Ma ía A güello Ma ina. (2025). Real-Wo ld Ou comes o FLT3 Inhibi o s in Acu e Myeloid Leukemia, a
Mul icen e S udy. MAR Oncology and Hema ology. (2025) 5:08
Real-Wo ld Ou comes o FLT3 Inhibi o s in Acu e Myeloid Leukemia, a
Mul icen e S udy
Ma ía A güello Ma ina, MD¹, I ene A naiz Ma in, MD², Guzmán López de Hon ana To es, MD³
Ma ía Ángeles Foncillas, MD⁴
¹Hospi al Uni e si a io de Guadalaja a, Guadalaja a, Spain.
²Hospi al Uni e si a io de Ge a e, Ge a e, Spain.
³Hospi al Uni e si a io P íncipe de As u ias, Alcalá de Hena es, Spain.
⁴Hospi al Uni e si a io In an a Leono , Mad id, Spain.
*Co espondence o: Ma ía A güello Ma ina, MD, Hospi al Uni e si a io de Guadalaja a, Guadalaja a,
Spain.
Copy igh .
© 2025 Ma ía A güello Ma ina This is an open access a icle dis ibu ed unde he C ea i e Commons
A ibu ion License, which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided
he o iginal wo k is p ope ly ci ed.
Recei ed: 21 Aug 2025
Published: 25 Aug 2025
MAR Oncology and Hema ology (2025) 5:08
Resea ch A icle
Ma ía A güello Ma ina, MAR Oncology and Hema ology (2025) 5:08.
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Ma ía A güello Ma ina. (2025). Real-Wo ld Ou comes o FLT3 Inhibi o s in Acu e Myeloid Leukemia, a
Mul icen e S udy. MAR Oncology and Hema ology. (2025) 5:08
Abs ac
Backg ound: Acu e myeloid leukemia (AML) wi h FLT3 mu a ions ca ies a poo p ognosis.
FLT3 inhibi o s, such as midos au in, combined wi h s anda d chemo he apy, ha e shown
imp o ed ou comes o FLT3-mu a ed AML pa ien s. Howe e , eal-wo ld da a on hei
e icacy and sa e y a e limi ed. This s udy assesses midos au in's eal-wo ld e icacy, he iming
o molecula diagnosis, and he impac o an i ungal p ophylaxis managemen .
Me hods: This e ospec i e mul icen e s udy was conduc ed ac oss ou Spanish hospi als,
including 15 pa ien s wi h FLT3-mu a ed AML ea ed be ween 2019 and 2024. Da a on
demog aphics, clinical cha ac e is ics, diagnos ic imelines, and ea men s we e collec ed and
analyzed.
Resul s: The a e age ime o ob ain FLT3 mu a ion esul s was 13.3 days, exceeding he
ecommended 8-day window pe PETHEMA, NCCN, and ELN guidelines, and delaying
midos au in ini ia ion o a mean o 24.5 days pos -diagnosis. Despi e hese delays, 80% o
pa ien s achie ed comple e emission (CR), wi h 62.5% a aining nega i e minimal esidual
disease (MRD) s a us pos -induc ion. An i ungal p ophylaxis was adminis e ed o 60% o
pa ien s, p ima ily wi h posaconazole (62.5%), wi hou midos au in dose adjus men s.
Al e na i e an i ungals (mica ungin o luconazole) we e used o a oid CYP3A in e ac ions pe
PETHEMA ecommenda ions. No signi ican di e ences in ad e se e en a es we e obse ed
be ween an i ungal egimens.
Conclusion: The eal-wo ld use o midos au in demons a es e icacy compa able o clinical
ials. Howe e , delays in FLT3 mu a ion es ing hinde adhe ence o ea men ini ia ion
guidelines, po en ially impac ing ou comes. Addi ionally, he lack o obus e idence ega ding
in e ac ions be ween midos au in and an i ungal agen s highligh s he need o s anda dized
an i ungal p ophylaxis s a egies in FLT3-mu a ed AML. Add essing hese challenges is
essen ial o op imize ou comes in eal-wo ld se ings.
