EDITED BY
Bi gi Knoechel,
Dana–Fa be Cance Ins i u e, Uni ed S a es
REVIEWED BY
Alix Eden Sei ,
Child en’s Hospi al o Philadelphia,
Uni ed S a es
*CORRESPONDENCE
Pablo Velasco
[email p o ec ed]
RECEIVED 30 July 2023
ACCEPTED 06 Sep embe 2023
PUBLISHED 20 Sep embe 2023
CITATION
Velasco P, Bau is a F, Rubio A, Aguila Y, Ri es S,
Dapena JL, Pé ez A, Rami ez M, Saiz-Lade a C,
Izquie do E, Escude o A, Camós M,
Vega-Ga cía N, O ega M, Hidalgo-Gómez G,
Palacio C, Menéndez P, Bueno C, Mon e o J,
Romecín PA, Zazo S, Al a ez F, Pa as J,
O ega-Saba e C, Chulián S, Rosa M, Ci illo D,
Ga cía E, Ga cía J, Manzano-Muñoz A,
Minguela A and Fus e JL (2023) The elapsed
acu e lymphoblas ic leukemia ne wo k
(ReALLNe ): a mul idisciplina y p ojec om he
spanish socie y o pedia ic hema ology and
oncology (SEHOP).
F on . Pedia . 11:1269560.
doi: 10.3389/ ped.2023.1269560
COPYRIGHT
© 2023 Velasco, Bau is a, Rubio, Aguila , Ri es,
Dapena, Pé ez, Rami ez, Saiz-Lade a, Izquie do,
Escude o, Camós, Vega-Ga cia, O ega,
Hidalgo-Gómez, Palacio, Menéndez, Bueno,
Mon e o, Romecín, Zazo, Al a ez, Pa as,
O ega-Saba e , Chulián, Rosa, Ci illo, Ga cía,
Ga cía, Manzano-Muñoz, Minguela and Fus e .
This is an open-access a icle dis ibu ed unde
he e ms o he C ea i e Commons A ibu ion
License (CC BY). The use, dis ibu ion o
ep oduc ion in o he o ums is pe mi ed,
p o ided he o iginal au ho (s) and he
copy igh owne (s) a e c edi ed and ha he
o iginal publica ion in his jou nal is ci ed, in
acco dance wi h accep ed academic p ac ice.
No use, dis ibu ion o ep oduc ion is
pe mi ed which does no comply wi h hese
e ms.
The elapsed acu e lymphoblas ic
leukemia ne wo k (ReALLNe ): a
mul idisciplina y p ojec om he
spanish socie y o pedia ic
hema ology and oncology (SEHOP)
Pablo Velasco1*, F ancisco Bau is a2, Alba Rubio3, Yu ena Aguila 4,
Susana Ri es5,6, Jose L. Dapena5,6, An onio Pé ez7,8,9,
Manuel Rami ez10, C is ina Saiz-Lade a10, Elisa Izquie do8,11,
Adela Escude o8,11, Mi eia Camós6,12,13, Ne ea Vega-Ga cía6,13,
Ma ga i a O ega14,15, Glo ia Hidalgo-Gómez14,15, Ca los Palacio14,15,
Pablo Menéndez16,17,18,19, Cla a Bueno16,17,18,20, Joan Mon e o21,22,
Paola A. Romecín16,17, San iago Zazo23, Fede ico Al a ez23,
Juan Pa as23, Ca men O ega-Saba e 24, Sal ado Chulián25,26,
Ma ía Rosa24,25, Da ide Ci illo27, Elena Ga cía10, Jo ge Ga cía10,
Albe Manzano-Muñoz22,28, Al edo Minguela29,30 and
Jose L. Fus e 30,31
1
Pedia ic Oncology and Hema ology Depa men , Vall d’Heb on Ba celona Hospi al, Campus, Ba celona,
Spain,
2
T ial and Da a Cen um, P inses Maxima Cen um, P incess Máxima Cen e o Pedia ic Oncology,
U ech , Ne he lands,
3
Pedia ic Oncology and Hema ology Depa men , Hospi al In an il Uni e si a io
Niño Jesús, Mad id, Spain,
4
Pedia ic Oncology and Hema ology Depa men , Hospi al Miguel Se e
Hospi al, Za agoza, Spain,
5
Leukemia and Lymphoma Uni , Pedia ic Cance Cen e Ba celona (PCCB),
Hospi al San Joan de Déu de Ba celona, Ba celona, Spain,
6
Pedia ic Cance Cen e Ba celona (PCCB),
Ins i u de Rece ca San Joan de Déu, Leukemia and Pedia ic Hema ology Diso de s, De elopmen al
Tumo s Biology G oup, Ba celona, Spain,
7
T ansla ional Resea ch in Pedia ic Oncology, Hema opoie ic
T ansplan a ion and Cell The apy G oup, Hospi al La Paz Ins i u e o Heal h Resea ch (IdiPAZ), La Paz
Uni e si y Hospi al, Mad id, Spain,
8
Pedia ic Hema o-Oncology Depa men , La Paz Uni e si y Hospi al,
Mad id, Spain,
9
Pedia ic Depa men , Uni e sidad Au onoma de Mad id, Mad id, Spain,
10
Hema ology and
Oncology Labo a o y, Fundación Pa a La In es igación Biomédica Hospi al In an il Uni e si a io Niño
Jesús, Mad id, Spain,
11
Depa men o Gene ics, Ins i u e o Medical and Molecula Gene ics (INGEMM), La
Paz Uni e si y Hospi al, Mad id, Spain,
12
Cen o de In es igación Biomédica en Red de En e medades
Ra as (CIBERER), Ins i u o de Salud Ca los III, Mad id, Spain,
13
Hema ology Labo a o y, Hospi al San Joan
de Déu Ba celona, Ba celona, Spain,
14
Hema ology Se ice, Vall d’Heb on Ba celona Hospi al, Campus,
Ba celona, Spain,
15
Vall d’Heb on Ins i u e o Oncology (VHIO), Vall d’Heb on Ba celona Hospi al Campus,
Ba celona, Spain,
16
Josep Ca e as Leukemia Rese ach Ins i u e, De elopmen al Leukemia and
Immuno he apy g oup, Ba celona, Spain,
17
Red Española de Te apias A anzadas (TERAV)-Ins i u o de
Salud Ca los III (ISCIII) (RICORS, RD21/0017/0029), Mad id, Spain,
18
CIBER-ONC, ISCIII, Ba celona, Spain,
19
Ins i ució Ca alana de Rece ca I Es udis A ança s (ICREA), Ba celona, Spain,
20
Depa men o
Biomedicine, School o Medicine, Uni e si y o Ba celona, Ba celona, Spain,
21
