Asparaginase-associated pancreatitis in childhood acute lymphoblastic leukaemia: an observational Ponte di Legno Toxicity Working Group study

Wolthers, Benjamin Ole; Frandsen, Thomas Leth; Baruchel, André; Attarbaschi, Andishe; Barzilai, Shlomit; Colombini, Antonella; Escherich, Gabriele; Grell, Kathrine; Inaba, Hiroto; Kovács, Gábor; Liang, Der‐Cherng; Mateos, Marion K.; Mondelaers, Veerle; Möricke, Anja; Ociepa, Tomasz; Samarasinghe, Sujith; Silverman, Lewis B.; Sluis, Inge M. van der; Stanulla, Martin; Vrooman, Lynda M.; Yano, Michihiro; Zápotocká, Ester; Schmiegelow, Kjeld

doi:10.1016/s1470-2045(17)30424-2

Cited by 92 publications

(128 citation statements)

References 24 publications

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“…AAP is most often diagnosed within two weeks of asparaginase exposure (median of 11 days with PEG-asparaginase), but the interval may be longer 175 . The diagnostic criteria defined by the PTWG 7 are similar to those developed for pancreatitis in general 176 and require two of three criteria to be met: (i) abdominal symptoms suggestive of AAP, (ii) characteristic findings of pancreatitis on imaging, and (iii) serum lipase or amylase or both at least three times the UNL, and both enzymes should be measured because of a poor correlation between the two 175 . If imaging shows pancreatic necrosis or hemorrhage and/or the abdomimal symptoms and elevated pancreatic enzymes at least three times the UNL persist for more than 72 hours, AAP is classified as severe and otherwise as mild.…”

Section: Asparaginase-associated Pancreatitismentioning

confidence: 99%

“…In addition to transient or permanent discontinuation of asparaginase therapy, treatment of AAP includes appropriate triage, fluid resuscitation, antibiotics (until an infection is ruled out), and monitoring for and treatment of AAP-related complications 177 . The mortality rate is low, but patients systemically affected at AAP diagnosis are at increased risk of developing pseudocysts, acute or persistent diabetes mellitus, and chronic/relapsing pancreatitis 175, 178 . Octreotide has been tested in few patients, but the benefit thereof remains to be determined 179, 180 .…”

Section: Asparaginase-associated Pancreatitismentioning

confidence: 99%

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Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy

et al. 2017

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During chemotherapy for childhood acute lymphoblastic leukemia, all organs can be affected by severe acute side effects, the most common being opportunistic infections, mucositis, central or peripheral neuropathy (or both), bone toxicities (including osteonecrosis), thromboembolism, sinusoidal obstruction syndrome, endocrinopathies (especially steroid-induced adrenal insufficiency and hyperglycemia), high-dose methotrexate-induced nephrotoxicity, asparaginase-associated hypersensitivity, pancreatitis, and hyperlipidemia. Few of the non-infectious acute toxicities are associated with clinically useful risk factors, and across study groups there has been wide diversity in toxicity definitions, capture strategies, and reporting, thus hampering meaningful comparisons of toxicity incidences for different leukemia protocols. Since treatment of acute lymphoblastic leukemia now yields 5-year overall survival rates above 90%, there is a need for strategies for assessing the burden of toxicities in the overall evaluation of anti-leukemic therapy programs.

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Section: Asparaginase-associated Pancreatitismentioning

confidence: 99%

Section: Asparaginase-associated Pancreatitismentioning

confidence: 99%

Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy

et al. 2017

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“…Another cause of AP is the l -asparaginase treatment of acute lymphoblastic leukemia (ALL) (6, 7). According to Cancer Research UK, there were 832 new cases of ALL diagnosed in the United Kingdom in 2015.…”

Section: Introductionmentioning

confidence: 99%

“…Antileukemic drugs based on l -asparaginase are currently used in the clinic as an effective treatment for childhood ALL (8–12). However, in up to 10% of cases, the asparaginase treatment has to be truncated due to development of AP, a serious and incurable illness (6, 7, 13–17). Although asparaginase-based drugs have been used in the clinic for many years (8), the mechanism of this side effect has not been well explored and understood.…”

Section: Introductionmentioning

confidence: 99%

Galactose protects against cell damage in mouse models of acute pancreatitis

Peng¹,

Gerasimenko²,

Tsugorka³

et al. 2018

Journal of Clinical Investigation

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Acute pancreatitis (AP), a human disease in which the pancreas digests itself, has substantial mortality with no specific therapy. The major causes of AP are alcohol abuse and gallstone complications, but it also occurs as an important side effect of the standard asparaginase-based therapy for childhood acute lymphoblastic leukemia. Previous investigations into the mechanisms underlying pancreatic acinar cell death induced by alcohol metabolites, bile acids, or asparaginase indicated that loss of intracellular ATP generation is an important factor. We now report that, in isolated mouse pancreatic acinar cells or cell clusters, removal of extracellular glucose had little effect on this ATP loss, suggesting that glucose metabolism was severely inhibited under these conditions. Surprisingly, we show that replacing glucose with galactose prevented or markedly reduced the loss of ATP and any subsequent necrosis. Addition of pyruvate had a similar protective effect. We also studied the effect of galactose in vivo in mouse models of AP induced either by a combination of fatty acids and ethanol or asparaginase. In both cases, galactose markedly reduced acinar necrosis and inflammation. Based on these data, we suggest that galactose feeding may be used to protect against AP.

