"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.
Université Pierre & Marie Curie
Hôpital 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*
NPM1mut/FLT3 ITDneg
100
P=0.71
Relapse-free Survival [%]
Relapse-free Survival [%]
100
80
Donor n=38
60
No-Donor n=97
40
FLT3 ITDpos
NPM1WT/FLT3 ITDneg/CEBPAWT
20
0
P=0.003
80
60
Donor n=60
40
20
No-Donor n=148
0
0
1
2
3 4 5 6 7
Time [months]
8
9
10
0
1
2
3 4 5 6 7
Time [months]
8
9
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
Panel A
75
50
all other insertion sites
25
0
100
P=0.001
Insertion site within the beta-1 sheet
0 1 2 3 4 5 6 7 8 9 10 11 12 13
time (years)
Overall Survival (%)
Relapse Free Survival (%)
100
Panel B
P=0.002
75
50
all other insertion sites
25
0
Insertion site within the beta-1 sheet
0 1 2 3 4 5 6 7 8 9 10 11 12 13
time (years)
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%)
cohort-b
3 (8.5%)
8 (22%)
25 (69.5 %)
197 days (38-225)
136 days (38-225)
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 β1-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 β1-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