Ne wo king Biomedical
Resea ch Cen e in Bioenginee ing, Bioma e ials and Nanomedicine (CIBER-BBN), Mad id, Spain,
22
Depa men o Biomedical Sciences, Facul y o Medicine and Heal h Sciences, Uni e si a de Ba celona,
Ba celona, Spain,
23
In o ma ion P ocessing and Telecommunica ions Cen e , Uni e sidad Poli écnica de
Mad id, Mad id, Spain,
24
Ma hema ical Oncology Labo a o y (MOLAB), Uni e si y o Cas illa-La Mancha,
Ciudad Real, Spain,
25
Depa men o Ma hema ics, Uni e sidad de Cádiz, Cádiz, Spain,
26
Biomedical
Resea ch and Inno a ion Ins i u e o Cádiz (INiBICA), Hospi al Uni e si a io Pue a del Ma , Cádiz, Spain,
27
Ba celona Supe compu ing Cen e (BSC), Ba celona, Spain,
28
Nanobioenginee ing G oup, Ins i u e o
Bioenginee ing o Ca alonia (IBEC), Ba celona Ins i u e o Science and Technology (BIST), Ba celona,
Spain,
29
Immunology Depa men , Hospi al Clínico Uni e si a io Vi gen de la A ixaca, Mu cia, Spain,
30
Ins i u o Mu ciano de In es igación Biosani a ia (IMIB), Mu cia, Spain,
31
Paedia ic Oncohema ology
Depa men . Hospi al Clínico Uni e si a io Vi gen de la A ixaca, Mu cia, Spain
Acu e lymphoblas ic leukemia (ALL) is he mos common pedia ic cance , wi h
su i al a es exceeding 85%. Howe e , 15% o pa ien s will elapse;
consequen ly, hei su i al a es dec ease o below 50%. The e o e, se e al
TYPE Pe spec i e
PUBLISHED 20 Sep embe 2023
|
DOI 10.3389/ ped.2023.1269560
F on ie s in Pedia ics 01 on ie sin.o g
esea ch and inno a ion s udies a e ocusing on pedia ic elapsed o e ac o y ALL (R/R
ALL). D i en by his con ex and ollowing he Eu opean s a egic plan o implemen
p ecision medicine equi ably, he Relapsed ALL Ne wo k (ReALLNe ) was launched unde
he umb ella o SEHOP in 2021, aiming o connec bedside pa ien ca e wi h expe
g oups in R/R ALL in an in e disciplina y and mul icen ic ne wo k. To achie e his
objec i e, a boa d consis ing o expe s in diagnosis, managemen , p eclinical esea ch,
and clinical ials has been es ablished. The equi emen s o ea men cen e s ha e been
e alua ed, and he a ailable oncogenomic and unc ional s udy esou ces ha e been
assessed and o ganized. A shipping pla o m has been de eloped o p ocess samples
equi ing s udy de i a ion, and an in eg a ed diagnos ic commi ee has been es ablished
o epo esul s. These biological da a, as well as pa ien ou comes, a e collec ed in a
na ional egis y. Addi ionally, samples om all pa ien s a e s o ed in a biobank. This
comp ehensi e eposi o y o da a and samples is expec ed o os e an en i onmen
whe e p eclinical esea che s and da a scien is s can seek o mee he complex needs o
his challenging popula ion. This p oo o concep aims o demons a e ha a ne wo k-
based o ganiza ion, such as ha embodied by ReALLNe , p o ides he ideal niche o he
equi able and e ficien implemen a ion o “wha ’snex ”in he managemen o child en
wi h R/R ALL.
KEYWORDS
elapsed acu e lymphoblas ic leukemia, p ecision medicine, cance egis y, a ificial in elligence,
unc ional assay
1. In oduc ion
Acu e lymphoblas ic leukemia (ALL) is he mos common
childhood cance . A ound 300 new cases a e diagnosed each yea
in Spain, ep esen ing one-qua e o all pedia ic malignancies.
In Spain, 85% o pa ien s will su i e in he long- e m (1).
Howe e , 15% will expe ience a fi s elapse o will be e ac o y
o fi s line chemo he apy (R/R ALL) and, o hose, he o e all
su i al d ops below 50% and 30% espec i ely (2,3). As a
consequence, ALL emains one o he main causes o cance
dea h among child en (4).
The In e na ional Be lin-F ank u -Müns e (I-BFM) S udy
G oup and he Spanish Socie y o Pedia ic Hema ology and
Oncology (SEHOP) ha e de eloped ea men p o ocols o
pedia ic R/R ALL o imp o e hese s a is ics. In 2015, he LAL/
SEHOP-PETHEMA-2015 guidelines we e es ablished by he
ALL-wo king g oup o SEHOP. This guideline is based on he
s anda d p o ocols om he In ReALL 2010 s anda d and high-
isk ials (NCT01802814, NCT03590171) and i aimed o
ha monize he ea men o child en wi h ALL a fi s elapse in
Spain. The da a ga he ed om he a o emen ioned p o ocols and
guideline ha e demons a ed ha he leukemia genomics, ime
elapsed om fi s diagnosis o elapse, loca ion o elapse, and
esponse a e e-induc ion in e ms o minimal esidual disease
(MRD), a e c i ical in defining isk g oups ha may equi e
mo e in ensi e o al e na i e ea men s, such as immuno he apy
o a ge ed he apies (4–6). Based on hese findings, upcoming
clinical ials in his popula ion will ely on he use o ad anced
gene ic s udies and s anda dized MRD moni o ing o isk
s a ifica ion; howe e , no all cen e s in Spain ha e access o he
necessa y echnology o pe o m hese echniques.
The LAL/SEHOP/PETHEMA-2015 guideline p o ided he fi s
egis y o clinical da a om pedia ic pa ien s a e fi s elapse o
ALL in Spain; ne e heless, a mo e comp ehensi e egis y collec ing
accu a e biological and clinical da a ha co e s he en i e popula ion
is needed o ha e a b oade iew o he si ua ion in ou coun y ha
can be used as a baseline o u u e compa ison. Mo eo e , i is
necessa y o c ea e a na ionwide biobank whe e umo ma e ial
can be s o ed o u he esea ch ha can be coupled wi h o he
clinical and biological da a. This is a undamen al piece o
p omo e esea ch in his field in Spain, and o o e come he
his o ical limi a ions o he p eclinical esea che s o ha e access o
samples necessa y o pe o m high-quali y esea ch.
Recen ly, he Eu opean Socie y o Pedia ic Oncology published
he 2021–2026 Eu opean S a egic Cance Plan o Child en and
Adolescen s, which ocused on he mission o “cu e mo e and cu e
be e ”(7). To his end, hey de eloped se en esea ch objec i es
cen e ed on equi y, p ecision medicine, unde s anding he biology
and causes o cance , imp o ing quali y o li e, and le e aging big
da a and a ificial in elligence.
In line wi h hese p inciples, a a Eu opean le el, academic
socie ies like he Inno a i e The apies o Child en wi h Cance
(ITCC) conso ium (8) and, in Spain, he In e na ional Mul icen e
Clinical T ial-SEHOP (ECLIM-SEHOP) pla o m (9), wo k o
enable access o new he apies h ough clinical ials. Mo eo e ,
expe s in R/R ALL om bo h I-BFM and ITCC a e cu en ly
wo king on es ablishing commi ees designed o discuss complex
cases e e ed om na ional boa ds, like he FEDRRAL umo boa d
om IBFM esis an disease g oup, o he in e na ional leukemia
a ge boa d (iLTB), whe e child en wi h elapsed/ e ac o y
hema ological malignancies, a e discussed (NCT05270096).
All his inno a ion in he diagnosis and ea men o R/R ALL
has inc eased he complexi y in managing hese pa ien s, which
ep esen s a significan challenge o cen e s o implemen and
in e p e he mos cu en diagnos ic me hods and o access
clinical ials o new d ugs.
Velasco e al. 10.3389/ ped.2023.1269560
F on ie s in Pedia ics 02 on ie sin.o g
The Relapsed Acu e Lymphoblas ic Leukemia Ne wo k
(ReALLNe ) is a p ojec es ablished unde he umb ella o
SEHOP in Ma ch 2021. The goal o ReALLNe is o b idge he
gap be ween bedside pa ien ca e and he clinical and esea ch
expe field. This will b ing inno a ion quickly and
comp ehensi ely o all cen e s ac oss Spain in an equi able
manne . Simul aneously, i seeks o influence he p omo ion and
o ganiza ion o esea ch s udies, ensu ing hey a e d i en by eal
heal hca e needs. The me hods o achie e his include: (1)
es ablishing a ne wo k o labo a o ies o conduc ing biological
s udies and ad anced esea ch, (2) consolida ing a ne wo k o
hospi als able o p o iding access o clinical ials, and (3)
es ablishing a sha ed da a esou ce and biobank o R/R ALL
samples.
In he ollowing subsec ions, we p esen he s uc u e upon
which ReALLNe has been buil o add ess hese objec i es, as
well as he p elimina y esul s o he ne wo k and o hcoming
s eps.
2. Relapse and e ac o y ALL na ional
egis y
The cance egis y o e s se e al benefi s. I aids in iden i ying
isk ac o s, in o ms clinical p ac ice and ea men decisions,
e alua es he e ec i eness and ou comes o ea men s, acili a es
esea ch and collabo a ion, moni o s ends and dispa i ies, and
se es as a basis o guidelines and public heal h in e en ions (10).
To ca alog and eco d all he in o ma ion gene a ed, a na ional
egis y o pedia ic R/R ALL has been c ea ed. This egis y
sys ema ically collec s clinical and biological da a om pa ien s
in a coded o ma . This was c ea ed using he RedCap sys em
(11), hos ed on he se e s o Vall d’Heb on Resea ch Ins i u e
(VHIR).
Upon he signing o in o med consen by he pa ien and hei
amily, he ea ing physician can access he egis y, whe e he
pa ien will be iden ified by a unique code. Va iables will be
en e ed ollowing he pa ien ’s cou se wi h R/R ALL, including
fi s diagnosis, fi s and subsequen elapses o e ac o iness.
The use will be allowed o access hei da a and g aphs, which
enhances he egis an ’s expe ience and acili a es i s use as hei
own local egis y. In he ollowing s ages, i is planned o
inco po a e Pa ien -Repo ed Ou come Measu es (PROMs) and
Pa ien -Repo ed Expe ience Measu es (PREMs) in o he egis y
o gene a e addi ional ou come in o ma ion o be e espond o
pa ien ’s p e e ences.
3. ReALL boa d
As an ini ial s ep, he boa d was cons i u ed by expe s in R/R
ALL om clinical, diagnos ic, esea ch, and ma hema ical and
compu a ional fields. In Oc obe 2021, he ReALLNe pla o m
was launched wi hin he secu ed en i onmen o he SEHOP
websi e (www.sehop.o g) o p o essionals. This pla o m o e s
a ious esou ces such as a discussion o um whe e physicians
om any Spanish cen e can submi inque ies abou specific
cases and pa icipa e in discussions wi hin 48 h o consul a ion.
The da a o his consul a ions a e no included in he egis y.
