Haemorrhage</span><p id="par0300" class="elsevierStylePara elsevierViewall">The incidence of bleeding complications by L-ASA is estimated to be between 5&#37; &#40;children&#41; and 40&#37; &#40;in adults&#41;&#46; The incidence of intracranial haemorrhage is less than 0&#46;5&#37; in both adults and paediatric patients&#46; The same ALL can lead to an initial coagulopathy unrelated to chemotherapy which may increase the risk of bleeding and thrombotic episodes&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a> In these cases&#44; in addition to starting chemotherapy treatment as early as possible&#44; we must establish measures to prevent bleeding in the cytoreduction or debulking phase &#40;transfusions of platelets and plasma correction times&#41;&#46;</p><p id="par0305" class="elsevierStylePara elsevierViewall">Haemorrhagic complications of L-ASA are rare despite the high frequency of hypofibrinogenemia induced by this drug&#46; The attitude towards hypofibrinogenemia is not clearly established&#58; in children&#44; fibrinogen determination is not usually done&#59; in adults&#44; some authors recommend fibrinogen or cryoprecipitate transfusion whenever serum levels are lower than 50&#8211;150<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#44; while others only indicate replacement when bleeding occurs&#44; monitoring fibrinogen levels weekly&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Recommendations</span><ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0145"><span class="elsevierStyleLabel">1&#46;</span><p id="par0315" class="elsevierStylePara elsevierViewall">Fibrinogen levels should be monitored at least weekly in adult patients receiving L-ASA&#46;</p></li><li class="elsevierStyleListItem" id="lsti0150"><span class="elsevierStyleLabel">2&#46;</span><p id="par0320" class="elsevierStylePara elsevierViewall">Do not replace plasma factors through transfusions of fresh frozen plasma as this product could reverse L-ASA-induced asparagine depletion&#44; and thus reduce the antileukemic efficacy&#46;</p></li><li class="elsevierStyleListItem" id="lsti0155"><span class="elsevierStyleLabel">3&#46;</span><p id="par0325" class="elsevierStylePara elsevierViewall">In case of cerebral thrombosis&#44; administer anticoagulation effectively and correct coagulation disorders that favour haemorrhagic transformation&#44; such as severe thrombocytopenia or hypofibrinogenemia&#46;</p></li><li class="elsevierStyleListItem" id="lsti0160"><span class="elsevierStyleLabel">4&#46;</span><p id="par0330" class="elsevierStylePara elsevierViewall">Whenever any grade 3&#8211;4 bleeding event occurs&#44; such as a cerebral haemorrhage&#44; discontinue L-ASA administration&#46; This would be final if the causal relationship is clearly established&#46;</p></li></ul></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Pancreatitis</span><p id="par0335" class="elsevierStylePara elsevierViewall">The incidence of pancreatitis is around 5&#8211;10&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">1&#44;22</span></a> Diagnosis is based on clinical criteria &#40;abdominal pain&#44; nausea and vomiting&#41; associated with laboratory &#40;elevated amylase and lipase&#41; and&#47;or radiological criteria&#46; In most patients&#44; it is mild or moderate&#44; although severe in some&#44; with pseudocysts or multiple organ failure that can be fatal&#46; It can occur without a significant elevation of both pancreatic enzymes in up to a quarter of patients with pancreatitis&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a> It has been suggested that there might be a genetic predisposition for its development&#44;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a> and polymorphisms have been described involving L-ASA&#39;s action pathway genes&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a></p><p id="par0340" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Recommendations</span></p><p id="par0345" class="elsevierStylePara elsevierViewall">Pancreatitis should be suspected in all patients receiving L-ASA who develop abdominal and&#47;or back pain&#46;<ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0165"><span class="elsevierStyleLabel">1&#46;</span><p id="par0350" class="elsevierStylePara elsevierViewall">When an asymptomatic elevation of amylase and lipase occurs&#44; a temporary suspension of L-ASA is recommended&#44; restarting after normalization&#46;</p></li><li class="elsevierStyleListItem" id="lsti0170"><span class="elsevierStyleLabel">2&#46;</span><p id="par0355" class="elsevierStylePara elsevierViewall">Analgesia and supportive treatment should be administered &#40;nutritional support&#44; haemodynamic stabilization in severe forms and antibiotics in cases where infection cannot be ruled out&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0175"><span class="elsevierStyleLabel">3&#46;</span><p id="par0360" class="elsevierStylePara elsevierViewall">Octreotide may be administered&#44; although its role is not well defined&#46;</p></li><li class="elsevierStyleListItem" id="lsti0180"><span class="elsevierStyleLabel">4&#46;</span><p id="par0365" class="elsevierStylePara elsevierViewall">Drug suspension until complete resolution of symptoms and laboratory abnormalities&#44; reintroducing it in mild to moderate cases &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#44; after individual assessment of risks <span class="elsevierStyleItalic">versus</span> benefits&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0185"><span class="elsevierStyleLabel">5&#46;</span><p id="par0370" class="elsevierStylePara elsevierViewall">In severe cases&#44; it should be suspended indefinitely&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">24</span></a></p></li></ul></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Hepatotoxicity</span><p id="par0375" class="elsevierStylePara elsevierViewall">It is difficult to establish the frequency of L-ASA-induced hepatotoxicity&#44; since multiple concurrent causes can contribute&#44; although it is a common complication associated with the use of this drug&#46; The diagnosis of L-ASA-induced hepatotoxicity should be strengthened if there is liver involvement