Gene mutations and response to treatment with all-trans retinoic acid in elderly patients with acute myeloid leukemia. Results from the AMLSG Trial AML HD98B.
BACKGROUND
In a previous randomized trial, AML HD98B, we showed that administration of all-trans retinoic acid in addition to intensive chemotherapy improved the outcome of older patients with acute myeloid leukemia. The objectives of this study were to evaluate the prognostic impact of gene mutations and to identify predictive genetic factors for the all-trans retinoic acid treatment effect.


METHODS
Data from mutation analyses of the NPM1, CEBPA, FLT3, and MLL genes were correlated with outcome in patients 61 years and older treated within the AML HD98B trial.


RESULTS
The frequencies of mutations were: NPM1, 23%; CEBPA, 8.5% (analysis restricted to patients with a normal karyotype); FLT3 internal tandem duplications (ITD), 17%; FLT3 tyrosine kinase domain mutations, 5%; and MLL partial tandem duplications, 4.5%. The genotype mutant NPM1 was positively and adverse cytogenetics as well as higher white blood cell count negatively correlated with achievement of complete remission. In Cox regression analysis, a significant interaction between the genotype mutant NPM1 without FLT3-ITD and treatment with all-trans retinoic acid was identified, in that the beneficial effect of all-trans retinoic acid on relapse-free and overall survival was restricted to this subgroup of patients. Other significant factors for survival were age, adverse cytogenetics, and logarithm of white cell count.


CONCLUSIONS
In elderly patients with acute myeloid leukemia, NPM1 mutations are associated with achievement of complete remission, and the genotype 'mutant NPM1 without FLT3-ITD' appears to be a predictive marker for response to all-trans retinoic acid given as an adjunct to intensive chemotherapy (ClinicalTrials.gov Identifier: NCT00151242).
Schlenk
Richard F
RF
Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany. richard.schlenk@uniklinik-ulm.de
Döhner
Konstanze
K
Kneba
Michael
M
Götze
Katharina
K
Hartmann
Frank
F
Del Valle
Francesco
F
Kirchen
Heinz
H
Koller
Elisabeth
E
Fischer
Jörg T
JT
Bullinger
Lars
L
Habdank
Marianne
M
Späth
Daniela
D
Groner
Silja
S
Krebs
Bernhard
B
Kayser
Sabine
S
Corbacioglu
Andrea
A
Anhalt
Andreas
A
Benner
Axel
A
Fröhling
Stefan
S
Döhner
Hartmut
H
D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D000090243:Nucleophosmin; D010865:Pilot Projects; D015996:Survival Rate; D016896:Treatment Outcome; D014212:Tretinoin / Q000627:therapeutic use*
D015415:Biomarkers; C000716967:NPM1 protein, human; D000090243:Nucleophosmin; D014212:Tretinoin