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
Jan 14, 2016
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 Presentation
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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).
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.
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