with a pattern of cholestasis accompanied by some grade of hypoalbuminemia&#44; hypertriglyceridemia&#44; hypoglycaemia&#44; hyperammonemia&#44; or hypofibrinogenemia&#46; In paediatric series&#44; the incidence of any grade of L-ASA-induced hepatotoxicity is between 30&#37; and 60&#37;&#44; while the frequency of grades 3&#8211;4 is between 3&#37; and 7&#37;&#44; with either L-native ASA&#44; <span class="elsevierStyleItalic">Erwinia</span> or PEG-ASP&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a> In adults&#44; the frequency of grade 3&#8211;4 hepatotoxicity may be between 14 and 52&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a></p><p id="par0380" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Recommendations</span><ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0190"><span class="elsevierStyleLabel">1&#46;</span><p id="par0385" class="elsevierStylePara elsevierViewall">Rule out other treatable causes of liver disease and avoid concomitant hepatotoxic drugs&#46;</p></li><li class="elsevierStyleListItem" id="lsti0195"><span class="elsevierStyleLabel">2&#46;</span><p id="par0390" class="elsevierStylePara elsevierViewall">Close monitoring of liver&#44; metabolic and coagulation function&#46;</p></li><li class="elsevierStyleListItem" id="lsti0200"><span class="elsevierStyleLabel">3&#46;</span><p id="par0395" class="elsevierStylePara elsevierViewall">When administering PEG-ASP&#44; as its half-life is 6 days&#44; its toxic effect can last up to 15 days from time of administration&#44; so hepatotoxicity could be more frequent&#44; and perhaps more serious&#44; at least in adult patients who are more susceptible and have less hepatic reserve&#46;</p></li><li class="elsevierStyleListItem" id="lsti0205"><span class="elsevierStyleLabel">4&#46;</span><p id="par0400" class="elsevierStylePara elsevierViewall">Suspend the remaining doses of L-ASA if grade 3&#8211;4 hepatotoxicity occurs&#44; until the biochemical parameters of liver function are normalized&#46; Patients with signs and symptoms of hepatic encephalopathy or with very pronounced toxicities &#40;bilirubin &#62;10&#8211;15<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#41; should be hospitalized&#46;</p></li><li class="elsevierStyleListItem" id="lsti0210"><span class="elsevierStyleLabel">5&#46;</span><p id="par0405" class="elsevierStylePara elsevierViewall">If toxicity was caused by <span class="elsevierStyleItalic">Erwinia</span> or native L-ASA&#44; both with short half-life&#44; it would be reasonable to reintroduce L-ASA at protocol-specified doses under close monitoring&#44; resuspending if grade 3&#8211;4 hepatotoxicity reoccur&#46; If hepatotoxicity was PEG-ASP-induced&#44; it seems reasonable not to administer this drug and&#44; instead&#44; offer the patient a short half-life L-ASA form&#46;</p></li></ul></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Neurological toxicity</span><p id="par0410" class="elsevierStylePara elsevierViewall">The incidence of nonvascular neurological complications appears to be higher in adult patients compared to paediatric&#44; although it is below 10&#37; in both cases&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">26</span></a> Visual abnormalities&#44; seizures&#44; lethargy and coma are among the most common forms&#46; The development of reversible posterior leukoencephalopathy syndrome has also been described&#44; which has a characteristic radiologic translation in the occipital region of the MRI&#39;s T2 sequence&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">27</span></a></p><p id="par0415" class="elsevierStylePara elsevierViewall">The development of hyperammonemia associated with L-ASA has been suggested as a possible mechanism&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">28</span></a> Notably&#44; the high risk of neurological complications with other drugs used for the treatment of ALL &#40;MTX&#44; vincristine&#44; glucocorticoids&#41; makes it difficult to attribute the cause of the neurological disorder only to L-ASA&#46;</p><p id="par0420" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Recommendations</span><ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0215"><span class="elsevierStyleLabel">1&#46;</span><p id="par0425" class="elsevierStylePara elsevierViewall">Assess the risk&#8211;benefit of continuing treatment for each patient&#44; considering the characteristics of the complication&#44; the risk of disease and the L-ASA&#39;s administered&#47;pending doses&#46;</p></li><li class="elsevierStyleListItem" id="lsti0220"><span class="elsevierStyleLabel">2&#46;</span><p id="par0430" class="elsevierStylePara elsevierViewall">In severe complications&#44; such as reversible posterior leukoencephalopathy syndrome or generalized seizures temporary or permanent discontinuation of L-ASA should be considered&#46;</p></li></ul></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Hyperglycaemia</span><p id="par0435" class="elsevierStylePara elsevierViewall">L-ASA-induced hyperglycaemia is caused by a decrease in insulin production&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">29</span></a> Hyperglycaemia occurs in up to 23&#37; of paediatric patients and in up to 76&#37; of adults&#44; although grade 3&#8211;4 affects to less than a quarter and can be linked to glucocorticoids&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a> A short insulin treatment may be required for some of these patients&#44; although the vast majority of them normalize blood glucose levels after treatment with L-ASA is completed&#46; The incidence of serious complications associated with hyperglycaemia &#40;such as ketoacidosis&#41; is very rare&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Recommendations</span><p id="par0440" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0055"><li class="elsevierStyleListItem" id="lsti0225"><span class="elsevierStyleLabel">1&#46;</span><p id="par0445" class="elsevierStylePara elsevierViewall">Frequent determination of blood glucose in patients receiving L-ASA&#46;</p></li><li class="elsevierStyleListItem" id="lsti0230"><span class="elsevierStyleLabel">2&#46;</span><p id="par0450" class="elsevierStylePara