"FLT3-ITD and FLT3 Inhibitors

in the Setting of Allogeneic Stem Cell

Transplantation for AML"
Pr. Mohamad MOHTY
Head, Clinical Hematology and
Cellular Therapy Dpt.
Universit Pierre & Marie Curie
Hpital Saint-Antoine
Paris, France

FLT3 Mutations
- ~ 25% of patients with AML
- High incidence in AML with
NPM1 mutations (40%)
t(15;17)(q21;q21)/PML-RARA (40-45%)
JMD
TK1
TK2

t(6;9)(p23;q34)/DEK-NUP214 (75%)

- Associated with inferior prognosis:

Allelic ratio (mut/wt)
ITD insertion site

FMS-like tyrosine kinase 3

Nakao M, Leukemia 1996; Whitman SP, Cancer Res 2001; Thiede C, Blood 2002;
Kottaridis PD, Blood 2002; Gale RE, Blood 2008; Breitenbuecher F, Blood 2008

FLT3-ITD - Negative Prognostic Impact

in the Context of Other Genetic Aberrations
Multivariable Analysis on Overall Survival
n=398 ECOG E1900
Total cohort
FLT3-ITD

HR
1.59

p-value
0.003

HR
2.54

p-value
0.001

Intermediate-risk
FLT3-ITD

Patel JP, et al. N Engl J Med. 2012;366:1079-89.

NPM1mut/FLT3 ITDneg a Predictive Genotype for

Allogeneic Stem Cell Transplantation in CN-AML*
NPM1

mut

100

P=0.71

Relapse-free Survival [%]

Relapse-free Survival [%]

100

/FLT3 ITD

FLT3 ITDpos
NPM1WT/FLT3 ITDneg/CEBPAWT

neg

80

Donor n=38

60

No-Donor n=97

40
20
0

P=0.003

80
60

Donor n=60

40
20

No-Donor n=148

0
0

3 4 5 6 7
Time [months]

10

3 4 5 6 7
Time [months]

10

*excluding CEBPAmut cases

Schlenk et al., N Engl J Med. 2008;358:1909-18

FLT3-ITD A Negative Prognostic Marker

after allo-HSCT in 1st CR

FLT3-ITDneg n=86

FLT3-ITDpos n=120
FLT3-ITDpos n=120

FLT3-ITDneg n=86

MVA: HR 3.4 (95%-CI 1.46-7.94)

n=158

MVA: HR 2.7 (95%-CI 1.37-5.26)

n=158
Brunet S, et al. J Clin Oncol. 2012;30:735-41.

NH2

Structure of FLT3-Receptor:
Impact of Insertion Site
amino acid
572-578
579-592
593-603

JM
ITDs

TK1

604-609
610-615
616-623
624-630
> 630

JM-B: binding motif

JM-S: switch motif
JM-Z: zipper motif
hinge region of JM
beta1-sheet
nucleotide binding loop
beta2-sheet
3`of beta2-sheet

Juxtamembrane
domain
Tyrosine
kinase 1
domain

COOH

Functional regions according to Griffith et al. Mol Cell. 2004;13(2):169-78.

FLT3-ITDpos
RFS and OS according to insertion site

Kayser et al., Blood 2009;114:2386-92.

Tyrosine Kinase Inhibitors

Selectivity and Potency

Staurosporine

Midostaurin

Sorafenib

Sunitinib

Quizartinib

Karaman MW, et al. Nature Biotechnology 2008;26 (1):127-132

Zarrinkar PP, et al. Blood. 2009;114(14):2984-2992..

Sorafenib in Relapsed Patients with

FLT3-ITD positive AML

Population:
n=65 patients (n=63 relapsed/refractory, n=2 in CR)
Two cohorts:
a) n=29 pts. after allo-HSCT
b) n=36 pts. after intensive chemotheray
Treatment: Sorafenib starting dose 2 x 400 mg
Median duration and dose
a) 76 days (14-904)
600 mg/d
b) 74 days (1-270)
486,5 mg/d
Response
CMR
CR/CRi
PR/HR/BMR
refractory
Resistance
a)
b)

cohort-a
7 (24%)
7 (24%)
14 (48.5%)
1 (3.5%)

197 days (38-225)

136 days (38-225)

cohort-b
3 (8.5%)
8 (22%)
25 (69.5 %)

Metzelder et al., Leukemia 2012; epub 08.05.2012

Sorafenib in Relapsed Patients after

allo-HSCT with FLT3-ITD positive AML
Time to treatment failure
n=36
n=29

Median treatment duration 74 days (1-270 days)

median dose 600 mg/d
Sorafenib treatment
Allogeneic HSCT
Metzelder et al., Leukemia 2012; epub 08.05.2012

Quizartinib in Relapsed Patients with

FLT3-ITD positive AML
Population:
n=99 patients (relapsed/refractory)
Two cohorts:
a) n=25 pts. after allogeneic HSCT
b) n=74 pts. after intensive chemotherapy
Treatment: Quizartinib starting dose 90mg/135mg
Response
CR/CRi
PR/HR/BMR
refractory

cohort-a
14 (56%)
6 (24%)
5 (20%)

Median response duration

cohort-b
30 (41%)
17 (23%)
27 (36%)

11.3 weeks
Lewis et al., ASH 2012 #673

TKIs in Patients with FLT3-ITD positive AML

before and after allo-HSCT
Active Clinical Trials
Sorafenib Maintenance Therapy for Patients With AML After Allogeneic Stem Cell
Transplant (NCT01398501); Massachusetts General Hospital, n=28, Start Date:
August 2011, Estimated Primary Completion Date: August 2014
A Study of AC220 Given After Transplant in Subjects With Acute Myeloid Leukemia
(NCT01468467); Astellas Pharma Inc, n=30, Start Date: April 2012, Estimated Study
Completion Date: March 2015
Sorafenib Tosylate Before and After Donor Bone Marrow Transplantation in Treating
Patients With Acute Myeloid Leukemia (NCT01578109); Sidney Kimmel
Comprehensive Cancer Center, n=36, Start Date: January 2012, Estimated Primary
Completion Date: December 2015
A double-blind, placebo-controlled, randomized, multi-center phase II trial to assess
the efficacy of Sorafenib-maintenance therapy in FLT3-ITD positive AML in complete
hematological remission after allogenic stem cell transplantation ; EudraCT Number:
2010-018539-16
University of Marburg, n=200

Conclusions
FLT3-ITD is frequently present in adult AML with
highest incidence in patients aged 18 to 60 years
In normal caryotype AML, important cooperating gene
mutations are NPM1-mut and DNMT3A-mut
Mutant/wild type ratio and insertion in the 1-sheet are
important prognostic markers in FLT3-ITD positive
AML

Conclusions
Allo-HSCT in first CR in FLT3-ITD positive AML results
in improved outcome especially in those patients
lacking a high mutant/wild type ratio and/or insertion
in the 1-sheet
TKIs showed remarkable activity as single agent in
relapsed/refractory FLT3-ITDpos AML, especially, after
allo-HSCT
Drug-Drug interactions may heavily influence TKI
metabolism via Cytochrome P450 3A4
TKIs

can

block

glucuronidation

of

drugs

e.g.

paracetamol which may lead to sever hepatotoxicity