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"FLT3-ITD and FLT3 Inhibitors in the Setting of Allogeneic Stem Cell Transplantation for AML"

"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

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"FLT3-ITD and FLT3 Inhibitors in the Setting of Allogeneic Stem Cell Transplantation for AML"

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  1. "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

  2. FLT3 Mutations • - ~ 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 JMD TK1 TK2 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

  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. NPM1mut/FLT3 ITDneg a Predictive Genotype for Allogeneic Stem Cell Transplantation in CN-AML* FLT3 ITDpos NPM1WT/FLT3 ITDneg/CEBPAWT NPM1mut/FLT3 ITDneg 100 100 P=0.71 P=0.003 80 80 Donor n=38 60 60 Relapse-free Survival [%] Relapse-free Survival [%] No-Donor n=97 Donor n=60 40 40 20 20 No-Donor n=148 0 0 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

  5. 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 2.7 (95%-CI 1.37-5.26) n=158 MVA: HR 3.4 (95%-CI 1.46-7.94) n=158 Brunet S, et al. J Clin Oncol. 2012;30:735-41.

  6. Structure of FLT3-Receptor: Impact of Insertion Site NH2 amino acid 572-578 579-592 593-603 604-609 610-615 616-623 624-630 > 630 JM-B: bindingmotif JM-S: switchmotif JM-Z: zippermotif hinge regionof JM beta1-sheet nucleotidebindingloop beta2-sheet 3`of beta2-sheet Juxta- membrane domain JM ITDs Tyrosine kinase 1 domain TK1 COOH Functional regions according to Griffith et al. Mol Cell. 2004;13(2):169-78.

  7. FLT3-ITDpos RFS and OS according to insertion site Kayser et al., Blood 2009;114:2386-92.

  8. Tyrosine Kinase InhibitorsSelectivity 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 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

  10. Sorafenib in Relapsed Patients afterallo-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

  11. 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

  12. 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: 2010-018539-16University of Marburg, n=200

  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

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