FLT3 INHIBITORS
Upcoming SlideShare
Loading in...5
×

Like this? Share it with your network

Share
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Be the first to comment
    Be the first to like this
No Downloads

Views

Total Views
655
On Slideshare
655
From Embeds
0
Number of Embeds
0

Actions

Shares
Downloads
7
Comments
0
Likes
0

Embeds 0

No embeds

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
    No notes for slide

Transcript

  • 1. "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. Université Pierre & Marie Curie Hôpital Saint-Antoine Paris, France
  • 2. 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 MutationsMutations 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
  • 3. 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.
  • 4. 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] Relapse-freeSurvival[%] 0 1 2 3 4 5 6 7 8 9 10 0 20 40 60 80 100 Time [months] Relapse-freeSurvival[%] 0 1 2 3 4 5 6 7 8 9 10 0 20 40 60 80 100
  • 5. Brunet S, et al. J Clin Oncol. 2012;30:735-41. FLT3-ITD – A Negative Prognostic Marker after 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
  • 6. 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 TyrosineTyrosine kinase 1kinase 1 domaindomain NH2
  • 7. time (years) RelapseFreeSurvival(%) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 0 25 50 75 100 time (years) OverallSurvival(%) 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.
  • 8. 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..
  • 9. 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-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)
  • 10. Sorafenib in Relapsed Patients after allo-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
  • 11. 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 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
  • 12. • 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 TKIs in Patients with FLT3-ITD positive AML before and after allo-HSCT Active Clinical Trials
  • 13. 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
  • 14. 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