Clinical improvement is linked directly to the administration of vemurafenib. (A) Drug therapy of the first 420 days (60 weeks, start: day 0); vemurafenib was started on day 37 because of the worsening clinical condition during stratum I (vinblastine/prednisone), paused during initial salvage therapy of stratum III (2-CdA/Ara-C), and reduced in dose in 2 stages and discontinued during continuation therapy part 2 (6-MP/MTX/vinblastine/prednisone). Subsequently, continuation therapy part 3 (6-MP/MTX) was carried out until day 730 (supplemental Figure 1). (B) Vemurafenib resulted in immediate improvement in fever, CRP, and TP. Each cessation of vemurafenib during the chemotherapy cycles caused intermittent fever, rise in CRP, and falling levels of TP, which reversed on continuation. (C) MRT of cranial lesions, which decreased in size visibly already during therapy with vinblastine/prednisone (T1-weighted MRI). (D) CC-chemokine ligand 2 (CCL2) concentration was closely correlated with clinical signs of disease activity. Points represent the median, and error bars the top and bottom of triplicate measurements per time point. The LCH disease activity score (DAS), which stayed high during initial chemotherapy, immediately improved on start with vemurafenib. It is important to note that the DAS after 2-CdA/Ara-C is confounded by chemotherapy-induced cytopenia. (E) During vemurafenib therapy, the percentage of BRAF^V600E mutant alleles increased. Following stratum III therapy, no more mutant alleles were measurable.