elsevierViewall">Maintaining treatment with L-ASA with an adequate dietary and pharmacological control of blood glucose is generally safe&#46;</p></li><li class="elsevierStyleListItem" id="lsti0235"><span class="elsevierStyleLabel">3&#46;</span><p id="par0455" class="elsevierStylePara elsevierViewall">In cases of ketoacidosis it may be necessary to temporarily or permanently suspend the administration of L-ASA&#46;</p></li></ul></p></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Authorship</span><p id="par0460" class="elsevierStylePara elsevierViewall">All authors have contributed equally to the completion of this work&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflict of interests</span><p id="par0465" class="elsevierStylePara elsevierViewall">PB&#44; JLD&#44; PM and SR have participated in consultancy activities for Jazz Pharmaceuticals Inc&#46; and Shire-Baxalta&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:11 [
        0 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        1 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Methodology and objectives"
        ]
        2 => array:3 [
          "identificador" => "sec0015"
          "titulo" => "Types of asparaginase"
          "secciones" => array:1 [
            0 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Dose&#44; dose equivalence&#44; frequency and route of administration"
            ]
          ]
        ]
        3 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Using asparaginase according to current protocols"
        ]
        4 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Drug interactions"
        ]
        5 => array:3 [
          "identificador" => "sec0035"
          "titulo" => "Adverse effects"
          "secciones" => array:1 [
            0 => array:3 [
              "identificador" => "sec0040"
              "titulo" => "Hypersensitivity"
              "secciones" => array:1 [
                0 => array:2 [
                  "identificador" => "sec0045"
                  "titulo" => "Prognostic implications&#44; changes and suspension of asparaginase"
                ]
              ]
            ]
          ]
        ]
        6 => array:3 [
          "identificador" => "sec0050"
          "titulo" => "Silent inactivation"
          "secciones" => array:7 [
            0 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Thrombosis"
            ]
            1 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Haemorrhage"
            ]
            2 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "Pancreatitis"
            ]
            3 => array:2 [
              "identificador" => "sec0070"
              "titulo" => "Hepatotoxicity"
            ]
            4 => array:2 [
              "identificador" => "sec0075"
              "titulo" => "Neurological toxicity"
            ]
            5 => array:2 [
              "identificador" => "sec0080"
              "titulo" => "Hyperglycaemia"
            ]
            6 => array:2 [
              "identificador" => "sec0085"
              "titulo" => "Recommendations"
            ]
          ]
        ]
        7 => array:2 [
          "identificador" => "sec0090"
          "titulo" => "Authorship"
        ]
        8 => array:2 [
          "identificador" => "sec0095"
          "titulo" => "Conflict of interests"
        ]
        9 => array:2 [
          "identificador" => "xack276262"
          "titulo" => "Acknowledgements"
        ]
        10 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2016-11-22"
    "fechaAceptado" => "2016-12-04"
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Barba P&#44; Dapena JL&#44; Montesinos P&#44; Rives S&#46; Asparaginasas en el tratamiento de la leucemia linfobl&#225;stica aguda&#46; Med Clin &#40;Barc&#41;&#46; 2017&#59;148&#58;225&#8211;231&#46;</p>"
      ]
    ]
    "multimedia" => array:4 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1802
            "Ancho" => 2841
            "Tamanyo" => 151029
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Management algorithm for asparaginase hypersensitivity reactions&#46; <span class="elsevierStyleSup">a</span>If an asparaginase activity test cannot be performed&#44; and differentiation between an infusional or a hypersensitivity reaction is not possible&#44; a formulation change is recommended&#44; either to PEG-asparaginase or to <span class="elsevierStyleItalic">Erwinia</span> asparaginase&#46; <span class="elsevierStyleSup">b</span>Mainly&#44; a change to <span class="elsevierStyleItalic">Erwinia</span> L-ASA to avoid cross-reactivity&#46; <span class="elsevierStyleSup">c</span>Not recommended&#46; It can be considered in cases of very severe reaction and if the formulation cannot be changed and&#47;or if the planned treatment has been almost completed&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 2035
            "Ancho" => 2986
            "Tamanyo" => 357015
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Management algorithm in case of pancreatitis&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">SD&#58; standard deviation&#59; IM&#58; intramuscular&#59; IV&#58; intravenous&#59; PEG asparaginase&#58; <span class="elsevierStyleItalic">E&#46; coli</span> asparaginase conjugated with polyethylene glycol&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">Erwinia chrysanthemi</span> asparaginase<br>One IM dose of 25&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">Erwinia chrysanthemi</span> asparaginase<br>One IV dose of 25&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Native <span class="elsevierStyleItalic">Escherichia coli</span> asparaginase<br>One IM dose of 25&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PEG-asparaginase<br>One IM dose of 2500<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Half-life&#44; days &#40;mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;65<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;31<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;79&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;28<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#46;73<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Equivalent doses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&#44;000&#8211;25&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> every 2 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&#44;000&#8211;25&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> every 2 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6000&#8211;10&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> every 2&#8211;3 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2500&#8211;3500<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> every 2 weeks<br>1000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> every 2 weeks<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1384838.png"