Twen y- ou pa ien s om 15 egions we e discussed be ween
Oc obe 2021 and July 2023 (Table 1). Pa ien s’ages anged
om 8 mon hs o 16 yea s, wi h mos o hem ha ing a poo
p ognosis R/R ALL, 6 pa ien s had high- isk fi s elapse o ALL
(ea ly and e y ea ly), 6 had a second o la e elapse, and 3 had
e ac o y disease. Twen y- h ee ea ing physicians ollowed he
ecommenda ions o he ReALLBoa d. Immuno he apy was
adminis e ed in se en pa ien s, and a ge ed he apy based on
unc ional assays was gi en in wo pa ien s. The boa d
discussions esul ed in a o al o 15 e e als, in ol ing bo h
pa ien s and samples, o he iden ified cen e s o expe ise wi hin
ReALLNe . Ou o hese e e als, 2 pa ien s we e di ec ed o
pa icipa e in a clinical ial, 3 pa ien s we e e e ed o CAR-T
he apy, and 3 pa ien s we e e e ed o hema opoie ic s em
ansplan a ion (HSCT). In e ms o samples, 5 samples we e
e e ed o unc ional assays by d ug esponse p ofiling (DRP)
and dynamic BH3 p ofiling (DBP), while 2 samples we e e e ed
o nex -gene a ion sequencing (NGS) analysis. A da a cu -o
(July 15 h, 2023), 18 pa ien s emain ali e and in comple e
emission (CR), 1 is ali e wi h disease a e subsequen elapse,
and 5 pa ien s ha e died, 3 o hem due o disease p og ession
and 2 due o ea men - ela ed oxici y.
4. Pla o m o shipping, analysis, and
biobanking o samples
To acili a e he e e al o samples, ReALLNe has c ea ed a
sample shipping p o ocol ha ensu es he ans e o biological
ma e ial (i.e., bone ma ow elapse, pe iphe al blood, and ge m
issue) wi hin 24 h ac oss he en i e Spanish e i o y. This
p o ocol p io i izes he esh deli e y o samples unless a
ecep ion wi hin 48 h o ex ac ion canno be gua an eed, in
which case ozen samples a e p io i ized. Once he samples
a i e a he diagnos ic hubs (Hospi al San Joan de Déu in
Ba celona, Hospi al Uni e si a io La Paz in Mad id), hey a e
p ocessed o s o age in he biobank, oncogenomic es s
(Sec ion 5) and unc ional assays (Sec ion 6). To expedi e
decision-making and sample e e al, a comp ehensi e logis ical
p ocess has been de ised and g aphically ep esen ed. This
scheme p o ides de ailed ins uc ions on how o access all hese
esou ces and is a ailable o all ea ing physicians ia he p i a e
SEHOP websi e (Figu e 1A).
5. Oncogenomic es ing
Se e al gene ic al e a ions ha e been demons a ed o p edic
un a o able ou comes and, consequen ly, can benefi om
inno a i e s a egic ea men s such as immuno he apy o
a ge ed he apies (5,12,13). Nex gene a ion sequencing (NGS)
is cu en ly applied in some cen e s o iden i y hese al e a ions.
Howe e , nume ous cen e s lack he a ailabili y o unding o
Velasco e al. 10.3389/ ped.2023.1269560
F on ie s in Pedia ics 03 on ie sin.o g
TABLE 1 Desc ip ion o cases discussed in he ReALLBoa d, ecommenda ions, adhe ence o hem, e e als o pa ien s o samples, and ou come.
Case Age
(y)
ALL
lineage
Da e o
ReALLBoa d
Cy ogene ics Relapse o
e ac o y c i e ia
Recommenda ion Adh Re e al o
ano he
cen e
Cu en
s a us
1 4 B-ALL No 2021 Hype diploidy. CRLF2
ea angemen
Ve y ea ly isola ed bone
ma ow fi s elapse
LAL/SEHOP-PETHEMA
2015 HR and blina umomab
Yes No Ali e, CR
2 10 T-ALL Dec 2021 NOS Isola ed bone ma ow
ou h elapse
Vene oclax + bo ezomib
a e DRP/DBP
Yes Sample, o
DRP/DBP
Dea h o
disease
3 11 B-ALL Jan 2022 ETV6::RUNX1 Isola ed bone ma ow
second elapse
CAR-T Yes Pa ien , o
CAR-T
Ali e, CR
4 0.6 B-ALL Jan 2022 KMT2A::AFF1 Re ac o y combined
fi s elapse
CAR-T and DRP/DBP Yes Sample, o
DRP/DBP
Dea h o
disease
5 16 B-ALL Jan 2022 ETV6::RUNX1 Ve y ea ly isola ed bone
ma ow fi s elapse
LAL/SEHOP-PETHEMA
2015 HR and blina umomab
Yes No Ali e, CR
6 5 B-ALL Feb 2022 NOS Ea ly isola ed bone
ma ow fi s elapse
LAL/SEHOP-PETHEMA
2015 HR
Yes No Ali e, CR
7 13 B-ALL Ma 2022 Hype diploidy. TP53
mu
Re ac o y isola ed bone
ma ow fi s elapse
CAR-T Yes Pa ien , o
CAR-T
Ali e, CR
8 9 T-ALL May 2022 ETP Ea ly isola ed bone
ma ow fi s elapse,
a e HSCT
Vene oclax a e DRP/DBP
and HSCT
Yes Sample, o
DRP/DBP
Ali e, CR
9 4 B-ALL May 2022 ETV6::RUNX1 Re ac o y isola ed bone
ma ow fi s elapse
Blina umomab, Ino uzumab
and HSCT
Yes Pa ien , o
HSCT
Ali e, CR
10 16 T-ALL Aug 2022 NOS MRD pe sis ence du ing
fi s line ea men
Nela abine and HSCT Yes Pa ien , o
HSCT
Ali e, CR
11 8 T-ALL Aug 2022 NOS Ea ly ex amedulla y
(ocula ) second elapse
a e HSCT
Nela abine, adio he apy, IT Yes No Dea h o
disease
12 11 MPAL Sep 2022 ZEB::BCL11B La e isola ed bone
ma ow fi s elapse,
a e HSCT
TVTC No No T ea men
ela ed dea h
13 11 T-ALL Oc 2022 CDKN2A del Re-eme gence, MRD 1% CVC and HSCT Yes Sample, o
NGS
T ea men
