FLT3-internal tandem duplication and age are the major prognostic factors in patients with relapsed acute myeloid leukemia with normal karyotype.
BACKGROUND
Several genetic aberrations with prognostic impact in first-line therapy have been described in patients with acute myeloid leukemia and normal karyotype. However, little is known about the influence of these aberrations on outcome after relapse. This study aimed to identify clinical and molecular risk factors for patients with relapsed acute myeloid leukemia with normal karyotype.


METHODS
We analyzed 94 patients with acute myeloid leukemia and normal karyotype after first relapse for clinical and molecular risk factors for survival. All patients had received first-line treatment and follow-up within two prospective, multicenter trials. Leukemic blasts were analyzed at diagnosis for genetic aberrations in the FLT3, NPM1, CEBPA, WT1, IDH1 and IDH2 genes by polymerase chain reaction and/or direct sequencing.


RESULTS
A second complete remission was achieved in 52% of patients who received re-induction therapy. The presence of an FLT3-internal tandem duplication, duration of first complete remission less than 6 months and age above the median of 47 years were associated with a significantly lower rate of second complete remission. The median survival after relapse was 11 months and the 6-year survival rate was 28%. In multivariate analysis, FLT3-internal tandem duplication and age above the median were the only independent negative prognostic factors for survival. The 6-year survival rate of patients with none of these factors was 56%, whereas it was significantly inferior in patients with one or both of these factors (15% and 6%, respectively). This was also true for patients who underwent allogeneic stem cell transplantation after relapse.


CONCLUSIONS
FLT3-internal tandem duplication and age are the major prognostic factors in patients with relapsed acute myeloid leukemia with a normal karyotype. Patients with at least one of these risk factors have a dismal outcome and might be considered for investigational treatment approaches after relapse. (ClinicalTrials.gov Identifier: NCT00209833).
Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany. wagner.katharina@mh-hannover.de
Katharina
K
Wagner
Frederik
F
Damm
Felicitas
F
Thol
Gudrun
G
Göhring
Kerstin
K
Görlich
Michael
M
Heuser
Irina
I
Schäfer
Brigitte
B
Schlegelberger
Gerhard
G
Heil
Arnold
A
Ganser
Jürgen
J
Krauter
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003561:Cytarabine / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D020440:Gene Duplication; D006801:Humans; D053208:Kaplan-Meier Estimate; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D000090243:Nucleophosmin; D011379:Prognosis; D012008:Recurrence; D033581:Stem Cell Transplantation / Q000379:methods; D020080:Tandem Repeat Sequences / Q000235:genetics*; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
C000716967:NPM1 protein, human; D003561:Cytarabine; D000090243:Nucleophosmin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
J Clin Oncol. 2004 Feb 15;22(4):624-33
14726504
J Clin Oncol. 2010 Feb 1;28(4):578-85
20038731
Haematologica. 2008 May;93(5):775-9
18367491
Blood. 2010 Jan 21;115(3):453-74
19880497
J Clin Oncol. 2005 Mar 20;23(9):1969-78
15632409
Leukemia. 2002 Sep;16(9):1699-704
12200684
N Engl J Med. 2008 May 1;358(18):1909-18
18450602
Blood. 2011 Mar 24;117(12):3294-301
21270442
J Clin Oncol. 2009 Jun 20;27(18):3000-6
19380453
Stat Med. 1986 May-Jun;5(3):255-60
3738291
J Clin Oncol. 2005 Sep 10;23(26):6285-95
16155011
Haematologica. 2004 Aug;89(8):998-1008
15339685
Leukemia. 2006 Jul;20(7):1217-20
16642044
J Clin Oncol. 2010 Apr 10;28(11):1856-62
20212254
Leukemia. 2006 Apr;20(4):604-9
16453003
Blood. 2005 Dec 1;106(12):3740-6
16051734
Haematologica. 2010 Nov;95(11):1857-64
20634493
Blood. 2002 Oct 1;100(7):2393-8
12239147
Blood. 2009 May 7;113(19):4505-11
19221039
Haematologica. 2008 Jul;93(7):976-82
18591623
Blood. 2009 Oct 1;114(14):2984-92
19654408
J Clin Oncol. 2003 Dec 15;21(24):4642-9
14673054
Blood. 2010 Jul 29;116(4):614-6
20421455
J Clin Oncol. 2010 Oct 1;28(28):4339-45
20733134
Blood. 2002 Dec 15;100(13):4372-80
12393388
Leuk Res. 2010 Jun;34(6):752-6
19878996
Ann Hematol. 2004 Jun;83(6):336-44
15034758
J Clin Oncol. 2008 Oct 1;26(28):4595-602
18559874
J Clin Oncol. 2010 Aug 1;28(22):3636-43
20567020
N Engl J Med. 2005 Jan 20;352(3):254-66
15659725
Blood. 2010 Jun 24;115(25):5222-31
20368469
Blood. 2002 Jul 1;100(1):59-66
12070009
Blood. 2002 Jun 15;99(12):4326-35
12036858
Blood. 2002 Oct 1;100(7):2387-92
12239146
J Clin Oncol. 2010 May 10;28(14):2356-64
20368538