              ]
            ]
          ]
          "notaPie" => array:1 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">In some protocols 1000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> every 2 weeks has been considered sufficient&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Half-life and equivalent doses of the three asparaginase formulations&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">NSAIDs&#58; non-steroidal anti-inflammatory drugs&#59; CTCAE&#58; <span class="elsevierStyleItalic">Common Terminology Criteria for Adverse Events</span>&#46;</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; Dueck et al&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Grade&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Reaction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Transient erythema or rash&#44; fever &#60;38<span class="elsevierStyleHsp" style=""></span>&#176;C&#59; intervention not indicated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Intervention or interruption of the infusion are indicated&#59; responds quickly to symptomatic treatment &#40;e&#46;g&#46; antihistamines&#44; NSAIDs&#44; opioids&#44; etc&#46;&#41;&#59; prophylactic drugs indicated &#8804;24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Extended &#40;e&#46;g&#46; do not respond quickly to symptomatic medication and&#47;or a brief interruption of the infusion&#41;&#59; recurrence of symptoms after initial improvement&#59; hospitalization indicated by clinical sequelae &#40;e&#46;g&#46; renal failure&#44; pulmonary infiltrates&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Life threatening episodes&#59; urgent intervention indicated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Death&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1384837.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">CTCAE criteria for toxicity in hypersensitivity reactions&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:30 [
            0 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Asparaginase-associated pancreatitis in children with acute lymphoblastic leukaemia in the NOPHO ALL2008 protocol"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46;A&#46; Raja"
                            1 => "K&#46; Schmiegelow"
                            2 => "B&#46;K&#46; Albertsen"
                            3 => "K&#46; Prunsild"
                            4 => "B&#46; Zeller"
                            5 => "G&#46; Vaitkeviciene"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/bjh.12733"
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Haematol"
                        "fecha" => "2014"
                        "volumen" => "165"
                        "paginaInicial" => "126"
                        "paginaFinal" => "133"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24428625"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0160"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacokinetics&#44; pharmacodynamics&#44; efficacy&#44; and safety of a new recombinant asparaginase preparation in children with previously untreated acute lymphoblastic leukemia&#58; a randomized phase 2 clinical trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46; Pieters"
                            1 => "I&#46; Appel"
                            2 => "H&#46;J&#46; Kuehnel"
                            3 => "I&#46; Tetzlaff-Fohr"
                            4 => "U&#46; Pichlmeier"
                            5 => "I&#46; van der Vaart"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood-2008-04-149443"
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood"
                        "fecha" => "2008"
                        "volumen" => "112"
                        "paginaInicial" => "4832"
                        "paginaFinal" => "4838"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18805963"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0165"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Asparaginase pharmacokinetics and implications of therapeutic drug monitoring"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "B&#46; Asselin"
                            1 => "C&#46; Rizzari"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3109/10428194.2014.1003056"
                      "Revista" => array:6 [
                        "tituloSerie" => "Leuk Lymphoma"
                        "fecha" => "2015"
                        "volumen" => "56"
                        "paginaInicial" => "2273"
                        "paginaFinal" => "2280"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25586605"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0170"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Thrombotic complications in childhood acute lymphoblastic leukemia&#58; a meta-analysis of 17 prospective studies comprising 1752 pediatric patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "V&#46; Caruso"
                            1 => "L&#46; Iacoviello"
                            2 => "A&#46; di Castelnuovo"
                            3 => "S&#46; Storti"
                            4 => "G&#46; Mariani"
                            5 => "G&#46; de Gaetano"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood-2006-04-015511"
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood"
                        "fecha" => "2006"
                        "volumen" => "108"
                        "paginaInicial" => "2216"
                        "paginaFinal" => "2222"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16804111"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0175"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Changes in antithrombin and fibrinogen levels during induction chemotherapy with L-asparaginase in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma&#46; Use of supportive coagulation therapy and clinical outcome&#58; the CAPELAL study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Hunault-Berger"
                            1 => "P&#46; Chevallier"
                            2 => "M&#46; Delain"
                            3 => "C&#46;E&#46; Bulabois"
                            4 => "S&#46; Bologna"
                            5 => "M&#46; Bernard"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3324/haematol.12948"
                      "Revista" => array:6 [
                        "tituloSerie" => "Haematologica"
                        "fecha" => "2008"
                        "volumen" => "93"
                        "paginaInicial" => "1488"
                        "paginaFinal" => "1494"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18728028"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0180"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia&#58; a report from the Children&#39;s Oncology Group"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "N&#46;L&#46; Seibel"
                            1 => "P&#46;G&#46; Steinherz"
                            2 => "H&#46;N&#46; Sather"
                            3 => "J&#46;B&#46; Nachman"
                            4 => "C&#46; Delaat"
                            5 => "L&#46;J&#46; Ettinger"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood-2007-02-070342"
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood"
                        "fecha" => "2008"
                        "volumen" => "111"
                        "paginaInicial" => "2548"
                        "paginaFinal" => "2555"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18039957"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0185"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Best practices in adolescent and young adult patients with acute lymphoblastic leukemia&#58; a focus on asparaginase"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "N&#46; Boissel"
                            1 => "L&#46;S&#46; Sender"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1089/jayao.2015.0014"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Adolesc Young Adult Oncol"
                        "fecha" => "2015"
                        "volumen" => "4"
                        "paginaInicial" => "118"
                        "paginaFinal" => "128"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26421220"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0190"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hypersensitivity reactions to L-asparaginase do not impact on the remission duration of adults with acute lymphoblastic leukemia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "R&#46;A&#46; Larson"
                            1 => "M&#46;H&#46; Fretzin"
                            2 => "R&#46;K&#46; Dodge"
                            3 => "C&#46;A&#46; Schiffer"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Leukemia"
                        "fecha" => "1998"
                        "volumen" => "12"
                        "paginaInicial" => "660"
                        "paginaFinal" => "665"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9593262"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0195"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prevention and management of asparaginase&#47;pegasparaginase-associated toxicities in adults and older adolescents&#58; recommendations of an expert panel"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "W&#46; Stock"
                            1 => "D&#46; Douer"
                            2 => "D&#46;J&#46; DeAngelo"
                            3 => "M&#46; Arellano"
                            4 => "A&#46; Advani"
                            5 => "L&#46; Damon"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3109/10428194.2011.596963"
                      "Revista" => array:6 [
                        "tituloSerie" => "Leuk Lymphoma"
                        "fecha" => "2011"
                        "volumen" => "52"
                        "paginaInicial" => "2237"
                        "paginaFinal" => "2253"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21827361"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0200"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Allergic reactions associated with intravenous versus intramuscular pegaspargase&#58; a retrospective chart review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "L&#46;S&#46; Abbott"
                            1 => "M&#46; Zakova"
                            2 => "F&#46; Shaikh"
                            3 => "N&#46; Shewaramani"
                            4 => "A&#46; Punnett"
                            5 => "L&#46;L&#46; Dupuis"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s40272-015-0129-1"
                      "Revista" => array:6 [
                        "tituloSerie" => "Paediatr Drugs"
                        "fecha" => "2015"
                        "volumen" => "17"
                        "paginaInicial" => "315"
                        "paginaFinal" => "321"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25862348"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0205"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparison of allergic reactions to intravenous and intramuscular pegaspargase in children with acute lymphoblastic leukemia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "W&#46;C&#46; Petersen"
                            1 => "D&#46; Clark"
                            2 => "S&#46;L&#46; Senn"
                            3 => "W&#46;T&#46; Cash"
                            4 => "S&#46;E&#46; Gillespie"
                            5 => "C&#46;E&#46; McCracken"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3109/08880018.2013.876134"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Hematol Oncol"
                        "fecha" => "2014"
                        "volumen" => "31"
                        "paginaInicial" => "311"
                        "paginaFinal" => "317"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24498943"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0210"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparison of allergic reactions to pegasparaginase given intravenously versus intramuscularly"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46; Pidaparti"
                            1 => "B&#46; Bostrom"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/pbc.23380"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Blood Cancer"
                        "fecha" => "2012"
                        "volumen" => "59"
                        "paginaInicial" => "436"
                        "paginaFinal" => "439"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22021170"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0215"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparative pharmacokinetic studies of three asparaginase preparations"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "B&#46;L&#46; Asselin"
                            1 => "J&#46;C&#46; Whitin"
                            2 => "D&#46;J&#46; Coppola"
                            3 => "I&#46;P&#46; Rupp"
                            4 => "S&#46;E&#46; Sallan"
                            5 => "H&#46;J&#46; Cohen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.1993.11.9.1780"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "1993"
                        "volumen" => "11"
                        "paginaInicial" => "1780"
                        "paginaFinal" => "1786"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8355045"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0220"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pegylated asparaginase &#40;Oncaspar&#41; in children with ALL&#58; drug monitoring in reinduction according to the ALL&#47;NHL-BFM 95 protocols"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46;J&#46; M&#252;ller"
                            1 => "L&#46; L&#246;ning"
                            2 => "A&#46; Horn"
                            3 => "D&#46; Schwabe"
                            4 => "M&#46; Gunkel"
                            5 => "M&#46; Schrappe"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Haematol"
                        "fecha" => "2000"
                        "volumen" => "110"
                        "paginaInicial" => "379"
                        "paginaFinal" => "384"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10971395"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0225"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A randomized comparison of native <span class="elsevierStyleItalic">Escherichia coli</span> asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia&#58; a Children&#39;s Cancer Group study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "V&#46;I&#46; Avramis"
                            1 => "S&#46; Sencer"
                            2 => "A&#46;P&#46; Periclou"
                            3 => "H&#46; Sather"
                            4 => "B&#46;C&#46; Bostrom"
                            5 => "L&#46;J&#46; Cohen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood"
                        "fecha" => "2002"
                        "volumen" => "99"
                        "paginaInicial" => "1986"
                        "paginaFinal" => "1994"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11877270"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0230"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparison of intramuscular therapy with Erwinia asparaginase and asparaginase Medac&#58; pharmacokinetics&#44; pharmacodynamics&#44; formation of antibodies and influence on the coagulation system"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "B&#46;K&#46; Albertsen"
                            1 => "H&#46; Schr&#248;der"
                            2 => "J&#46; Ingerslev"
                            3 => "P&#46; Jakobsen"
                            4 => "V&#46;I&#46; Avramis"
                            5 => "H&#46;J&#46; M&#252;ller"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Haematol"
                        "fecha" => "2001"
                        "volumen" => "115"
                        "paginaInicial" => "983"
                        "paginaFinal" => "990"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11843837"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0235"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hypersensitivity or development of antibodies to asparaginase does not impact treatment outcome of childhood acute lymphoblastic leukemia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;H&#46; Woo"
                            1 => "L&#46;J&#46; Hak"
                            2 => "M&#46;C&#46; Storm"
                            3 => "J&#46;T&#46; Sandlund"
                            4 => "R&#46;C&#46; Ribeiro"
                            5 => "G&#46;K&#46; Rivera"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.2000.18.7.1525"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2000"
                        "volumen" => "18"
                        "paginaInicial" => "1525"
                        "paginaFinal" => "1532"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10735901"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0240"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A desensitization protocol in children with L-asparaginase hypersensitivity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "S&#46; Akbayram"
                            1 => "M&#46; Do&#287;an"
                            2 => "C&#46; Akg&#252;n"
                            3 => "H&#46; Caksen"
                            4 => "A&#46;F&#46; Oner"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/MPH.0b013e3181e003c7"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pediatr Hematol Oncol"
                        "fecha" => "2010"
                        "volumen" => "32"