ela ed dea h
14 9 B-ALL No 2022 FLT3 mu Re-eme gence du ing
midos au in
main enance
Follow up Yes Sample, o
DRP/DBP
Ali e wi h
disease
15 10 B-ALL Ma 2022 BCR::ABL1 Combined bone ma ow
second elapse
Pona inib (CT) +IT Yes Pa ien , o CT Ali e, CR
16 5 B-ALL Ma 2023 NOS La e isola ed bone
ma ow fi s elapse
LAL/SEHOP-PETHEMA
2015 SR
Yes No Ali e, CR
17 8 B-ALL Ma 2023 NOS La e combined bone
ma ow fi s elapse
LAL/SEHOP-PETHEMA
2015 SR
Yes No Ali e, CR
18 3 B-ALL Ma 2023 NOS Ea ly isola ed medulla y
second elapse
CAR-T Yes Pa ien , o
CAR-T
Ali e, CR
19 14 B-ALL Ap 2023 KRAS mu Poo esponse o
induc ion o la e isola ed
bone ma ow fi s
elapse
LAL/SEHOP-PETHEMA
2015 HR and blina umomab
Yes No Ali e, CR
20 9 B-ALL Ap 2023 Hype diploidy. JAK2
mu , IKZF1 del,
PAX5mu
La e combined bone
ma ow fi s elapse
LAL/SEHOP-PETHEMA
2015 SR
Yes No Ali e, CR
21 10 T-ALL Ap 2023 NOS Ve y ea ly isola ed bone
ma ow fi s elapse
CT Yes Pa ien , o CT Ali e, CR
22 12 T-ALL May 2023 NOS Ea ly isola ed bone
ma ow fi s elapse
LAL/SEHOP-PETHEMA
2015 HR
Yes Sample, o FC Ali e, CR
23 4 B-ALL Jul 2023 TCF3::PBX1 Ea ly isola ed bone
ma ow second elapse
a e CAR-T and HSCT
NGS and DRP/DBP Yes Sample, o
NGS and DRP/
DBP
Ali e, CR
24 16 B-ALL Jul 2023 CRLF2 o e exp essed La e isola ed bone
ma ow fi s elapse
LAL/SEHOP-PETHEMA
2015 SR
Yes No Ali e, CR
Adh, adhe ence; CR, comple e esponse. CT, clinical ial; CVC, clo a abine, e oposide, and cyclophosphamide; DBP, B H3 p ofiling; DRP, d ug esponse p ofiling; ETP,
ea ly T-cell p ecu so leukemia; FC, flow cy ome y; HSCT, hema opoe ic s em cell ansplan a ion; IT, in a hecal he apy; NGS, nex gene a ion sequency; NOS, no
o he wise specified; MPAL, mixed pheno ype acu e leukaemia; MRD, minimal esidual disease; TVTC, opo ecan, ino elbine, hio epa, and clo a abine.
Velasco e al. 10.3389/ ped.2023.1269560
F on ie s in Pedia ics 04 on ie sin.o g
molecula p ofile by NGS in hei egion. In hese si ua ions,
ReALLNe ’s highly expe ienced oncogenomics eam p ocesses he
submi ed samples in i s in eg a ed diagnos ic uni s. To his end,
we e alua ed he comme cial and cus om NGS panels a ailable
in Spanish e i o y, achie ed consensus on he minimal genes o
be analyzed in he con ex o R/R ALL, and c ea ed a common
epo shee .
An in eg a i e diagnos ic commi ee has been es ablished,
appoin ed o analyze, discuss and epo oncogenomic and
unc ional esul s coming om he ne wo k’s diagnos ic hubs o
indi idual cen e s.
Simila molecula pla o ms ha e been es ablished in o he
coun ies, like he LEAP conso ium p ojec (14) in he US and
INFORM (15) in Ge many, showing ha be ween 8% and 12%
o pa ien s wi h a elapsed malignancy can benefi oma
a ge ed ea men based on oncogenomic s udies and guided by
a mul idisciplina y na ional boa d.
In subsequen s eps, we aim o inco po a e addi ional
echniques o a mo e comp ehensi e analysis in he ne wo k’s
hubs. In ascending o de o complexi y, hese echniques will
include whole-exome sequencing (WES), ansc ip ome
sequencing (RNA-seq), and whole-genome sequencing (WGS).
In addi ion o iden i ying umo DNA a ian s in pa ien s wi h
R/R ALL, we highligh he impo ance o complemen ing gene ic
s udies wi h he analysis o ge mline DNA om hese pa ien s.
In compliance wi h he p inciples o he Helsinki Decla a ion,
in o med consen is ob ained om all pa icipan s, ensu ing
e hical conduc h oughou he esea ch p ocess. The
iden ifica ion o ge mline al e a ions using, o example, cul u ed
fib oblas s, pe iphe al blood, o sali a in emission could help o
ecognize cance p edisposi ion synd omes (16–18) ha inc ease
he isk o leukemia de elopmen , o en unde diagnosed bu
c i ical o he co ec managemen o pa ien s and hei amilies.
The ge mline analysis also allows he iden ifica ion o gene ic
polymo phisms ha can significan ly influence he up ake,
me abolism, and elimina ion o cu en ly used d ugs, p o iding
addi ional help ul in o ma ion du ing he ea men o pedia ic
pa ien s (19,20). Ge minal gene ic esul s analyzed will be
epo ed om he gene ic counseling uni s o he diagnos ic
cen e s, in case ele an findings a e disco e ed.
The moni o ing o MRD has p o en o be a p edic i e ac o in
R/R ALL and has been u ilized o in ensi y ea men in ALL elapse
p o ocols (5,21). Clone-specific MRD assessmen has eme ged as
highly sensi i e and has been selec ed o use in se e al upcoming
clinical ials in R/R ALL. The e o e, ReALLNe seeks o assis
cen e s ha ha e no ye implemen ed he eal- ime PCR-based
quan ifica ion o IG/TR ea angemen s o MRD assessmen by
p o iding his se ice h ough i s diagnos ic hubs.
