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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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slide1

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)

slide3

Frequency of FLT3-ITD and NPM1 mutations

Döhner et al., Blood, 2010;115:453-474)

flt3 itd and npm1 mutations clinical significance
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.

aim of study
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
slide6

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

slide8

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
slide9

Overall survival

Patients with cryopreserved cells n=158

All study patients n=357

years from diagnosis

slide10

OS according to FLT3-ITD status (n=158)

FLT3wt n=134

FLT3-ITD n=24

years from diagnosis

slide13

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

slide14

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

slide15

OS according to FLT3-ITD and NPM1 status (n=158)

NPM1mut/FLT3wt n=43

NPM1mut/FLT3-ITD; NPM1wt n=115

years from diagnosis

slide16

OS of patients in CR1 according to FLT3-ITD and NPM1 status (n=97)

NPM1mut/FLT3wt n=33

NPM1mut/FLT3-ITD; NPM1wt n=64

slide17

LFS of patients in CR1 according to FLT3-ITD and NPM1 status (n=97)

NPM1mut/FLT3wt n=33

NPM1mut/FLT3-ITD; NPM1wt n=64

slide18

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

slide19

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

conclusion
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.