                        "paginaInicial" => "e187"
                        "paginaFinal" => "e191"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20505537"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0245"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Validity and reliability of the US National Cancer Institute&#39;s Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events &#40;PRO-CTCAE&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46;C&#46; Dueck"
                            1 => "T&#46;R&#46; Mendoza"
                            2 => "S&#46;A&#46; Mitchell"
                            3 => "B&#46;B&#46; Reeve"
                            4 => "K&#46;M&#46; Castro"
                            5 => "L&#46;J&#46; Rogak"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/jamaoncol.2015.2639"
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA Oncol"
                        "fecha" => "2015"
                        "volumen" => "1"
                        "paginaInicial" => "1051"
                        "paginaFinal" => "1059"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26270597"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0250"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Optimizing asparaginase therapy for acute lymphoblastic leukemia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "C&#46; Rizzari"
                            1 => "V&#46; Conter"
                            2 => "J&#46; Star&#253;"
                            3 => "A&#46; Colombini"
                            4 => "A&#46; Moericke"
                            5 => "M&#46; Schrappe"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/CCO.0000000000000017"
                      "Revista" => array:7 [
                        "tituloSerie" => "Curr Opin Oncol"
                        "fecha" => "2013"
                        "volumen" => "25"
                        "numero" => "Suppl&#46; 1"
                        "paginaInicial" => "S1"
                        "paginaFinal" => "S9"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24305505"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0255"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Venous thrombotic complications in adults undergoing induction treatment for acute lymphoblastic leukemia&#58; results from a meta-analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "V&#46; Caruso"
                            1 => "L&#46; Iacoviello"
                            2 => "A&#46; di Castelnuovo"
                            3 => "S&#46; Storti"
                            4 => "M&#46;B&#46; Donati"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "J Thromb Haemost"
                        "fecha" => "2007"
                        "paginaInicial" => "621"
                        "paginaFinal" => "623"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0260"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Predicting asparaginase-associated pancreatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "H&#46;M&#46; Knoderer"
                            1 => "J&#46; Robarge"
                            2 => "D&#46;A&#46; Flockhart"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/pbc.21037"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Blood Cancer"
                        "fecha" => "2007"
                        "volumen" => "49"
                        "paginaInicial" => "634"
                        "paginaFinal" => "639"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16937362"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0265"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Polymorphisms of asparaginase pathway and asparaginase-related complications in children with acute lymphoblastic leukemia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Ben Tanfous"
                            1 => "B&#46; Sharif-Askari"
                            2 => "F&#46; Ceppi"
                            3 => "H&#46; Laaribi"
                            4 => "V&#46; Gagn&#233;"
                            5 => "J&#46; Rousseau"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1158/1078-0432.CCR-14-0508"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Cancer Res"
                        "fecha" => "2015"
                        "volumen" => "21"
                        "paginaInicial" => "329"
                        "paginaFinal" => "334"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24907114"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0270"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical course and outcome in children with acute lymphoblastic leukemia and asparaginase-associated pancreatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "S&#46;L&#46; Kearney"
                            1 => "S&#46;E&#46; Dahlberg"
                            2 => "D&#46;E&#46; Levy"
                            3 => "S&#46;D&#46; Voss"
                            4 => "S&#46;E&#46; Sallan"
                            5 => "L&#46;B&#46; Silverman"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/pbc.22076"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Blood Cancer"
                        "fecha" => "2009"
                        "volumen" => "53"
                        "paginaInicial" => "162"
                        "paginaFinal" => "167"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19405141"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0275"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparison of <span class="elsevierStyleItalic">Escherichia coli</span>-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies&#58; results of a randomized European Organisation for Research and Treatment of Cancer-Children&#39;s Leukemia Group phase 3 trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Duval"
                            1 => "S&#46; Suciu"
                            2 => "A&#46; Ferster"
                            3 => "X&#46; Rialland"
                            4 => "B&#46; Nelken"
                            5 => "P&#46; Lutz"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood"
                        "fecha" => "2002"
                        "volumen" => "99"
