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T. Herold et al.
After pre-selection of variables in training set 1 and 2, penalized logistic regression (Lasso) in training set 1 was used to develop a predictive classifier that was able to identify patients with RD. Details regarding the development of the classifier are given in the Online Supplementary Appendix and Online Supplementary Figure S2, or were published previously.21
The predictor was validated in a fully independent cohort of patients where gene expression was analyzed by a different method, namely RNA-Seq. The final predictor and cut off were developed before the validation data set became available.
Cut-off development
Our aim was to provide a meaningful cut off to guide clinical decision making. In the case of AML, this means that patients should not be excluded from induction chemotherapy unless there is a very high likelihood that it will be ineffective. Therefore, from the clinical perspective, a high specificity of the predictor is desir- able. The cut off was, therefore, designed to have a specificity of 0.9 in training set 1. However, by adjusting the cut off to achieve high specificity, the sensitivity of the predictor decreases.
A
Statistical analysis
All statistical analyses were performed using the R 3.3.1 soft- ware package (R Foundation for Statistical Computing, Vienna, Austria). Definitions of response to treatment are shown in Figure 1A. We used a slightly modified definition of RD as recommended by Cheson et al.4 In the original definition, patients had to survive at least seven days post induction treatment and have persistent AML in blood or bone marrow after induction treatment. To address the difference in treatment length between various induc- tion regimens [HAM (5 days), “7+3” [7 days], TAD (9 days) or sHAM (11 days)], only patients surviving at least 16 days after the start of treatment, independently of the treatment arm, were con- sidered for the development of the predictor in the training sets. Day 16 was selected because the first induction response testing in AMLCG trials was scheduled at this time point. Only patients who started study treatment and those with a definite induction result (CR/CRi or RD) were included in training set 1 and in the analysis of RD in the validation set. Patients with death in aplasia or of indeterminate cause were excluded from training set 1 (but not from the validation set). This subgroup of patients (n=15) in
B
Figure 1. Definitions of response and study design. (A) Figure showing the details of the response definition. (B) Flow chart showing the study design and distribution of patients. *Patients analyzed by targeted sequencing for 68 genes recurrently mutated in acute myeloid leukemia. RD: resistant disease; AML: acute myeloid leukemia; PB: periph- eral blood; PS29MRC: Predictive Score 29 MRC; HOVON: Haemato-Oncology Foundation for Aults in the Netherlands.
haematologica | 2018; 103(3)