Gene Mutations as Predicitive Markers for Postremission Therapy in Younger Adults with Normal Karyotype AML.

Background: Mutations in the genes encoding NPM1, FLT3 (FLT3 ITD, FLT3 TKD), CEBPA, MLL (PTD) and NRAS have been identified as molecular markers in acute myeloid leukemia (AML) exhibiting a normal karyotype. Most recent studies focused on the prognostic value of single markers not taking into account their potential interactions. In addition, little is known about the predictive value of these markers on postremission therapy.

Aims: To evaluate the prognostic impact of NPM1, FLT3, CEBPA, MLL and NRAS gene mutations on response to induction therapy, relapse-free (RFS) and overall survival (OS) as well as the predictive impact of these mutations on RFS and OS following different postremission therapies.

Methods: Patients [16 to 60 years of age] were entered on four AMLSG treatment trials [AML-2/95, AML-1/99, AML HD93, AML HD98A]. As a consistent feature, in all four trials a genetic randomization was performed assigning all patients with an HLA-matched family donor (MRD) to allogeneic stem cell transplantation (SCT) in first complete remission (CR). Leukemia cells were analyzed for mutations in the above genes as previously described.

Results: Between 1993 and 2004, 872 patients exhibiting a normal karyotype were registered. Median age was 48 years; median follow-up time was 49 months. Mutations were identified as follows (total number of samples analyzed; incidence of mutations): NPM1 (n=526; 53%), FLT3-ITD (n=531; 31%), FLT3-TKD (n=617; 11%), CEBPA (n=509; 14%), MLL-PTD (640; 8%), and NRAS (641; 13%). CR rate was 76%. In a logistic regression model, the NPM1+/FLT3-ITD- (p<.0001) and the CEBPA+ genotypes (p=0.05) were associated with induction success. Of 666 patients achieving a CR after induction therapy, 171 had a MRD and 143 (84%) of these received an allogeneic SCT in first CR. In survival analyses, the variable “availability of a MRD” was included on a strict intent-to-treat basis. Cox proportional hazard models for RFS and OS revealed age <48 years (hazard ratio (HR) 0.72 and 0.62, respectively), availability of a MRD (HR 0.62 and 0.75), the CEBPA+ (HR 0.42 and 0.36) and the NPM1+/FLT3-ITD- (HR 0.34 and 0.43) genotype as prognostic factors. To better define the role of allogeneic SCT in first CR, subgroup analyses were performed according to the combined FLT3-ITD and NPM1 mutation status (NPM1+/FLT3-ITD- versus all other combinations). These analyses revealed a marked difference in HR estimation for the variable “availability of a MRD”. In the NPM1+/FLT3-ITD- subgroup, HR for RFS and OS were 0.89 (95%-CI 0.49–1.64) and 0.93 (95%-CI 0.51–1.67) translating into a nearly equivalent RFS after 4 years of 61% (MRD) and 57% (no MRD). In contrast, in the subgroup defined by all other combinations of FLT3-ITD and NPM1 mutations, HR for RFS and OS were 0.56 (95%-CI 0.39–0.81) and 0.69 (95%-CI 0.48–0.98) translating into a marked difference in 4 years RFS of 47% (MRD) and 23% (no MRD).

Conclusions: Specific genotypes emerge as highly significant prognostic factors for response to induction therapy and for survival in AML patients exhibiting a normal karyotype. The genotypic marker constellation NPM1+/FLT3-ITD- also fulfils the criteria of a predictive marker indicating a strong beneficial effect of allogeneic SCT in first CR only in the subgroup of patients without the NPM1+/FLT3-ITD- marker constellation.