flt3-itd and npm1 gene mutations
DESCRIPTION
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). - PowerPoint PPT PresentationTRANSCRIPT
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.