Introduction
Lymphatic malformations (LMs) are low-flow congenital malformations of lymphatic vessels. These malformations develop in utero and usually present in early childhood, though they can manifest at older ages depending on when they become visible and/or symptomatic.1, 2 LMs are often disfiguring, causing social stigma and decreased quality of life.3Depending on their location, they can also cause serious medical complications, such as airway obstruction and life-threatening infections.
The framework for treating LMs is similar to the approach to cancer, utilizing both local therapies (sclerotherapy, surgery) and systemic therapies (medications). For LMs requiring systemic therapy, sirolimus, an mTOR inhibitor, has become standard based on a phase 2 trial demonstrating partial response in 47 of 57 pediatric patients with complex vascular anomalies.4 The rationale for evaluating sirolimus was based on mutations in the RAS/MAPK/mTOR pathway in vascular anomalies, and data demonstrating this pathway plays a key role in angiogenesis and lymphangiogenesis.5, 6Notably, the trial was not done based on molecular phenotype, therefore the heterogeneous response may reflect differing molecular phenotypes.
Until recently, there were few options for patients with vascular anomalies requiring systemic therapy but unresponsive to sirolimus. However, recently, molecularly-targeted therapies have emerged as options for a subset of patients with specific genetic changes, including PI3K inhibitors in PI3K-related overgrowth spectrum (PROS)7, 8, TIE2 inhibitors in TIE2-mutant venous malformations9, and MEK inhibitors in MAP2K-mutant arteriovenous malformations10. Here, we describe two patients with EML4::ALK fusion-positive LMs who were successfully treated with ALK inhibitors. This report adds ALK inhibitors to the growing toolbox of genotypically-targeted therapies for LMs.