6. Func ional assays
Inno a i e echniques a e employed o e alua e specific
leukemia d ug sensi i i y h ough ex i o unc ional s udies, such
as DRP o DBP. Ca ying ou in i o cy o oxici y es s on he
neoplas ic cells could help he sea ch o a mo e pe sonalized
he apeu ic op ion. These s udies a e pe o med in eal ime,
yielding esul s wi hin a sho ime ame. Wi h his app oach we
FIGURE 1
(A) Logis ical ep esen a ion o he ReALLNe R/R ALL ne wo k on he SEHOP websi e o p o essionals. (B) Illus a es he algo i hm o ques ions ollowed
by he Clinical T ial Decision P og am o ma ch pa ien s wi h he mos sui able ials. Schema ic ep esen a ion o he esou ces p o ided by he pla o m,
each ep esen ed by an icon. Selec ing each icon allows access o he espec i e esou ce. ReALLBoa d: Access o consul a ions o he expe
commi ee. CTDM (Clinical T ial Decision Make ): A decision-making p og am p o iding he bes clinical ials ailo ed o indi idual pa ien needs. Tes
Tube Icon: Rep esen s he necessa y documen s o sending samples o diagnosis and p ese a ion (Biobank). This p ocess akes place a he
ReALLNe diagnos ics hubs, La Paz Uni e si y Hospi al (Mad id) and San Joan de Déu Hospi al (Ba celona). RedCAp: A pseudonymized egis y o
clinical and diagnos ic a iables o pedia ic pa ien s wi h R/R ALL. IgH/TCR RQ-PCR: Real- ime PCR-based quan ifica ion o IG/TR ea angemen s.
NGS: Nex Gene a ion Sequencing. D ug Response P ofiling: Func ional assay a he Ins i u de Rece ca de Josep Ca e as (Pablo Menéndez Lab).
Dynamic BH3 P ofiling: Func ional assay a he Uni e si y o Ba celona (Joan Mon e o Lab).
Velasco e al. 10.3389/ ped.2023.1269560
F on ie s in Pedia ics 05 on ie sin.o g
aim o alida e i s po en ial o assis clinicians in pe sonalizing
he apy, s a i ying pa ien s, and iden i ying mo e e ec i e and
less oxic ea men s o R/R ALL. The objec i e o ReALLNe is o
alida e hese s udies h ough his esea ch. In he mean ime, he
esul s a e epo ed as expe imen al findings awai ing alida ion.
6.1. Dynamic BH3 p ofiling
Pedia ic leukemia o en p esen s esis ance o apop osis (many
gene ic al e a ions in ALL lead o an inc ease in an i-apop o ic
p o eins o he BCL-2 amily). In his p ojec , we use new unc ional
assays o c ea e a d ug esponse p ofile, including he DBP, which
can p edic which ea men s will be mos e ec i e in elimina ing a
specific umo . DBP has al eady been used o e alua e he apies in
di e en ypes o cance (22) and has been success ully es ed in
ALL (23–26). In addi ion, we can execu e his assay o iden i y an i-
apop o ic adap a ions and use ha in o ma ion o design new
he apeu ic s a egies o ALL, p e en ing i om becoming esis an
and es o ing i s sensi i i y o cell dea h.
6.2. D ug esponse p ofiling
Fu he mo e, an addi ional DRP me hod analyzes cell dea h
engagemen on cance cells co-cul u ed wi h mesenchymal s em
cells (MSC) isola ed om bone ma ow (BM). I is well-known
ha BM s oma con e s chemo esis ance o leukemic cells in a
a ie y o hema ological malignancies (27,28). In o de o mimic
BM mic oen i omen , he assays a e ca ied ou by co-cul i a ing
leukemic cells wi h BM- MSCs. Inc easing doses o he d ugs o
be es ed will be added o his co-cul u e, alone o in combina ion
wi h he s anda d chemo he apy acco ding o he ype o
leukemia. D ugs, which a e in e oga ed, a e chosen based on
FDA and/o EMA app o ed medica ions ha specifically a ge
hema ologic malignancies such us uxoli inib, ene oclax,
fluda abine, quiza imib, bo ezomib, among o he s. Blas s-MSC
co-cul u es a e incuba ed o 36 h wi h each d ug combina ion,
he deg ee o apop osis o cell iabili y is de ec ed by flow cy ome y.
7. Da a and compu a ional science
7.1. Da a science
Ea ly iden ifica ion o he apeu ic scheme ailu es is c ucial o
p e en oxici y and ini ia e al e na i e ea men s p omp ly. To
achie e his, we p opose a esea ch wo k package ocused on
bioma hema ical modeling. Ou app oach in ol es conduc ing in
silico analysis o pa ien cha ac e is ics associa ed wi h he ac ual
disease, enabling he iden ifica ion o key bioma ke s o
p edic i e pu poses. The e m “in silico” e e s o he use o
compu e simula ions and da a analysis o de elop o e alua e
medicinal p oduc s o medical in e en ions (29).
Le e aging inno a i e echniques om machine lea ning (ML)
and a ificial in elligence (AI), da a science me hods could
con ibu e an addi ional laye o pa ien classifica ion. These
echniques can pe o m ea u e ex ac ion, gleaning ele an
insigh s om aw da a, and po en ially leading o mo e
sophis ica ed pa ien s a ifica ion and imp o ed heal hca e
ou comes. By ex ac ing clinical, genomic, and immunopheno ypic
in o ma ion, we can label each pa ien based on hei esponse o
disease sub ype, c ea ing a labeled da ase ha can be analyzed
using supe ised algo i hms. To add ess po en ial a ia ions in he
numbe o pa ien sub coho s and selec he op imal pa ame e s
o each model, we will employ k- old c oss- alida ion echniques.
