Lang, Min

Purpose: The discovery of MAPK/ERK pathway mutations has led to the approval of MEK-inhibitor (MEKi) cobimetinib in histiocytic neoplasms. However, the pivotal clinical trial that led to the approval of cobimetinib included only 4 patients with Langerhans cell histiocytosis (LCH). Therefore, there is a need to define outcomes with MEKi therapy in patients with LCH. We undertook a multi-center collaboration through the Adult LCH Working Group for the Histiocyte Society to address this gap in knowledge. Methods: Adults with LCH who received MEKi therapy were included from five institutions. Objective response rate (ORR) was evaluated using PET/CT criteria, and CT/MRI if PET scan was not available; response categories were categorized into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Progression-free (PFS) and overall survival (OS) were calculated from the time of targeted therapy initiation. Risk organ disease was defined as liver, spleen, or bone marrow involvement. Results: 25 adults with LCH were included in this study; median age at MEKi initiation 43y (range, 18-85). Most common systems involved at diagnosis were bone (52%), pituitary (44%), and lung (36%). Risk organ involvement was observed in 7 (28%, 6 liver, 1 liver and spleen) and 2 (8%) patients had intra-axial CNS involvement. Median lines of prior therapy received were 2 (range: 1-5), and 4 (16%) patients received MEKi in first-line. MAPK/ERK pathway status was assessed via target capture next generation sequencing (NGS) in 22 (96%) cases. Amongst those who underwent NGS, alterations identified included: BRAF V600E (2/22, 9%), BRAF deletions (11/22 50%), MAP2K1 or MEK mutations (4/22, 18%), and MAPK1 or ERK2 (n=1, 5%). Overall, 5 patients also received BRAF inhibitors (4 patients as first therapy prior to MEKi and 1 concomitantly due to BRAF V600E positive melanoma). Specific MEKi agents utilized included cobimetinib (n=13) and trametinib (n=12). Among the response evaluable patients (n=23), ORR to MEKi treatment was 78% (9 CR, 9 PR, 4 SD, 1 PD). Among the 7 patients with liver involvement, responses were seen in 2 (29%) cases. ORR did not significantly differ according to mutation status among those with NGS data (78% MAPK mutated vs. 100% unmutated; p=1.0). In this subcohort, all of the 4 cases that did not respond to MEKi had liver involvement; 3 had BRAF deletions (2 SD and 1 PD), and one had MAPK1 mutation (SD). Median follow-up duration after MEKi initiation in the entire cohort was 18 months (95% CI 6 - 30). The median PFS and OS were not reached; 2-year PFS and OS were 78.1% and 79.9%, respectively (Figure 1A). The median PFS was much shorter in those with liver involvement (7 months [95% CI 0 - 14]) compared with those without liver disease (not reached [95% CI 19-not reached] P=0.047; Figure 1B). PFS did not differ significantly between MAPK pathway mutated and unmutated patients (p=0.34) Adverse events (AEs) were reported in 36% (n=9) and most commonly included rash (n=5) and fatigue (n=3). Four patients experienced grade 3-4 AEs including rash, fatigue, and thrombocytopenia. Common causes of MEKi discontinuation included AEs (n=3), progression (n=2), and drug holiday (n=2). At last follow-up, 5 patients died and 18 remained on MEKi. Death was attributable to LCH (n=3), concomitant malignancy (n=1), or unknown causes (n=1). Conclusions: In our multi-institutional study of adults with LCH, we found MEKi therapy to be highly efficacious. However, liver involvement correlated with a lack of response and worse PFS, while mutational status did not. Future studies are needed to evaluate optimum treatment for high-risk subgroups of LCH like liver disease.

Abstract Background The effect of transjugular intra-hepatic portosystemic shunt (TIPS) placement on renal function and the correlation of post-TIPS Cr with mortality remain unclear. This study aimed to assess the effect of TIPS placement on renal function and to examine the relationship between post-TIPS Cr and mortality risk. Methods A total of 593 patients who underwent de novo TIPS placement between 2004 and 2017 at a single institution were included in the study. The pre-TIPS Cr level (T0; within 7 days before TIPS placement) and post-TIPS Cr levels, at 1–2 days (T1), 5–12 days (T2), and 15–40 days (T3), were collected. Predictors of Cr change after TIPS placement and the 1-year mortality rate were analysed using multivariable linear-regression and Cox proportional-hazards models, respectively. Results Overall, 21.4% of patients (n = 127) had elevated baseline Cr (≥1.5 mg/dL; mean, 2.51 ± 1.49 mg/dL) and 78.6% (n = 466) had normal baseline Cr (<1.5 mg/dL; mean, 0.92 ± 0.26 mg/dL). Patients with elevated pre-TIPS Cr demonstrated a decrease in post-TIPS Cr (difference, −0.60 mg/dL), whereas patients with normal baseline Cr exhibited no change (difference, <0.01 mg/dL). The 30-day, 90-day, and 1-year mortality rates were 13%, 20%, and 32%, respectively. Variceal bleeding as a TIPS-placement indication (hazard ratio = 1.731; P = 0.036), higher T0 Cr (hazard ratio = 1.834; P = 0.012), and higher T3 Cr (hazard ratio = 3.524; P < 0.001) were associated with higher 1-year mortality risk. Conclusion TIPS placement improved renal function in patients with baseline renal dysfunction and the post-TIPS Cr level was a strong predictor of 1-year mortality risk.