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FLT3-ITD and NPM1 gene mutations

Improvement of leukemia free survival and reduction of relapse incidence by allogeneic stem cell transplantation in elderly patients with AML irrespective of the FLT3-ITD mutation and NPM1 status (except NPM1mut/FLT3wt).

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FLT3-ITD and NPM1 gene mutations

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  1. Improvement of leukemia free survival and reduction of relapse incidence by allogeneic stem cell transplantation in elderly patients with AML irrespective of the FLT3-ITD mutation and NPM1 status (except NPM1mut/FLT3wt). D. Niederwieser, F. Schueler, U. Hegenbart, G. Maschmeyer, T. Fischer, C. Junghanss, H. H. Wolf, H. G. Sayer, U. Kreibich, G. Doelken for the East German Study Group Hematology and Oncology (OSHO)

  2. FLT3-ITD and NPM1 gene mutations FLT3-ITD NPM1

  3. Frequency of FLT3-ITD and NPM1 mutations Döhner et al., Blood, 2010;115:453-474)

  4. FLT3-ITD and NPM1 mutationsClinical significance FLT3-internal tandem duplication is an indicator of poor outcome in AML. Kottaridis et al. Blood 2001, 1752-1759. NPM1mut is associated with improved outcome. Falini B et al. N Engl J Med 2005; 352:254–266. NPM1mut together with FLT3-ITD is not associated with improved outcome. Thiede et al. Blood 2006, 4011-4020. Analyses to date have been performed in younger patient populations and have not taken treatment into account.

  5. Aim of study • Evaluate FLT3-ITD as a prognostic factor in a homogenous group of elderly patients (>60 years) treated with one protocol • Evaluate NPM1mut alone and in combination with FLT3-ITD as a prognostic factor for OS, EFS and relapse incidence • Evaluate the role of FLT3-ITD and NPM1mut on outcome following chemotherapy and SCT

  6. Treatment protocol (AML 2004; >60 years) TBI-SCT 200 cGy single fraction Chimerism Analyses -3 -2 -1 0 28 56 84 CSP 6.25 mg/kg p.o. b.i.d. days -3 to +84 then taper (Fludara: 30 mg/m2 day -4 to -1) 15 mg/kg p.o. b.i.d. Intergroup 15 (36) Consol 1 10 Consol 2 10 Consol 2 43 Curative 158 (357) R 9:1 n pts material (n pts ) Consol 1 93 CR Induction 1 143 (321) Registration (410) PR CR HLA - matched related or unrelated donor Induction 2 Palliative (53) Allogeneic SCT 44 MMF

  7. Patient characteristics (CR 1)

  8. Analytical methods • Molecular • FLT3-ITD and NPM1mut were analyzed on material frozen at time of diagnosis by capillary electrophoresis after PCR amplification • Murphy et al; Journal of Molecular Diagnostics, 2003, 96-1002. • Falini et al, NEJM, 2005, 254-266. • Statistics • Log-rank (Mantel-Cox) Test

  9. Overall survival Patients with cryopreserved cells n=158 All study patients n=357 years from diagnosis

  10. OS according to FLT3-ITD status (n=158) FLT3wt n=134 FLT3-ITD n=24 years from diagnosis

  11. OS of patients in CR1 according to FLT3-ITD status (n=97) FLT3wt n=75 FLT3-ITD n=22

  12. LFS of patients in CR1 according to FLT3-ITD status (n=97) FLT3wt n=75 FLT3-ITD n=22

  13. LFS of patients in CR1 according to FLT3-ITD and treatment (n=97) FLT3wt (allo-Tx) n=34 FLT3wt (chemo) n=41 FLT3-ITD (allo-Tx) n=10 FLT3-ITD (chemo) n=12

  14. Relapse rate of patients in CR1 according to FLT3-ITD status and SCT/chemotherapy treatment (n=97) FLT3-ITD (chemo) n=12 FLT3-ITD (allo-Tx) n=10 FLT3wt (chemo) n=41 FLT3wt (allo-Tx) n=34

  15. OS according to FLT3-ITD and NPM1 status (n=158) NPM1mut/FLT3wt n=43 NPM1mut/FLT3-ITD; NPM1wt n=115 years from diagnosis

  16. OS of patients in CR1 according to FLT3-ITD and NPM1 status (n=97) NPM1mut/FLT3wt n=33 NPM1mut/FLT3-ITD; NPM1wt n=64

  17. LFS of patients in CR1 according to FLT3-ITD and NPM1 status (n=97) NPM1mut/FLT3wt n=33 NPM1mut/FLT3-ITD; NPM1wt n=64

  18. LFS of patients in CR1 according to FLT3-ITD and NPM1 status (n=97) NPM1mut/FLT3wt (allo-Tx) n=14 NPM1mut/FLT3wt (chemo) n=19 NPM1mut/FLT3-ITD; NPM1wt (allo-Tx) n=30 NPM1mut/FLT3-ITD; NPM1wt (chemo) n=34

  19. Relapse rate of patients in CR1 according to FLT3-ITD/NPM1 status and SCT/chemotherapy treatment (n=97) NPM1mut/FLT3-ITD; NPM1wt (chemo) n=34 NPM1mut/FLT3-ITD; NPM1wt (allo-Tx) n=30 NPM1mut/FLT3wt (chemo) n=19 NPM1mut/FLT3wt (allo-Tx) n=14

  20. Uni- and multivariate analysis

  21. Conclusion • FLT3-ITD is a prognostic factor for OS and LFS in elderly patients in CR1 but not at diagnosis. • NPM1mut in association with FLT3wt is associated with improved outcome in CR1 patients but not at diagnosis. • SCT in comparison to chemotherapy: • improves outcome in both FLT3-ITD and FLT3wt patients. • does not improve outcome in the specific case of NPM1mut and FLT3wt but in all other combinations. • reduces relapse rates in all combinations except NPM1mut/FLT3wt but especially in FLT3-ITD AML patients.

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