Some me hodologies ha e al eady explo ed he use o flow
cy ome y da a, leading o he eme gence o compu a ional
flow cy ome y as a g owing field (30). Complemen a y o flow
cy ome y, genomic da a om hese pa ien s will also be a ailable
a he ime o elapse. They ha e p o en use ul o cha ac e ize
mu abili y ho spo s (31) and o cha ac e ize he ela i e unc ional
impac o d i e and passenge mu a ions (32). Some genomic
ea u es, such as copy numbe al e a ions (CNA), umo
mu a ional bu den (TMB) o neoan igen load, will p o ide us
wi h gene al in o ma ion on he he e ogenei y and disease
p og ession s a us o hese pa ien s. As hey a e also quan i a i e
measu es, hey could easily be in eg a ed in o supe ised
algo i hms and p edic i e models, oge he wi h flow cy ome y
da a.
Howe e , ce ain limi a ions pe sis , including challenges in
ansla ing hese s udies o clinical se ings in an in e p e able
manne o clinicians. The inclusion o a bioma hema ical b anch
in his p ojec will p o ide use - iendly ools o implemen a ion
in hospi als. Cons uc ing p edic i e algo i hms will also equi e
add essing se e al open p oblems, including da a no maliza ion,
me hods o impu ing missing da a, model compa ison, ea u e
selec ion, and in e p e a ion. These challenges a e pe inen o
any medical da ase and mus be adequa ely esol ed o de elop
obus and clinically ele an p edic i e models.
7.2. Clinical ial decision make
In o de o keep ea ing physicians up- o-da e wi h he open
clinical ials in Spain and o acili a e he discussion o clinical
cases wi hin he ReALLBoa d, we ha e de eloped a decision-
suppo so wa e p og am, add essed o he a ending physicians,
known as he Clinical T ial Decision Make (CTDM). Based on a
se ies o mu ually exclusi e ques ions ela ed o he clinical and
biological cha ac e is ics o he disease, he algo i hm p o ides a
lis o po en ial clinical ials o which he pa ien may be
eligible and ha a e a ailable in any o he SEHOP hospi als
(Figu e 1B). This me hod is an icipa ed o a o he access o
pa ien s o clinical ials, he eby b oadening he a ay o
oppo uni ies accessible o pa ien s.
8. Implemen a ion and unding
The au ho (s) decla e ha no financial suppo was ecei ed o
he esea ch, au ho ship, and/o publica ion o his a icle.
Velasco e al. 10.3389/ ped.2023.1269560
F on ie s in Pedia ics 06 on ie sin.o g
The ne wo k’s me hodology will enable a comp ehensi e
e alua ion o inno a i e echniques and he es ablishmen o a
mul is akeholde ask o ce, including pa ien ad oca es and
policymake s, o implemen he mos e ficien s a egies in o he
public heal h sys em ac oss all egions, wi h he aim o
p omo ing equi y in achie ing he objec i e o “cu e mo e and
cu e be e ”.
A p esen , he ReALLNe in as uc u e has been unded
h ough he suppo o pha maceu ical companies and he
suppo o SEHOP.
The SEHOP-PENCIL s udy (PMP21/00073 AES-ISCIII),
wi hin i s aim o implemen ing pe sonalized medicine
p og amme o pedia ic oncology in Spain, has iden ified
ReALLNe as an e ficien pla o m ocused and high specialized
on malignan hema ological diseases. As a esul , i has
es ablished common wo king g oups be ween bo h p ojec s, and
p o ide financial suppo o pa o oncogenomic s udies o e ed
by ReALLNe .
We also plan o finance esea ch modules h ough compe i i e
g an .
9. Conclusion
Resea ch ocused on “wha ’snex ”in he diagnosis and
managemen o pedia ic R/R ALL pa ien s o e s significan
oppo uni ies o imp o e esponses and educe oxici y h ough
mo e ailo ed ea men s. To in eg a e his esea ch in o bedside
pa ien ca e in a p agma ic and eal-li e con ex , i is c ucial o
o ganize his inno a ion in a comp ehensi e and accessible
manne o all ea ing physicians.
ReALLNe is an in e disciplina y and mul icen ic ne wo k
wi hin he Spanish scien ific academic communi y o SEHOP. I
es ablishes a pla o m o in oduce and alida e bo h exis ing and
eme ging diagnos ic echniques, alongside inno a i e esea ch, in
a collabo a i e en i onmen ha connec s expe s in diagnosis,
managemen , esea ch, and compu a ion in R/R ALL o e e y
pedia ic oncology depa men in Spain. I s p ima y objec i e is
o equip all physicians wi h he la es diagnos ic and decision-
making esou ces, while also p o iding a sys ema ically o ganized
da a egis y and sample biobank o ad ance esea ch in pedia ic
R/R ALL.
Da a a ailabili y s a emen
The o iginal con ibu ions p esen ed in he s udy a e included
in he a icle/Supplemen a y Ma e ials, u he inqui ies can be
di ec ed o he co esponding au ho s.
E hics s a emen
E hical e iew and app o al was no equi ed o he s udy o
human pa icipan s in acco dance wi h he local legisla ion and
ins i u ional equi emen s. W i en in o med consen om he
pa ien s/ pa icipan s OR pa ien s/pa icipan s legal gua dian/nex
o kin was no equi ed o pa icipa e in his s udy in acco dance
wi h he na ional legisla ion and he ins i u ional equi emen s.
Au ho con ibu ions
PV: Concep ualiza ion, Da a cu a ion, Fo mal Analysis,
Me hodology, P ojec adminis a ion, Valida ion, W i ing –
o iginal d a , W i ing – e iew & edi ing. FB: Concep ualiza ion,
Me hodology, P ojec adminis a ion, W i ing –o iginal d a ,
W i ing – e iew & edi ing. AR: Concep ualiza ion, Me hodology,
P ojec adminis a ion, W i ing –o iginal d a , W i ing – e iew
& edi ing. YA: Concep ualiza ion, Da a cu a ion, Me hodology,
P ojec adminis a ion, W i ing –o iginal d a , W i ing – e iew
& edi ing. SR: Concep ualiza ion, Me hodology, P ojec
adminis a ion, W i ing – e iew & edi ing. JD: Concep ualiza ion,
Me hodology, P ojec adminis a ion, W i ing – e iew & edi ing.
