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

TK1 - Associated with inferior prognosis:

Allelic ratio (mut/wt)
TK2
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
HR p-value
FLT3-ITD 1.59 0.003
Intermediate-risk
HR p-value
FLT3-ITD 2.54 0.001

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
/FLT3 ITD neg FLT3 ITDpos
NPM1WT/FLT3 ITDneg/CEBPAWT
100 100
P=0.71 P=0.003
Relapse-free Survival [%]

Relapse-free Survival [%]

80 80

Donor n=38
60 60

40
No-Donor n=97 40 Donor n=60

20 20

0 0 No-Donor n=148
0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
Time [months] Time [months]

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

n=158 n=158

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

 Structure of FLT3-Receptor:
NH2 Impact of Insertion Site
amino acid

572-578 JM-B: binding motif

Juxta-
579-592 JM-S: switch motif
membrane
593-603 JM-Z: zipper motif domain
JM 604-609 hinge region of JM
ITDs 610-615 beta1-sheet
TK1 Tyrosine
616-623 nucleotide binding loop kinase 1
624-630 beta2-sheet domain
> 630 3`of beta2-sheet
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 Panel B

100 P=0.001 100 P=0.002

Relapse Free Survival (%)

Overall Survival (%)

75 75

50 50
all other insertion sites all other insertion sites

25 25

Insertion site within the beta-1 sheet Insertion site within the beta-1 sheet
0 0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 0 1 2 3 4 5 6 7 8 9 10 11 12 13
time (years) 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 cohort-a cohort-b

CMR 7 (24%) 3 (8.5%)
CR/CRi 7 (24%) 8 (22%)
PR/HR/BMR 14 (48.5%) 25 (69.5 %)
refractory 1 (3.5%)
Resistance
a) 197 days (38-225)
b) 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 cohort-a cohort-b

CR/CRi 14 (56%) 30 (41%)
PR/HR/BMR 6 (24%) 17 (23%)
refractory 5 (20%) 27 (36%)

Median response duration 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