Key wo ds: Acu e myeloid leukemia; FLT3 mu a ion; Midos au in; Real-wo ld e idence;
An i ungal p ophylaxis; Minimal esidual disease.
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Ma ía A güello Ma ina. (2025). Real-Wo ld Ou comes o FLT3 Inhibi o s in Acu e Myeloid Leukemia, a
Mul icen e S udy. MAR Oncology and Hema ology. (2025) 5:08
Backg ound
Acu e myeloid leukemia (AML) is an agg essi e hema ologic malignancy cha ac e ized by he uncon olled
clonal p oli e a ion o imma u e myeloid cells in he bone ma ow, leading o supp essed no mal
hema opoiesis and pe iphe al issue in il a ion. AML is molecula ly he e ogeneous, exhibi ing di e se
clinical, mo phological, and immunopheno ypic ea u es. I has a apid onse , p og essi e cou se, and equen
esis ance o chemo he apy [1,2]. Wi h a median diagnosis age o 68, AML is he mos common acu e
leukemia in adul s, wi h a 5-yea su i al a e o app oxima ely 30%, a ying signi ican ly by age g oup [2,3].
FLT3 gene mu a ions a e common in AML and hold signi ican p ognos ic and he apeu ic implica ions. FLT3
(FMS-like y osine kinase 3) encodes a ecep o y osine kinase c ucial o hema opoiesis. Ac i a ing
mu a ions, such as in e nal andem duplica ions (ITD) and y osine kinase domain (TKD) poin mu a ions, a e
among he mos equen molecula abno mali ies in AML [4,5]. FLT3 mu a ions occu in ~30% o AML
cases a diagnosis, no ably in 70% o pa ien s wi h a no mal ka yo ype and 35% o hose wi h (15;17), wi h
a highe equency in de no o AML (26%) han seconda y AML (9%). These mu a ions co ela e wi h
hype cellula i y, highe elapse a es, and a e mo e common in women [6].
FLT3-ITD mu a ions a e linked o poo AML p ognosis, leading o leukocy osis, high blas cell pe cen ages,
g ea e ea men esis ance, inc eased elapse isk, and educed o e all su i al (OS) and p og ession- ee
su i al (PFS) [6]. While FLT3-ITD AML pa ien s can achie e comple e emission wi h in ensi e
chemo he apy, hey ha e highe elapse a es and wo se OS, pa icula ly hose wi h no mal ka yo ype and
in e media e cy ogene ic isk [7,8]. In con as , FLT3-TKD mu a ions ha e no demons a ed signi ican
p ognos ic ele ance despi e mul iple la ge-coho s udies [9–11].
Ad ances in gene ic p o iling ha e eshaped AML diagnos ics, p ognosis, and ea men s a egies [2]. In
2022, an upda ed AML classi ica ion [12] and a new sys em [13] inco po a ed molecula indings in o ou ine
clinical p ac ice, expanding ecognized gene ic abno mali ies. Though FLT3 mu a ions a e no conside ed
AML-de ining, hey hold c i ical p ognos ic and he apeu ic alue.
FLT3 inhibi o s a ge ing he ATP-binding si e o he y osine kinase domain ha e imp o ed su i al in
FLT3+ AML [14,15]. The FDA has app o ed wo FLT3 inhibi o s: midos au in and gil e i inib. Since 2019,
he Spanish Hema ology T ea men P og am (PETHEMA) has ecommended midos au in wi h dauno ubicin
and cy a abine as i s -line he apy o FLT3+ AML, o be adminis e ed om days +8 o +21 (o up o day 24
i induc ion ex ends o day 11). Midos au in should no be ini ia ed beyond his window. Du ing consolida ion
wi h high-dose cy a abine, midos au in is con inued unin e up ed. I is also ecommended du ing main enance
o pa ien s pos -consolida ion (high-dose A a-C o au ologous ansplan ) o 12 cycles o 28 days bu no
a e allogeneic ansplan a ion. The e is no su i al bene i in adding midos au in in consolida ion i omi ed
du ing induc ion [16]. Gil e i inib is indica ed as mono he apy o elapsed/ e ac o y FLT3+ AML [16].