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“…Ezek jelentkezhetnek nemritkán életet veszélyezte-tő, heveny formában [24], amely adverz események rendszeres felmérése és értékelése a hazánkban működő Magyar Gyermekonkológiai Hálózat egyik kiemelt tö-rekvése [28]. Ennek nyomán munkacsoportunk is kész-séges résztvevője és szervezője nemzetközi gyógyszer-biztonsági vizsgálatoknak [29]. A toxicitás megelőzésére több citosztatikumnak új, biztonságosabb formája is lé-tezik (főként pegilált vagy liposzomális kivitel) [26], illetve segítséget nyújt a vérplazma gyógyszerszintjének rutinszerű monitorozása (hazánkban évek óta figyelt paraméter a metotrexátkoncentráció, de bevezetés alatt áll az aszparaginázaktivitás mérése is).…”

Section: öSszefoglaló Közleményunclassified

Új és hagyományos irányok a gyermekkori akut lymphoblastos leukaemia biológiájában és ellátásában

et al. 2018

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Az utóbbi néhány évtized klinikai előrelépéseinek köszönhetően az akut lymphoblastos leukaemiás (ALL-) gyermekek nagy hányada ma az első vonalbeli kemoterápiás protokollok révén meggyógyul, és küzd a kortársak közé való visszatérés problémáival. Azonban a betegek jelentős részénél súlyos akut és késői terápiás mellékhatásokkal kell szá-molni. Emellett egyes betegcsoportok (például MLL-átrendeződéssel, hipodiploiditással, IKZF1-mutációval vagy korai prekurzor T-sejtes fenotípussal jellemezhető betegek) túlélése messze elmarad az átlagostól. Számukra nyújta-nak jobb klinikai kilátásokat az újabb betegellátási stratégiák: komplex géndiagnosztika, molekulárisan célzott daganatgátlás, immunonkológia és sejtterápia. Harminc feletti azon géneknek a száma, amelyek eltéréseit azonosították leukaemiás lymphoblastokban, és patobiológiai szerepük is valamennyire ismert. Ismerünk olyan betegcsoportot is (Philadelphia-like B-sejtes ALL), ahol a génexpressziós profilalkotás ad alapot a tirozin-kináz-inhibitorok használatá-nak. A leukaemiaasszociált immunfenotípus diagnóziskori áramlási citometriás meghatározásával és genetikai mód-szerekkel követhetővé vált a minimális residualis betegség. A blastfelszíni differenciációs klaszterek (elsősorban CD19, CD20 és CD22 a malignus B-sejteken) epitópjai monoklonális antitestekkel támadhatók. Fokozható a tumorellenes immunitás is, részben szintén a tumor sejtfelszíni markereinek (bispecifikus T-sejt-kapcsolóknál, kiméra antigénrecep-torú T-sejtes terápiánál), részben pedig a tumorspecifikus immunsejteknek (immunellenőrzőpont-gátlóknál) a kihasználása révén. A jelen közleményben áttekintést kívánunk adni a patogenetika új irányairól, a betegségkövetés modern módjairól és a célzott citotoxicitás innovatív lehetőségeiről biztató klinikai tanulmányok alapján. Orv Hetil. 2018; 159(20): 786-797. Keywords: akut lymphoblastos leukaemia, patogenezis, toxicitás, immunterápia, célzott molekuláris terápia New and traditional directions in the biology and management of childhood acute lymphoblastic leukemiaOwing to clinical trials and improvement over the past few decades, the majority of children with acute lymphoblastic leukemia (ALL) survive by first-line chemotherapy and combat with the problems of returning to community. However, many patients may have severe acute or late therapeutic side effects, and the survival rate in some groups (e.g., patients with MLL rearrangements, hypodiploidy, IKZF1 mutation or early precursor T cell phenotype) is far behind the average. Innovative strategies in medical attendance provide better clinical outcomes for them: complete gene diagnostics, molecularly targeted anticancer treatment, immuno-oncology and immune cell therapy. The number of genes with identified alterations in leukemic lymphoblasts is over thirty and their pathobiologic role is only partly clear. There are known patient groups where the use of specific drugs is based on gene expression profiling (e.g., tyrosine kinase inhibitors in Philadelphia-like B-cell ALL). The continuous assessment of min...

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Asparaginase-associated pancreatitis in childhood acute lymphoblastic leukaemia: an observational Ponte di Legno Toxicity Working Group study

Cited by 92 publications

References 24 publications

Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy

Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy

Galactose protects against cell damage in mouse models of acute pancreatitis

Új és hagyományos irányok a gyermekkori akut lymphoblastos leukaemia biológiájában és ellátásában

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