flt3 inhibitors
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"FLT3-ITD and FLT3 Inhibitors "FLT3-ITD and FLT3 Inhibitors
in the Setting of Allogeneic Stem Cell in the Setting of Allogeneic Stem Cell
Transplantation for AML"Transplantation for AML"
Pr. Mohamad MOHTYHead, Clinical Hematology and
Cellular Therapy Dpt.Université Pierre & Marie Curie
Hôpital Saint-AntoineParis, France
JMD
TK1
TK2
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
FLT3FLT3 Mutations Mutations
FMS-like tyrosine kinase 3
• - ~ 25% of patients with AML
• - High incidence in AML with• NPM1 mutations (40%)
• t(15;17)(q21;q21)/PML-RARA (40-45%)
• t(6;9)(p23;q34)/DEK-NUP214 (75%)
• - Associated with inferior prognosis:• Allelic ratio (mut/wt)
• ITD insertion site
FLT3-ITD - Negative Prognostic Impact in the Context of Other Genetic Aberrations
Multivariable Analysis on Overall Survival n=398 ECOG E1900
Total cohortHR p-value
FLT3-ITD 1.59 0.003
Intermediate-riskHR p-value
FLT3-ITD 2.54 0.001
Patel JP, et al. N Engl J Med. 2012;366:1079-89.
P=0.71 P=0.003
Donor n=60
No-Donor n=148
Donor n=38
No-Donor n=97
NPM1mut/FLT3 ITDneg
NPM1mut/FLT3 ITDneg a Predictive Genotype for Allogeneic Stem Cell Transplantation in CN-AML*
*excluding CEBPAmut cases
FLT3 ITDpos
NPM1WT/FLT3 ITDneg/CEBPAWT
Schlenk et al., N Engl J Med. 2008;358:1909-18
Time [months]
Rel
ap
se-f
ree
Su
rviv
al [
%]
0 1 2 3 4 5 6 7 8 9 10
0
20
40
60
80
100
Time [months]
Rel
ap
se-f
ree
Su
rviv
al [
%]
0 1 2 3 4 5 6 7 8 9 10
0
20
40
60
80
100
Brunet S, et al. J Clin Oncol. 2012;30:735-41.
FLT3-ITD – A Negative Prognostic Markerafter allo-HSCT in 1st CR
FLT3-ITDpos n=120
FLT3-ITDneg n=86
MVA: HR 3.4 (95%-CI 1.46-7.94)n=158
FLT3-ITDneg n=86
FLT3-ITDpos n=120
MVA: HR 2.7 (95%-CI 1.37-5.26)n=158
Functional regions according to Griffith et al. Mol Cell. 2004;13(2):169-78.
ITDs
COOH
572-578
579-592
593-603
604-609
610-615
616-623
624-630
> 630
amino acid
Structure of FLT3-Receptor:Impact of Insertion Site
JM
TK1
JM-B: binding motifJM-B: binding motif
JM-S: switch motifJM-S: switch motif
JM-Z: zipper motifJM-Z: zipper motif
hinge region of JMhinge region of JM
beta1-sheetbeta1-sheet
nucleotide binding loopnucleotide binding loop
beta2-sheetbeta2-sheet
3`of beta2-sheet3`of beta2-sheet
Juxta-Juxta-membranemembrane
domaindomain
TyrosineTyrosinekinase 1kinase 1domaindomain
NH2
time (years)
Rel
apse
Fre
e S
urv
ival
(%)
0 1 2 3 4 5 6 7 8 9 10 11 12 13
0
25
50
75
100
time (years)
Ove
rall
Su
rviv
al(%
)
0 1 2 3 4 5 6 7 8 9 10 11 12 13
0
25
50
75
100
Panel A Panel B
Insertion site within the beta-1 sheet
all other insertion sites
Insertion site within the beta-1 sheet
all other insertion sites
P=0.002P=0.001
FLT3-ITDpos RFS and OS according to insertion site
Kayser et al., Blood 2009;114:2386-92.
Tyrosine Kinase InhibitorsSelectivity and Potency
Staurosporine Midostaurin Sorafenib Sunitinib Quizartinib
Karaman MW, et al. Nature Biotechnology 2008;26 (1):127-132Zarrinkar PP, et al. Blood. 2009;114(14):2984-2992..
Sorafenib in Relapsed Patients with FLT3-ITD positive AML
Metzelder et al., Leukemia 2012; epub 08.05.2012
Population:n=65 patients (n=63 relapsed/refractory, n=2 in CR)
Two cohorts:a) n=29 pts. after allo-HSCTb) 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/db) 74 days (1-270) 486,5 mg/d
Response cohort-a cohort-bCMR 7 (24%) 3 (8.5%)CR/CRi 7 (24%) 8 (22%)PR/HR/BMR 14 (48.5%) 25 (69.5 %)refractory 1 (3.5%)
Resistancea) 197 days (38-225)b) 136 days (38-225)
Sorafenib in Relapsed Patients afterallo-HSCT with FLT3-ITD positive AML
Median treatment duration 74 days (1-270 days) median dose 600 mg/d
Metzelder et al., Leukemia 2012; epub 08.05.2012
Sorafenib treatment
Allogeneic HSCT
Time to treatment failure
n=29
n=36
Quizartinib in Relapsed Patients with FLT3-ITD positive AML
Lewis et al., ASH 2012 #673
Population:n=99 patients (relapsed/refractory)
Two cohorts:a) n=25 pts. after allogeneic HSCTb) n=74 pts. after intensive chemotherapy
Treatment: Quizartinib starting dose 90mg/135mg
Response cohort-a cohort-bCR/CRi 14 (56%) 30 (41%)PR/HR/BMR 6 (24%) 17 (23%)refractory 5 (20%) 27 (36%)
Median response duration 11.3 weeks
• 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: 2010-018539-16University of Marburg, n=200
TKIs in Patients with FLT3-ITD positive AMLbefore and after allo-HSCT
Active Clinical Trials
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