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Ma ía A güello Ma ina. (2025). Real-Wo ld Ou comes o FLT3 Inhibi o s in Acu e Myeloid Leukemia, a
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FLT3+ AML and an i ungal p ophylaxis pose challenges due o a high isk o in asi e ungal in ec ions (IFI).
Du ing AML induc ion, posaconazole p ophylaxis is s anda d due o se e e p olonged neu openia om
in ensi e chemo he apy [16]. IFI incidence in FLT3-mu a ed AML pa ien s is 10.5% (p obable/p o en) and
9.7% (possible) du ing induc ion, dec easing o 2.4% and 1.8% in consolida ion [17]. Bo h midos au in and
gil e i inib a e me abolized ia CYP3A, which is inhibi ed by azoles like o iconazole, i aconazole, and
posaconazole, inc easing FLT3 inhibi o plasma le els [18]. PETHEMA ad ises a oiding CYP3A induce s
and allows midos au in dose adjus men o 50% (25 mg e e y 12 hou s) i posaconazole o o iconazole
p ophylaxis is ini ia ed du ing induc ion o consolida ion [16].
This s udy e alua es eal-wo ld ou comes o FLT3 inhibi o he apy in FLT3+ AML, ocusing on e icacy,
sa e y, and he impac o an i ungal p ophylaxis.
Ma e ials and Me hods
S udy Design
This e ospec i e mul icen e s udy was conduc ed ac oss ou Spanish hospi als: Uni e si y Hospi al o
Guadalaja a, Uni e si y Hospi al o Ge a e, Uni e si y Hospi al P íncipe de As u ias, and Uni e si y Hospi al
In an a Leono . E hical app o al was ob ained om he espec i e E hics Commi ees. Pa ien s aged ≥18 yea s
diagnosed wi h FLT3+ AML be ween Janua y 2019 and Ma ch 2024 we e included.
S udy Popula ion
Fi een pa ien s we e en olled, wi h hei demog aphic and clinical cha ac e is ics summa ized in Table 1.
Table 1. Baseline Cha ac e is ics o he S udy Popula ion
Va iable
N (%)
Age
53 años ( ango 31 – 76).
Women
6 (40)
Type o AML
De no o
13 (87)
Seconda y
2 (13)
FLT3 mu a ion
ITD
11 (73)
TKD
4 (27)
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NPM1 mu a ed
No
4 (33)
Yes
11 (60)
Ka yo ype
No mal
12 (80)
Al e ed
1 (7)
No pe o med
2 (13)
ELN 2022 Risk Classi ica ion
Low
1 (7)
In e media e
11 (73)
High
3 (20)
In he pa ien wi h an al e ed ka yo ype, (8;21) and del(9)(q21q32) we e iden i ied, wi h (8;21) classi ied as
a o able isk despi e coexis ing wi h an FLT3 mu a ion. Among pa ien s wi h high- isk AML, he key
de e minan s we e:
RUNX1 and ASXL1 mu a ions in one pa ien .
RUNX1 mu a ion in he second pa ien .
RUNX1 and TP53 mu a ions in he hi d pa ien .
Da a Collec ion
Da a we e ex ac ed om elec onic medical eco ds, including demog aphic a iables, disease cha ac e is ics,
and ea men ou comes.
S a is ical Analysis
Desc ip i e s a is ics we e applied. Quali a i e a iables a e p esen ed as equencies and pe cen ages, while
quan i a i e a iables a e summa ized by mean, median, and ange.
