Asparaginase-induced acute pancreatitis in children: unveiling predictive biomarkers for precision care

Senna, Evelin Cristine Mendonça de; Rotella, Lucas; Ceconello, Daiane Keller; Silva, Klerize Anecely de Souza; Rechenmacher, Ciliana; Khayat, Andre Salim; Vieira, Alayde; Daudt, Liane Esteves; Michalowski, Mariana Bohns

doi:10.1590/s2175-97902025e24121

person Evelin Cristine Mendonça de Senna

schoolUniversidade Federal do Rio Grande do Sul, Porto Alegre, RS, BrazilschoolUniversidade de São Paulo, São Paulo, SP, Brazil

0009-0002-5149-3178

person Lucas Rotella

schoolUniversidade Federal do Pará, Belém, PA, Brazil

0009-0007-4104-2310

person Daiane Keller Ceconello

schoolUniversidade Federal do Rio Grande do Sul, Porto Alegre, RS, BrazilschoolHospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

0000-0002-2796-6708

person Klerize Anecely de Souza Silva

schoolUniversidade Federal do Rio Grande do Sul, Porto Alegre, RS, BrazilschoolHospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

0000-0002-2424-0354

person Ciliana Rechenmacher

schoolUniversidade Federal do Rio Grande do Sul, Porto Alegre, RS, BrazilschoolHospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

0000-0002-1321-5807

person Andre Salim Khayat

schoolUniversidade Federal do Pará, Belém, PA, Brazil

0000-0002-3451-6369.

person Alayde Vieira

schoolUniversidade Federal do Pará, Belém, PA, Brazil

0000-0001-9495-6932

person Liane Esteves Daudt

schoolUniversidade Federal do Rio Grande do Sul, Porto Alegre, RS, BrazilschoolHospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

person Mariana Bohns Michalowski

schoolUniversidade Federal do Rio Grande do Sul, Porto Alegre, RS, BrazilschoolHospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

0000-0002-9482-0776

Associated Editor: Moacyr Rêgo

person*Correspondence: M. B. Michalowski, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350 Bloco A, Av. Protásio Alves, 211 - Bloco B e C, CEP 90035-903, Santa Cecília, Porto Alegre, RS, Brasil, Phone: (51) 3359-8000, E-mail:
mmichalowski@hcpa.edu.br https://orcid.org/0000-0002-9482-0776, CV Lattes:
http://lattes.cnpq.br/3623764715432223. E. Senna,
evelinsenna3@gmail.com https://orcid.org/0009-0002-5149-3178. L. Rotella,
lucasrotella.lr@gmail com,
https://orcid.org/0009-0007-4104-2310. D. K. Cecconello, daia_
cecconello@hotmail.com https://orcid.org/0000-0002-2796-6708. K. A. S. Silva,
klerize.anecely@gmail.com https://orcid.org/0000-0002-2424-0354. C.Rechenmacher,
cilianare@gmail.com https://orcid.org/0000-0002-1321-5807. A. S. Khayat,
khayatas@gmail.com https://orcid.org/0000-0002-3451-6369. A. Vieira,
alayde.viera@gmail.com L. E. Daudt,
ldaudt@hcpa.edu.br https://orcid.org/0000-0001-9495-6932.

Gravity	Criteria	Prognosis
Mild pancreatitis	Absence of organ failure and absence of local and systemic complications.	Great
Moderate pancreatitis	Presence of transient organ failure, resolved within 48 hours, and/or local or systemic complications without persistent organ failure	Low mortality
Severe pancreatitis	Presence of persistent organ failure >48 hours	High morbidity/high mortality