AP: Concep ualiza ion, Me hodology, P ojec adminis a ion,
W i ing – e iew & edi ing. MR: Concep ualiza ion, Me hodology,
P ojec adminis a ion, W i ing – e iew & edi ing. CS:
Concep ualiza ion, Me hodology, P ojec adminis a ion, W i ing –
e iew & edi ing. EI: Concep ualiza ion, Me hodology, P ojec
adminis a ion, W i ing – e iew & edi ing. AE: Concep ualiza ion,
Me hodology, P ojec adminis a ion, W i ing –o iginal d a ,
W i ing – e iew & edi ing. MC: Concep ualiza ion, Me hodology,
P ojec adminis a ion, W i ing – e iew & edi ing. NV:
Concep ualiza ion, Me hodology, P ojec adminis a ion, W i ing –
o iginal d a , W i ing – e iew & edi ing. MO: Concep ualiza ion,
Me hodology, P ojec adminis a ion, W i ing – e iew & edi ing.
GH: Concep ualiza ion, Me hodology, P ojec adminis a ion,
W i ing – e iew & edi ing. CP: Concep ualiza ion, Me hodology,
P ojec adminis a ion, W i ing – e iew & edi ing. PM:
Concep ualiza ion, Me hodology, P ojec adminis a ion, W i ing –
e iew & edi ing. CB: Concep ualiza ion, Me hodology, P ojec
adminis a ion, W i ing –o iginal d a , W i ing – e iew &
edi ing. JM: Concep ualiza ion, Me hodology, P ojec
adminis a ion, W i ing –o iginal d a , W i ing – e iew &
edi ing. PR: Concep ualiza ion, Me hodology, P ojec
adminis a ion, W i ing – e iew & edi ing. SZ: Concep ualiza ion,
Me hodology, P ojec adminis a ion, W i ing – e iew & edi ing.
FA: Concep ualiza ion, Me hodology, P ojec adminis a ion,
W i ing – e iew & edi ing. JP: Concep ualiza ion, Me hodology,
P ojec adminis a ion, W i ing – e iew & edi ing. CO:
Concep ualiza ion, Me hodology, P ojec adminis a ion, W i ing –
o iginal d a , W i ing – e iew & edi ing. SC: Concep ualiza ion,
Me hodology, P ojec adminis a ion, W i ing –o iginal d a ,
W i ing – e iew & edi ing. MR: Concep ualiza ion, Me hodology,
P ojec adminis a ion, W i ing – e iew & edi ing. DC:
Concep ualiza ion, Me hodology, P ojec adminis a ion, W i ing –
e iew & edi ing. EG: Concep ualiza ion, Me hodology, P ojec
adminis a ion, W i ing – e iew & edi ing. JG: Concep ualiza ion,
Me hodology, P ojec adminis a ion, W i ing – e iew & edi ing.
AM: Me hodology, P ojec adminis a ion, W i ing – e iew &
edi ing, Concep ualiza ion. AM: Concep ualiza ion, Me hodology,
P ojec adminis a ion, W i ing – e iew & edi ing. JF:
Velasco e al. 10.3389/ ped.2023.1269560
F on ie s in Pedia ics 07 on ie sin.o g
Concep ualiza ion, Da a cu a ion, Me hodology, P ojec
adminis a ion, W i ing –o iginal d a , W i ing – e iew & edi ing.
Funding
The au ho (s) decla e financial suppo was ecei ed o he
esea ch, au ho ship, and/o publica ion o his a icle.
The p ojec has ecei ed financing om h ee pha maceu ical
companies: Amgen, Se ie , Pfize . Addi ionally, Amgen has
unded he publica ion o he a icle.
Acknowledgmen s
We would like o exp ess ou g a i ude o he Spanish Socie y
o Pedia ic Hema ology and Oncology (SEHOP) o hei
suppo in he de elopmen o his p ojec wi hin hei
o ganiza ion, pa icula ly o i s p esiden , Ana Fe nández-
Teijei o. We acknowledge he significan con ibu ions made by
F ancisco Lendinez and Ja ie Sancho, who manage he websi e.
Thei diligence has p o ided a use - iendly web en i onmen
o he p ojec , benefi ing all use s. We exp ess ou g a i ude o
Lucas Mo eno as PI and he eam a he SEHOP-PENCIL s udy
o hei ac i e pa icipa ion in he egis y, he in eg a ed
diagnos ic commi ee, and he oncogenomic s udies o
ReALLNe , hus d i ing p ecision medicine in R/R ALL. We
ex end ou g a i ude o all ea ing physicians. Thei dedica ion
o hei pa ien s and hei willingness o collabo a e ha e made
he es ablishmen o his ne wo k possible. Finally, we hank he
pa ien s and hei amilies. They a e he d i ing o ce and
compass o ou e o s.
Conflic o in e es
The p ojec has ecei ed unding om he pha maceu ical
companies Amgen, Se ie , and Pfize . The au ho s’;
ela ionships wi h hese companies a e as ollows: PV ecei ed
hono a ia o speaking a a symposia om Se ie . JF is a
consul an /ad iso y membe and ecei es hono a ia o speaking
a symposia om Amgen, Se ie and Pfize , and suppo o
a ending symposia om Se ie . FB had a consul ing o ad iso y
ole o Amgen and ecei ed hono a ia o speaking a a
symposium om Se ie . SR: ecei es hono a ia om Pfize ,
Amgen and Se ie as a ad iso y membe and suppo o
a ending medical cong esses. AR: ecei es suppo o a ending
symposia om Amgen. JM is co-in en o o dynamic BH3
p ofiling (pa en ed by Dana-Fa be Cance Ins i u e,
US10393733B2).
The emaining au ho s decla e ha he esea ch was conduc ed
in he absence o any comme cial o financial ela ionships ha
could be cons ued as a po en ial conflic o in e es .
Publishe ’s no e
All claims exp essed in his a icle a e solely hose o he
au ho s and do no necessa ily ep esen hose o hei a filia ed
o ganiza ions, o hose o he publishe , he edi o s and he
e iewe s. Any p oduc ha may be e alua ed in his a icle, o
claim ha may be made by i s manu ac u e , is no gua an eed
o endo sed by he publishe .
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