                        "paginaInicial" => "2734"
                        "paginaFinal" => "2739"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11929760"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0280"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Central nervous system complications during treatment of acute lymphoblastic leukemia in a single pediatric institution"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46; Parasole"
                            1 => "F&#46; Petruzziello"
                            2 => "G&#46; Menna"
                            3 => "A&#46; Mangione"
                            4 => "E&#46; Cianciulli"
                            5 => "S&#46; Buffardi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3109/10428191003754608"
                      "Revista" => array:6 [
                        "tituloSerie" => "Leuk Lymphoma"
                        "fecha" => "2010"
                        "volumen" => "51"
                        "paginaInicial" => "1063"
                        "paginaFinal" => "1071"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20470218"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0285"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "L-asparaginase-induced reversible posterior leukoencephalopathy syndrome in a child with acute lymphoblastic leukemia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "B&#46; Rathi"
                            1 => "R&#46;K&#46; Azad"
                            2 => "N&#46; Vasudha"
                            3 => "P&#46; Hissaria"
                            4 => "V&#46; Sawlani"
                            5 => "R&#46;K&#46; Gupta"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "65395"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Neurosurg"
                        "fecha" => "2002"
                        "volumen" => "37"
                        "paginaInicial" => "203"
                        "paginaFinal" => "205"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12372914"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0290"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hyperammonemic encephalopathy after induction chemotherapy for acute lymphoblastic leukemia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "T&#46;H&#46; Jaing"
                            1 => "J&#46;L&#46; Lin"
                            2 => "Y&#46;P&#46; Lin"
                            3 => "S&#46;H&#46; Yang"
                            4 => "J&#46;J&#46; Lin"
                            5 => "S&#46;H&#46; Hsia"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/MPH.0b013e3181b8beb1"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pediatr Hematol Oncol"
                        "fecha" => "2009"
                        "volumen" => "31"
                        "paginaInicial" => "955"
                        "paginaFinal" => "956"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19887962"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0295"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of L-asparaginase on carbohydrate metabolism"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "J&#46;P&#46; Whitecar"
                            1 => "G&#46;P&#46; Bodey"
                            2 => "C&#46;S&#46; Hill"
                            3 => "N&#46;A&#46; Samaan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Metabolism"
                        "fecha" => "1970"
                        "volumen" => "19"
                        "paginaInicial" => "581"
                        "paginaFinal" => "586"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/4913910"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0300"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Intensified PEG-L-asparaginase and antimetabolite-based therapy for treatment of higher risk precursor-B acute lymphoblastic leukemia&#58; a report from the Children&#39;s Oncology Group"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "W&#46;L&#46; Salzer"
                            1 => "M&#46; Devidas"
                            2 => "J&#46;J&#46; Shuster"
                            3 => "C&#46; Wang"
                            4 => "A&#46; Chauvenet"
                            5 => "B&#46;L&#46; Asselin"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/MPH.0b013e3180640d54"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pediatr Hematol Oncol"
                        "fecha" => "2007"
                        "volumen" => "29"
                        "paginaInicial" => "369"
                        "paginaFinal" => "375"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17551397"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
    "agradecimientos" => array:1 [
      0 => array:4 [
        "identificador" => "xack276262"
        "titulo" => "Acknowledgements"
        "texto" => "<p id="par0470" class="elsevierStylePara elsevierViewall">The authors wish to thank the invaluable assistance of Professor Josep Maria Ribera in the critical review of this work&#46; The recommendations contained in this article have the backing of the Spanish Society of Paediatric Haematology and Oncology &#40;SEHOP&#41; and the Spanish acute lymphocytic leukaemia group of the Haematological Malignancies Treatment Programme &#40;PETHEMA&#41;&#46; We also appreciate the logistical and technical support of Ms&#46; Marta Gonz&#225;lez&#46; This work has been supported by Jazz Pharmaceuticals Inc&#46;</p>"
        "vista" => "all"
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/23870206/0000014800000005/v1_201704020027/S2387020617301705/v1_201704020027/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "44145"
    "tipo" => "SECCION"
    "en" => array:2 [
      "titulo" => "Special article"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "en"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/23870206/0000014800000005/v1_201704020027/S2387020617301705/v1_201704020027/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020617301705?idApp=UINPBA00004N"
]
Indexed in:

Follow us:

Subscribe:

Article

Indexed in:

Follow us:

Subscribe:

Article

Subscribe to our newsletter
