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)

FLT3-ITD and NPM1 gene mutations

FLT3-ITDFLT3-ITD NPM1NPM1

Frequency of FLT3-ITD and NPM1 mutations

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

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

• 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

Induction 2

Induction 1143 (321)

Consol 193

PR

CR

CR

Allogeneic SCT 44

HLA - matched related or unrelated donor

Intergroup15 (36)

Curative158 (357)

Palliative(53)

Registration(410)

Consol 2 43

MMFMMF 15 mg/kg p.o. b.i.d.15 mg/kg p.o. b.i.d.(Fludara:

30 mg/m2 day -4 to -1)

(Fludara: 30 mg/m2 day -4 to -1)

TBI-SCT 200 cGy single fraction Chimerism Analyses

-3 560 28 84-2 -1

6.25 mg/kg p.o. b.i.d. days -3 to +84 then taper6.25 mg/kg p.o. b.i.d. days -3 to +84 then taperCSPCSP

Treatment protocol (AML 2004; >60 years)

n pts material (n pts )n pts material (n pts )

Consol 2 10

Consol 110

9:19:1RR

Patient characteristics (CR 1)

All patients

n = 97

FLT3wt

n = 75

FLT3-ITD

n = 22

p

Age (median, range) [years] 66 ( 60 - 78 ) 67 ( 60 - 77 ) 65 ( 61 - 78 ) .15

Sex ( male / female ) 52 / 45 38 / 37 14 / 8 .28

AML ( de novo / secondary/ treatment related ) 70 / 24 / 3 54 / 18 / 3 16 / 6 / - .84

Cytogenetic risks

standard ( normal, other )

high (abn 3q26, -5/5q-, -7/7q-,

abn 11q23, complex)

73

12

55

12

18

0

.06

Karnofsky status (median, range) 80 ( 30 - 100 ) 80 ( 50 - 100 ) 80 ( 30 - 100 ) .21

WBC at diagnosis (median, range) 7.0 (0.2 - 385) 4.8 (0.2 - 324) 40 (0.7 - 385) .003

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

Overall survival

All study patients n=357All study patients n=357

Patients with cryopreserved cells n=158Patients with cryopreserved cells n=158

years from diagnosis

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

FLT3-ITD n=24FLT3-ITD n=24

FLT3wt n=134FLT3wt n=134

years from diagnosis

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

FLT3-ITD n=22FLT3-ITD n=22

FLT3wt n=75FLT3wt n=75

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

FLT3-ITD n=22FLT3-ITD n=22

FLT3wt n=75FLT3wt n=75

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

FLT3-ITD (allo-Tx) n=10FLT3-ITD (allo-Tx) n=10

FLT3-ITD (chemo) n=12FLT3-ITD (chemo) n=12

FLT3wt (allo-Tx) n=34FLT3wt (allo-Tx) n=34

FLT3wt (chemo) n=41FLT3wt (chemo) n=41

Relapse rate of patients in CR1 according to FLT3-ITD status and SCT/chemotherapy

treatment (n=97)

FLT3wt (allo-Tx) n=34FLT3wt (allo-Tx) n=34

FLT3-ITD (chemo) n=12FLT3-ITD (chemo) n=12

FLT3wt (chemo) n=41FLT3wt (chemo) n=41

FLT3-ITD (allo-Tx) n=10FLT3-ITD (allo-Tx) n=10

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

NPM1mut/FLT3wt n=43NPM1mut/FLT3wt n=43

NPM1mut/FLT3-ITD; NPM1wt n=115NPM1mut/FLT3-ITD; NPM1wt n=115

years from diagnosis

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

NPM1mut/FLT3wt n=33NPM1mut/FLT3wt n=33

NPM1mut/FLT3-ITD; NPM1wt n=64NPM1mut/FLT3-ITD; NPM1wt n=64

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

NPM1mut/FLT3wt n=33NPM1mut/FLT3wt n=33

NPM1mut/FLT3-ITD; NPM1wt n=64NPM1mut/FLT3-ITD; NPM1wt n=64

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

NPM1mut/FLT3wt (allo-Tx) n=14NPM1mut/FLT3wt (allo-Tx) n=14

NPM1mut/FLT3-ITD; NPM1wt (allo-Tx) n=30NPM1mut/FLT3-ITD; NPM1wt (allo-Tx) n=30

NPM1mut/FLT3wt (chemo) n=19NPM1mut/FLT3wt (chemo) n=19

NPM1mut/FLT3-ITD; NPM1wt (chemo) n=34NPM1mut/FLT3-ITD; NPM1wt (chemo) n=34

Relapse rate of patients in CR1 according to FLT3-ITD/NPM1 status and SCT/chemotherapy

treatment (n=97)

NPM1mut/FLT3wt (allo-Tx) n=14NPM1mut/FLT3wt (allo-Tx) n=14

NPM1mut/FLT3-ITD; NPM1wt (allo-Tx) n=30NPM1mut/FLT3-ITD; NPM1wt (allo-Tx) n=30

NPM1mut/FLT3wt (chemo) n=19NPM1mut/FLT3wt (chemo) n=19

NPM1mut/FLT3-ITD; NPM1wt (chemo) n=34NPM1mut/FLT3-ITD; NPM1wt (chemo) n=34

Uni- and multivariate analysisOS LFS relapse NRM

univ. / multiv.p - value

univ. / multiv.p - value

univ. / multiv.p - value

univ. / multiv.p - value

Age ns / - ns / - ns / - ns / -

Sex (male / female) ns / - ns / - .09 / .82 .95 / -

AML (de novo, secondary, treatment related)

ns / - ns / - ns / - ns / -

Cytogenetic risks (standard, high) ns / - ns / - ns / - ns / -

Karnofsky status ns / - ns / - ns / - ns / -

WBC at diagnosis ns / - ns / - ns / - ns / -

Treatment (OSHO, Intergroup) ns / - ns / - ns / - ns / -

CR after 1 or 2 courses ns / - ns / - ns / - ns / -

2. consolidation: CT or allo HCT ns / - ns / - .05 / .02 ns / -

2. consolidation: CT or RD- or URD HCT ns / - ns / - ns / - .05 / .09

Interval CR - 2. consolidation or allo HCT ns / - ns / - .08 / .19 ns / -

FLT3-ITD or FLT3wt .06 / .25 .01 / .01 .01 / .15 ns / -

NPM1mut or NPM1wt ns / - ns / - ns / - ns / -

NPM1mut/FLT3wt or other .04 / .05 .01 / .07 .01 / .01 ns / -

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.