Table 1

Multiple Cox regression models for OS and RFS

ParameterStratumOS, n = 508
RFS, n = 333
HR95% CI
PHR95% CI
P
Lower CLUpper CLLower CLUpper CL
NPM1 pos vs neg wtFLT3 0.3 0.2 0.4 < .001 0.2 0.1 0.3 < .001 
FLT3ITD mutation level  wtNPM1 1.1 0.4 3.0 .789 0.6 0.2 2.2 .436 
FLT3ITD mutation level  NPM1+ 5.9 3.1 11.2 < .001 7.5 3.4 16.5 < .001 
Interaction NPM1*FLT3ITD mutation level   5.2 1.7 15.3 .003 12.7 3.0 55 .001 
moCEBPA vs wtCEBPA  0.6 0.3 1.04 .067 0.5 0.2 1.1 .075 
biCEBPA vs wtCEBPA  0.3 0.1 0.5 < .001 0.3 0.1 0.6 .001 
FLT3TKD pos vs neg  1.4 0.9 2.3 .149 1.0 0.5 2.2 .890 
MLL-PTD pos vs neg  0.9 0.6 1.4 .699 0.8 0.4 1.4 .377 
WBC, ×106/L 10-fold  1.4 1.1 1.8 .002 1.3 0.9 1.7 .118 
Platelets, ×106/L 10-fold  0.7 0.6 1.01 .059 0.8 0.6 1.2 .343 
Hemoglobin level, mg/dL +1 g/dL  1.0 0.99 1.005 .595 1.0 0.99 1.01 .858 
LDH, U/L 10-fold  1.2 0.8 1.8 .503 1.2 0.7 2.1 .616 
BM blasts, % +10%  1.0 0.997 1.01 .243 1.0 0.998 1.01 .178 
Age, y +10 y  1.4 1.2 1.5 < .001 1.2 1.1 1.4 < .001 
Performance status, ECOG 2-4 vs 0,1  1.3 0.996 1.6 .054 1.2 0.9 1.6 .310 
Sex Female vs male  0.9 0.7 1.1 .353 0.8 0.6 1.1 .243 
De novo AML vs non–de novo  0.9 0.7 1.3 .709 0.9 0.6 1.4 .781 
ParameterStratumOS, n = 508
RFS, n = 333
HR95% CI
PHR95% CI
P
Lower CLUpper CLLower CLUpper CL
NPM1 pos vs neg wtFLT3 0.3 0.2 0.4 < .001 0.2 0.1 0.3 < .001 
FLT3ITD mutation level  wtNPM1 1.1 0.4 3.0 .789 0.6 0.2 2.2 .436 
FLT3ITD mutation level  NPM1+ 5.9 3.1 11.2 < .001 7.5 3.4 16.5 < .001 
Interaction NPM1*FLT3ITD mutation level   5.2 1.7 15.3 .003 12.7 3.0 55 .001 
moCEBPA vs wtCEBPA  0.6 0.3 1.04 .067 0.5 0.2 1.1 .075 
biCEBPA vs wtCEBPA  0.3 0.1 0.5 < .001 0.3 0.1 0.6 .001 
FLT3TKD pos vs neg  1.4 0.9 2.3 .149 1.0 0.5 2.2 .890 
MLL-PTD pos vs neg  0.9 0.6 1.4 .699 0.8 0.4 1.4 .377 
WBC, ×106/L 10-fold  1.4 1.1 1.8 .002 1.3 0.9 1.7 .118 
Platelets, ×106/L 10-fold  0.7 0.6 1.01 .059 0.8 0.6 1.2 .343 
Hemoglobin level, mg/dL +1 g/dL  1.0 0.99 1.005 .595 1.0 0.99 1.01 .858 
LDH, U/L 10-fold  1.2 0.8 1.8 .503 1.2 0.7 2.1 .616 
BM blasts, % +10%  1.0 0.997 1.01 .243 1.0 0.998 1.01 .178 
Age, y +10 y  1.4 1.2 1.5 < .001 1.2 1.1 1.4 < .001 
Performance status, ECOG 2-4 vs 0,1  1.3 0.996 1.6 .054 1.2 0.9 1.6 .310 
Sex Female vs male  0.9 0.7 1.1 .353 0.8 0.6 1.1 .243 
De novo AML vs non–de novo  0.9 0.7 1.3 .709 0.9 0.6 1.4 .781 

The independent prognostic impact of the FLT3ITD mutation level on OS and RFS was evaluated using multivariate Cox regression models. The FLT3ITD mutation level was introduced as a continuous parameter into the model. Due to the known interaction between NPM1 and FLT3ITD, an interaction term NPM1*FLT3ITD mutation level was included in the model. Besides the FLT3ITD mutation level, mutations of the molecular markers NPM1 (NPM1+), CEBPA (moCEBPA; biCEBPA), FLT3TKD, MLL-PTD, and the clinical parameters age, sex, ECOG performance status, AML de novo, WBC, platelet count, hemoglobin level, LDH, and amount of BM blasts were introduced into the model. The multivariate prognostic factors were identified using a logistic regression model with a significance level of 5%.

OS indicates overall survival; RFS, relapse-free survival; moCEBPA, monoallelic CEBPA mutation; biCEBPA, biallelic CEBPA mutation; TKD, tyrosine kinase domain; PTD, partial tandem duplication; ITD, internal tandem duplication; WBC, white blood count; LDH, lactate dehydrogenase; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; CI, confidence interval; CL, confidence limit; pos, positive; neg, negative; and AML, acute myeloid leukemia.

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