Canadian Journal of Cardiology



      No causal therapies exist for severe pediatric-onset cardiomyopathy associated with germline mutations in RAS/mitogen-activated protein kinase (MAPK) pathway (RAS-CM). In order to evaluate the benefit of small molecule inhibitors of target of rapamycin (mTORi) or MAPK kinase (MEKi) in RAS-CM patients, we have sought to compile cases of compassionate use of these agents.

      Methods and Results

      Case series collecting pre-defined variables on safety and clinical outcome on 25 children with progressive RAS-CM receiving off-label or compassionate use mTORi or MEKi after exhaustion of standard therapies in 17 European and North-American centers. Over a follow-up period of 296 patient-months (median, 5.5 months; range, 1.5-50), transplant-free survival in critically ill patients < 6 months of age treated with mTORi and/or MEKi was 75% compared to 39% in natural history controls (p=0.031). Freedom from surgical intervention was 52% (11 of 21 patients in whom surgical outflow tract resection was indicated), and improvement in clinical functional status and decrease in NT-proBNP z-score by at least 20% from baseline occurred in 85% and 70.6% of patients, respectively (median [range] change in Ross classification -1.3 [-2 – 0] and in NT-proBNP z-score -1.8 [-3.7 - +0.4], p< 0.001, before treatment versus last treatment timepoint). No life-threatening adverse events related to mTORi or MEKi were observed. Skin and mucous membranes were the most common organs affected by side effects, requiring cessation or reduction of therapy in 16% of patients.


      Selected RASopathy patients may benefit from novel mechanism-informed therapeutics targeting the RAS/MAPK pathway. Clinical trials are needed to substantiate the findings reported in this case series.