TY - JOUR
T1 - Clinical relevance of molecular aberrations in paediatric acute myeloid leukaemia at first relapse
AU - Bachas, Costa
AU - Schuurhuis, Gerrit Jan
AU - Reinhardt, Dirk
AU - Creutzig, Ursula
AU - Kwidama, Zinia J.
AU - Zwaan, C. Michel
AU - van den Heuvel-Eibrink, Marry M.
AU - De Bont, Evelina S.J.M.
AU - Elitzur, Sarah
AU - Rizzari, Carmelo
AU - de Haas, Valérie
AU - Zimmermann, Martin
AU - Cloos, Jacqueline
AU - Kaspers, Gertjan J.L.
PY - 2014/9
Y1 - 2014/9
N2 - Outcome for relapsed paediatric acute myeloid leukaemia (AML) remains poor. Strong prognostic factors at first relapse are lacking, which hampers optimization of therapy. We assessed the frequency of molecular aberrations (FLT3, NRAS, KRAS, KIT, WT1 and NPM1 genes) at first relapse in a large set (n = 198) of relapsed non-French-American-British M3, non-Down syndrome AML patients that received similar relapse treatment. We correlated molecular aberrations with clinical and biological factors and studied their prognostic relevance. Hotspot mutations in the analysed genes were detected in 92 out of 198 patients (46·5%). In 72 of these 92 patients (78%), molecular aberrations were mutually exclusive for the currently analysed genes. FLT3-internal tandem repeat (ITD) (18% of total group) mutations were most frequent, followed by NRAS (10·2%), KRAS (8%), WT1 (8%), KIT (8%), NPM1 (5%) and FLT3-tyrosine kinase domain (3%) mutations. Presence of a WT1 aberration was an independent risk factor for second relapse (Hazard Ratio [HR] = 2·74, P = 0·013). In patients who achieved second complete remission (70·2%), WT1 and FLT3-ITD aberrations were independent risk factors for poor overall survival (HR = 2·32, P = 0·038 and HR = 1·89, P = 0·045 respectively). These data show that molecular aberrations at first relapse are of prognostic relevance and potentially useful for risk group stratification of paediatric relapsed AML and for identification of patients eligible for personalized treatment.
AB - Outcome for relapsed paediatric acute myeloid leukaemia (AML) remains poor. Strong prognostic factors at first relapse are lacking, which hampers optimization of therapy. We assessed the frequency of molecular aberrations (FLT3, NRAS, KRAS, KIT, WT1 and NPM1 genes) at first relapse in a large set (n = 198) of relapsed non-French-American-British M3, non-Down syndrome AML patients that received similar relapse treatment. We correlated molecular aberrations with clinical and biological factors and studied their prognostic relevance. Hotspot mutations in the analysed genes were detected in 92 out of 198 patients (46·5%). In 72 of these 92 patients (78%), molecular aberrations were mutually exclusive for the currently analysed genes. FLT3-internal tandem repeat (ITD) (18% of total group) mutations were most frequent, followed by NRAS (10·2%), KRAS (8%), WT1 (8%), KIT (8%), NPM1 (5%) and FLT3-tyrosine kinase domain (3%) mutations. Presence of a WT1 aberration was an independent risk factor for second relapse (Hazard Ratio [HR] = 2·74, P = 0·013). In patients who achieved second complete remission (70·2%), WT1 and FLT3-ITD aberrations were independent risk factors for poor overall survival (HR = 2·32, P = 0·038 and HR = 1·89, P = 0·045 respectively). These data show that molecular aberrations at first relapse are of prognostic relevance and potentially useful for risk group stratification of paediatric relapsed AML and for identification of patients eligible for personalized treatment.
KW - Acute myeloid leukaemia
KW - Event free survival
KW - Mutation analysis
KW - Overall survival
KW - Relapse
UR - http://www.scopus.com/inward/record.url?scp=84907597184&partnerID=8YFLogxK
U2 - 10.1111/bjh.12989
DO - 10.1111/bjh.12989
M3 - Article
C2 - 24962064
AN - SCOPUS:84907597184
SN - 0007-1048
VL - 166
SP - 902
EP - 910
JO - British Journal of Haematology
JF - British Journal of Haematology
IS - 6
ER -