Patients with LM have until recently been treated solely by nonpharmacological approaches, such as surgical resection, sclerotherapy, and laser therapy to provide local control and symptomatic relief, but these treatments are generally only effective on well-localized micro- and macrocystic LMs. The identification of oncogenic mutations that result in activation of the well-known PI3K/AKT/mTOR and RAS/MAPK pathways has enabled exploration of drug-based therapeutic interventions using small-molecule inhibitors that were developed for cancer treatment (Figure 2). In particular, inhibitors of mTOR and PI3Kα have shown efficacy in preventing PIK3CA-driven LM and survival in mouse models of LM (30, 49, 50, 58), and several clinical trials targeting vascular anomalies are ongoing (Table 1). Some trials report promising effects in the treatment of lymphatic anomalies and will be discussed here.

Selected clinical trials on targeted molecular therapy for LMs

The mTOR inhibitor rapamycin (trade name sirolimus) is a commonly used drug in clinical practice because of its immunosuppressive properties. Several phase I and II clinical trials (Palvella Therapeutics, NCT05050149; Lille University Hospital, NCT03243019) as well as a large multicenter phase III clinical trial (VASE, EudraCT no. 2015-001703-32; NCT02638389) have evaluated or are currently evaluating rapamycin efficacy and safety in pediatric and adult patients with vascular malformations, including LMs (Table 1). A review of 16 early studies, mostly consisting of case studies, including a total of 52 patients treated with sirolimus for microcystic LM, showed promising results. Clinically meaningful long-term improvement (up to 3 years) was noted in 92% (46 of 50) of the participants. Sirolimus yielded improvements in manifestations such as lymphatic leakage, bleeding, vesicle bulk, pain, and skin discoloration. Some participants experienced a rapid onset of effect within 2 weeks (59). Preliminary analysis of the larger phase III VASE trial on the first 101 patients with at least 6 months of treatment showed that 87% experienced functional improvement and less pain (60), although regression of overgrowth is limited. Earlier treatment, prior to active overgrowth, is likely to be more effective. Notably, a recent case report describes prenatal treatment with rapamycin of a fetus with a cervicofacial fetal LM with encouraging long-term outcome and limited side effects (61). In addition to inhibiting the AKT/mTOR pathway in endothelial cells that express the mutant PIK3CA, rapamycin exerts immunosuppressive effects through regulation of T cell function (62). These antiinflammatory functions may contribute to the beneficial effects of rapamycin in limiting LM growth.

The PI3K inhibitor alpelisib (BYL719) selectively inhibits the PI3Kα subunit (63) and was originally FDA approved for treatment of PIK3CA-mutated breast cancer. In 2022, alpelisib was approved by the FDA for patients with severe PROS requiring systemic treatment (Novartis; Vijoice, NCT04085653). Alpelisib has also been administered in a pilot study on LMs. Treatment of 6 patients, including 3 children, with LM for 6 months showed a 48% decrease in the size of lymphatic lesions (50), thus meriting further exploration of the use of alpelisib on LMs. Alpelisib is currently in phase II/III clinical study for pediatric and adult patients with PIK3CA-related LM (Novartis NCT05948943) (Table 1).

Other molecular treatments that target the PI3K pathway include the AKT inhibitor miransertib (Figure 2), which is currently in a phase II clinical trial for patients with PROS or Proteus syndrome (Merck Sharp & Dohme, NCT04980872). Miransertib is shown to inhibit PI3K signaling and decrease cell viability in patient-derived PIK3CA-mutant cells from venous malformations (64), but no trials specifically addressing the effect on LM are currently ongoing.

Inhibition of the RAS/MAPK pathway through MEK inhibition (Figure 2) has shown significant improvement in the lymphatic phenotype for patients with KLA (56, 65), CCLA (22, 57), and Noonan syndrome (66). Despite heterogeneity in both phenotype and genetics among the treated patients carrying gain-of-function mutations in positive regulators (NRAS, ARAF, SOS1) (56, 57, 66) or loss-of-function mutations in a negative regulator (CBL) (65) of the RAS/MAPK pathway, the observed clinical effects suggest MEK inhibitors as promising candidates for evaluation in clinical trials for patients with cystic LMs, in particular those associated with CLAs and unresponsive to sirolimus therapy. Currently, two MEK inhibitors, mirdametinib and trametinib, are undergoing clinical trials for fast-flow vascular malformations that are also associated with defects in RAS/MAPK pathway genes (NCT05983159, NCT06098872).

Additional medical approaches include sclerotherapy agents picibanil (OK-432) and TARA-002, which are in phase II and III clinical trials for LM (University of Iowa, NCT00010452; Protara Therapeutics, NCT05871970). These consist of a lyophilized strain of inactivated Streptococcus pyogenes bacteria, devoid of infectious properties, and are administered through intralesional injection. Originally developed as a stimulant for immune cytotoxicity against cancer (67), this treatment may also promote fibrotic changes within the LM lesion (68). Another widely used sclerotherapy agent is bleomycin, which is extracted from Streptomyces verticillus, that induces cell apoptosis. Additional sclerosing agents include ethanol, doxycycline, hypertonic glucose solution, and corticosteroids. There are complications associated with the use of each of these agents (69). However, OK-432 and bleomycin have shown highly beneficial results in the treatment of macrocystic LMs (67) and LMs of the head and neck (70), respectively, and continue to be the most commonly used treatments in clinical practice.