Resul s
Desc ip i e Analysis o FLT3 Inhibi o T ea men
All pa ien s ecei ed midos au in (50 mg e e y 12 hou s) du ing induc ion, in combina ion wi h in ensi e 3+7
chemo he apy (Ida ubicin 12 mg/m²/day IV on days 1–3 and Cy a abine 200 mg/m²/day IV as a con inuous
in usion on days 1–7). Howe e , he wo pa ien s diagnosed wi h seconda y AML ecei ed midos au in in
combina ion wi h VYXEOS.
The ime om diagnosis o FLT3 mu a ion esul and subsequen ini ia ion o FLT3 inhibi o he apy is
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summa ized in Table 2.
Table 2. Timing o FLT3 Mu a ion Diagnosis and Ta ge ed T ea men Ini ia ion
Pa ien
Time o FLT3 Mu a ion
Resul om Da e o Reques
(days)
Time o s a o FLT3
Inhibi o ea men om
FLT3 Mu a ion Resul
(days)
Time o s a o
FLT3 Inhibi o
om Da e o
Diagnosis (days).
1
4
5
9
2
9
1
10
3
7
1
8
4
5
1
6
5
8
7
15
6
21
20
41
7
9
0
9
8
41
0
41
9
14
24
38
10
13
44
58
11
3
4
7
12
32
20
52
13
8
1
9
14
17
38
55
15
9
1
10
FLT3 mu a ion analysis was eques ed o all pa ien s a he ime o bone ma ow biopsy upon diagnosis. The
mean u na ound ime o FLT3 mu a ion esul s was 13.3 days. T ea men ini ia ion occu ed a mean o 11.3
days a e ecei ing FLT3 esul s, wi h FLT3 inhibi o he apy commencing a mean o 24.5 days pos -
diagnosis.
Ad e se E ec s
Du ing midos au in ea men , 9 o 15 pa ien s (60%) expe ienced ad e se e ec s (Table 3), wi h QT in e al
p olonga ion and dia hea being he mos equen (33% each). T ea men was suspended in 4 pa ien s (44%):
wo due o QT in e al p olonga ion, one o li e unc ion abno mali ies, and one o en e i is. Among hem,
wo (67%) esumed ea men a a educed dose (25 mg e e y 12 hou s). Pa ien 5 succumbed o in es inal
obs uc ion. Addi ionally, Pa ien 1, who de eloped QT in e al p olonga ion, equi ed a dose educ ion o 25
mg e e y 12 hou s bu did no necessi a e ea men suspension.
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Table 3. Ad e se e ec s and ea men e olu ion wi h midos au in
An i ungal p ophylaxis p esc ip ion
Among he 15 pa ien s, 9 (60%) ecei ed an i ungal p ophylaxis du ing chemo he apy induc ion, while 6
(40%) did no . All 9 pa ien s who ecei ed midos au in du ing induc ion also ecei ed an i ungal p ophylaxis:
5 wi h posaconazole (62.5%), 3 wi h mica ungin (37.5%), and 1 wi h luconazole (12.5%). No signi ican
di e ences we e obse ed in ad e se e ec s o ea men suspension a es be ween pa ien s ecei ing
posaconazole and hose on an i ungals wi h lowe CYP3A4 inhibi ion.
Response o induc ion and consolida ion
Following induc ion, 12 pa ien s (80%) achie ed comple e emission (CR), including 7 o 9 (78%) ea ed
wi h midos au in. O hese 12, 10 (83%) a ained minimal esidual disease (MRD) nega i i y. Se en pa ien s
(58%) p oceeded o allogeneic s em cell ansplan a ion (allo-SCT), while 5 (42%) unde wen consolida ion
wi h high-dose A a-C and midos au in. One pa ien (Pa ien 5) died be o e ee alua ion, one (Pa ien 8) was
e ac o y, and ano he (Pa ien 15) achie ed pa ial esponse (PR) bu p og essed be o e allo-SCT.
