A distinct four-value blood signature of pyrexia under combination therapy of malignant melanoma with BRAF/MEK-inhibitors evidenced by an algorithm-defined pyrexia score

Abstract

ABSTRACTPyrexia is a frequent adverse event of BRAF/MEK-inhibitor combination therapy in patients with metastasized malignant melanoma (MM). The study’s objective was to identify laboratory changes which might correlate with the appearance of pyrexia. Initially, data of 38 MM (14 with pyrexia) patients treated with dabrafenib plus trametinib were analysed retrospectively. Graphical visualization of time series of laboratory values suggested that a rise in C-reactive-protein, in parallel with a fall of leukocytes and thrombocytes, were indicative of pyrexia. Additionally, statistical analysis showed a significant correlation between lactate dehydrogenase (LDH) and pyrexia. An algorithm based on these observations was designed using a deductive approach in order to calculate a pyrexia score (PS) for each laboratory assessment in treated patients. A second independent data set with 28 MM patients (8 with pyrexia) was used for the validation of the algorithm. PS based on the four parameters CRP, LDH, leukocyte and thrombocyte numbers, were statistically significantly higher in pyrexia patients, differentiated between groups (F=20,8; p=<0,0001) and showed a significant predictive value for the development of pyrexia (F=6,24; p=0,013). We provide first evidence that pyrexia in patients treated with BRAF/MEK-blockade can be identified and predicted by an algorithm that calculates a score.SUMMARY STATEMENTPyrexia is a severe side effect of BRAF/MEK-inhibitor therapy of malignant melanoma. An algorithm based on the four laboratory values, leukocyte and thrombocyte counts, CRP and LDH, was designed for detecting pyrexia. The used heuristic approach might serve as a blueprint for analysing unevenly sampled or even incomplete clinical data.