Reference	Lead Institution or Group	Period of Study	Chemotherapy Protocol	Number and % of Patients With AAP [n/N (%)]	ASN formulation and dosage	Definition of Pancreatitis Severity	Frequency of AAP Severity or AAP Complications
Samarasinghe et al., 2013	Great North Children’s Hospital, Newcastle, United Kingdom	20032011	UKALL 2003	48/3101 (1.5)	PEG Asn 1000 UI/m² IM	CTCAE 4.03: Grade 3 and 4	Grade 3: 35/48 (73%) 3 Grade 4: 13/48 (27%)
Raja, Schmiegelow, Frandsen,2012	University Hospital Rigshospitalet, Kobenhaven, Denmark	20082012	NOPHO ALL 2008	45/786 (5.7)	PEG Asn 1000 UI/m² IM	Only complications were described	19/45 (42%) had complications: 8 pseudocyst, 6 necrotizing pancreatitis, 5 pseudocysts +necrotizing pancreatitis, 30 SIRS
Kearney et al., 2009	Dana-Farber Cancer Institute, Boston, USA	19872003	DFCI ALL Consortium protocols 87-01, 91-01, 95-01, 0001	28/403 (7)	PEG Asn 2500 UI/m² IM	Only complications were described	5/28 (18%) pseudocyst
Barry et al., 2007	Dana-Farber Cancer Institute, Boston, USA	19912000	DFCI ALL Consortium protocols 91-01 and 95-01	34/844 (4)	PEG Asn 2500 UI/m² IM	CTCAE v. 3	Not specified
Schmidt et al., 2021	Sf.Maria Children's Hospital	2010-2019	ALL IC BFM 2002	5/165(3)	L-Asparaginase 5000 UI/M²	CTCAE	2/5 (40%) Grade 3/4

Gene	Function	RS	Alteration	Consequence	Odds/Hazard ratio	Reference
CPA2	Carboxypeptidase	rs199695765	C>T	Stop Codon	HR: 587	Liu et al., 2016
MYBBP1A	Nucleolar transcriptional regulator	rs3809849	G>C	Missense Variant	OR: 2.4%	Abaji et al., 2019
RGS6	Regulator of GTPase activity	rs17179470	G>T	Intron Variant	OR: 7.3	Wolthers et al., 2017
ULK2	Protein serine/ threonine kinase	rs281366	C>T	Non-coding exon variant	OR: 6.7	Wolthers et al., 2017
LINC01429/ NFATC2	lncRNA/ Transcription factors	rs62228256	C>T	Intron Variant	OR: 3.75	Wolthers et al., 2019
PRSS1/PRSS2	Proteases	rs10273639 rs13228878	T>C G>A	Intron Variants	OR: 0.62 OR: 0.76	Wolthers et al., 2019; Nielsen et al., 2022
CLDN2	Regulator of tissuespecific physiologic properties	rs4409525 rs12853674	G>C C>T	Upstream Variants	OR: 1.41	Derikx et al., 2015; Giri et al., 2016; Wolthers et al., 2019; Nielsen et al., 2022
MORC4	Possible ATP hydrolyzer	rs12688220	C>T	Upstream Variant	OR: 2.26	Wolthers et al., 2017; Derikx et al., 2015; Giri et al., 2016; Wolthers et al., 2019; Nielsen et al., 2022
CTRC	Regulator of trypsinogen activation and degradation	rs10436957	G>A	Intron Variant	OR: 0.66	Wolthers et al., 2019; Nielsen et al., 2022
SPINK1	Trypsin inhibitor	rs17107315	T>C	Missense Variant	OR: 2.87	Wolthers et al., 2017
CASR	Responsible for detecting changes in circulating calcium concentration	rs16832787	G>A	Intron Variant	OR: 0.78	Wolthers et al., 2019; Nielsen et al., 2022
CFTR	Function as a chloride channel	rs56296320	T>C	Intron Variant	OR: 0.34	Wolthers et al., 2019; Nielsen et al., 2022
EPHB2	Transmembrane receptor	rs4655107	G>A	Intron Variant	OR: 0.55	Wolthers et al., 2019; Nielsen et al., 2022
GALNTL6	Initial reaction catalyst in oligosaccharide biosynthesis	rs1505495	C>A	Missense Variant	OR: 0.49	Wolthers et al., 2019; Nielsen et al., 2022

Asparaginase-induced acute pancreatitis in children: unveiling predictive biomarkers for precision care

Abstract