Among he 8 pa ien s who ecei ed midos au in and we e ee alua ed, 5 (62.5%) achie ed CR wi h MRD
nega i i y, 2 (25%) achie ed CR wi h MRD posi i i y, and 1 (12.5%) emained e ac o y. De ailed
ee alua ion and consolida ion ou comes a e summa ized in Table 4.
Pa ien
Ad e se E ec
Requi ed T ea men
Suspension
T ea men Resumed
(Dose)
1
QT in e al p olonga ion
No
2
Dia hea
No
3
Li e p o ile al e a ion and
abdominal pain
Yes
No
4
Dia hea and mode a e
h ombocy openia
No
5
En e i is
Yes
Deceased
7
Dia hea
No
8
Se e e h ombocy openia
No
13
QT in e al p olonga ion
Yes
Yes (25 mg/12h)
14
QT in e al p olonga ion
Yes
Yes (25 mg/12h)
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Table 4. Ree alua ion and Consolida ion The apy
EMR: Minimal Residual Disease; CR: Comple e Remission; PR: Pa ial Remission; Allo-SCT: Allogeneic
S em Cell T ansplan a ion.
Follow-up
The median ollow-up du a ion o pa ien s in his s udy was 6 mon hs ( ange: 1–48 mon hs). Among he 12
pa ien s who esponded o induc ion he apy and comple ed consolida ion, 7 emain in comple e emission,
while 4 died du ing ollow-up. One pa ien is cu en ly unde going allogeneic s em cell ansplan a ion (allo-
SCT). De ailed ollow-up da a o each pa ien a e p esen ed in Table 5.
Pa ien
Response a e
Induc ion
MRD a e
Induc ion
Consolida ion The apy
1
CR
Nega i e
Allo-SCT
2
CR
Nega i e
A a-C + midos au in
3
CR
Posi i e
Allo-SCT
4
CR
Nega i e
A a-C + midos au in
5
Dea h
Dea h
Dea h
6
CR
Nega i e
Allo-SCT
7
CR
Nega i e
Allo-SCT
8
Re ac o y
Posi i e
Second-line ea men
9
CR
Nega i e
A a-C + midos au in
10
CR
Nega i e
A a-C + midos au in
11
CR
Nega i e
Allo-SCT
12
CR
Nega i e
Allo-SCT
13
CR
Posi i e
A a-C + midos au in
14
CR
Nega i e
Allo-SCT
15
PR
Posi i e
P og ession, Second-line
ea men
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Table 5. Pos -Consolida ion The apy Follow-up
Pa ien
Consolida ion The apy
Cu en S a us
Follow-up Time
(mon hs)
1
Allo-SCT
CR
11
2
A a-C + midos au in
CR
3
3
Allo-SCT
Dea h
6
4
A a-C + midos au in
Dea h
2
5
Dea h
Dea h
1
6
Allo-SCT
CR
37
7
Allo-SCT
CR
14
8
NA
Dea h
7
9
A a-C + midos au in
CR
49
10
A a-C + midos au in
CR
37
11
Allo-SCT
Allo-SCT
5
12
Allo-SCT
CR
6
13
A a-C + midos au in
Dea h
9
14
Allo-SCT
Dea h
11
15
NA
Dea h
5
Allo-SCT: Allogeneic hema opoie ic s em cell ansplan a ion, CR: Comple e Remision,
Discussion
This s udy con i ms ha midos au in's clinical bene i s and ole abili y, as obse ed in clinical ials, a e
ep oducible in eal-wo ld se ings, e en in small pa ien coho s. No ably, an i ungal p ophylaxis choice did
no signi ican ly a ec ole abili y o necessi a e ea men discon inua ion.
S udy Limi a ions
As a e ospec i e desc ip i e s udy wi h a limi ed sample size, he gene alizabili y o ou indings is
cons ained. Addi ionally, he s udy lacks he abili y o pe o m ad anced s a is ical analyses o ully con ol
o con ounding a iables. Desc ip i e e ospec i e s udies p ima ily iden i y pa e ns wi hin a popula ion a
a gi en ime and canno es ablish causal ela ionships.
