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"FLT3-ITD and FLT3 Inhibitors"FLT3-ITD and FLT3 Inhibitors
in the Setting of Allogeneic Stem Cellin the Setting of Allogeneic Stem Cell
Transplantation for AML"Transplantation for AML"
Pr. Mohamad MOHTY
Head, Clinical Hematology and
Cellular Therapy Dpt.Universit Pierre Marie Curie
H!pital "aint#$ntoine
Paris, %rance
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JMD
T!
T
&a'ao M, (eu'emia )**+ -hitman "P, Cancer es /00) Thiede C, 1lood /00/
2ottaridis PD, 1lood /00/ 3ale 4, 1lood /005 1reiten6uecher %, 1lood /005
%(T7%(T7M#tationsM#tations
FMS-like tyrosine kinase 3
- $ %& of patients 'ith AML
- (igh incidence in AML 'ith
&PM) m#tations )*+&,
t)!%!.,)/!/!,0PM(-$$ )*+-*%&, t)12,)p3/3*,0D42-&UP/)8).%&,
- Associated 'ith inferior prognosis
Allelic ratio )m#t0't, ITD insertion site
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%(T7-ITD - 4egati5e 6rognostic Impact
in the Conte7t of 8ther 9enetic Aberrations
M#lti5ariable Anal:sis on 85erall S#r5i5al
n;32< =C89 =!2++
Total cohort (> p-5al#e
%(T7-ITD !?%2 +?++3
Intermediate-ris@
(> p-5al#e%(T7-ITD ?%* +?++!
Patel 9P, et al. & 4ngl 9 Med. /0)/7++:)0;*#5*.
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6;+?.! 6;+?++3
Donor n;1+
4o-Donor n;!*FS and 8S according to insertion site
2ayser et al., 1lood /00*))8:/75+#*/.
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T:rosine inase Inhibitors
Selecti5it: and 6otenc:
Sta#rosporine Midosta#rin Sorafenib S#nitinib K#iartinib
2araman M-, et al. &ature 1iotechnology /005/+ A)B:)/;#)7/arrin'ar PP, et al. 1lood. /00*))8A)8B:/*58#/**/..
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Sorafenib in >elapsed 6atients 'ith
%(T7-ITD positi5e AML
Metelder et al., (eu'emia /0)/ epu6 05.0?./0)/
6op#lation
n;1% patients )n;13 relapsed0refractor: n; in C>,
T'o cohorts
a, n;2 pts? after allo-(SCT
b, n;31 pts? after intensi5e chemothera:
Treatment Sorafenib starting dose 7 *++ mg
Median d#ration and dosea, .1 da:s )!*-2+*, 1++ mg0d
b, .* da:s )!-.+, *esponse cohort-a cohort-b
CM> . )*&, 3 )
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Sorafenib in >elapsed 6atients after
allo-(SCT 'ith %(T7-ITD positi5e AML
Me*ian treat+ent *,ration (" *ays #1-2(0 *ays)
+e*ian *ose 600 +g*
Metelder et al., (eu'emia /0)/ epu6 05.0?./0)/
.ora/eni treat+ent
Allogenei H.'T
Ti+e to treat+ent /ail,re
n=2$
n=36
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K#iartinib in >elapsed 6atients 'ith
%(T7-ITD positi5e AML
(eEis et al., $"H /0)/ F+;7
6op#lationn;22 patients )relapsed0refractor:,
T'o cohorts
a, n;% pts? after allogeneic (SCT
b, n;.* pts? after intensi5e chemotherap:
Treatment K#iartinib starting dose 2+mg0!3%mg
>esponse cohort-a cohort-b
C>0C>i !* )%1&, 3+ )*!&,
6>0(>0GM> 1 )*&, !. )3&,refractor: % )+&, . )31&,
Median response d#ration !!?3 'ee@s
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.ora/eni Maintenane Terapy /or atients 4it AM5 A/ter Allogenei .te+ 'ell
Transplant )4CT+!32
'o+pletion Date: Dee+er 201%
A *o,le-lin*7 plaeo-ontrolle*7 ran*o+i@e*7 +,lti-enter pase II trial to assess
te e//iay o/ .ora/eni-+aintenane terapy in FLT3-ITD positi9e AM5 in o+plete
e+atologial re+ission a/ter allogeni ste+ ell transplantation ; =#draCT 4#mber
+!+-+!
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Concl#sions
%(T7-ITD is fre/#entl: present in ad#lt AML 'ith
highest incidence in patients aged !< to 1+ :ears
In normal car:ot:pe AML important cooperating gene
m#tations are &PM)-m#t and D&MT7$-m#t
M#tant0'ild t:pe ratio and insertion in the !-sheet are
important prognostic mar@ers in %(T7-ITD positi5e
AML
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Concl#sions
Allo-(SCT in first C> in %(T7-ITD positi5e AML res#lts
in impro5ed o#tcome especiall: in those patientslac@ing a high m#tant0'ild t:pe ratio and0or insertion
in the !-sheet
TIs sho'ed remar@able acti5it: as single agent in
relapsed0refractor: %(T7-ITDpos AML especiall: after
allo-(SCT
Dr#g-Dr#g interactions ma: hea5il: infl#ence TI
metabolism 5ia C:tochrome 6*%+3A*
TIs can bloc@ gl#c#ronidation of dr#gs e?g?
paracetamol 'hich ma: lead to se5er hepatoto7icit: