Discussion
Recurrent pLGGs represent a therapeutic challenge. Exhaustion of evidence-based regimens may lead to off-study use of experimental therapies or combinations. Multiple studies support the use of MEK inhibitors and lenalidomide alone to treat pLGGs, but to date, there is no clinical trial evaluating this combination15-19,21. We describe four patients treated with concurrent trametinib and lenalidomide for multiply-progressive CNS or PNS tumors. Each patient had previously tolerated monotherapy with trametinib. However, two of four patients experienced significant thromboembolic events, requiring termination of this combination regimen.
Thromboembolic events have not been described in case reports or early-phase clinical trials of single-agent trametinib or lenalidomide in pediatric patients with CNS tumors.17,20,21,23-27The risk for thrombosis in adults treated with trametinib or lenalidomide monotherapy is also extremely low.28-30However, deep vein thrombosis (DVT) and pulmonary embolism (PE) were observed when trametinib was combined with the BRAF inhibitor, dabrafenib, for treatment of melanoma or non-small cell lung cancer.31
Similarly, immunomodulatory agents are associated with an increased risk for myocardial infarction, stroke, DVT, and PE in adults with multiple myeloma when used concomitantly with dexamethasone or chemotherapy.32,34 The proposed mechanism for hypercoagulability is poorly understood but likely involves decreases in anticoagulant proteins and increases in platelet aggregation.35 This may be potentiated by other prothrombotic agents, such as high-dose dexamethasone, as well as the direct action of immunomodulatory agents on endothelial cells previously damaged by chemotherapy.32
Cardiotoxicity has been associated with MEK and BRAF inhibitors and is thought to result from interference with the MAPK pathway, which may have a cardioprotective role.31 Disruption of vascular endothelial growth factor signaling via downstream blockade of MEK leads to decreased nitric oxide production, thereby contributing to vasoconstriction, hypertension, and an imbalance between pro and anti-thrombotic factors. Angiogenesis, cellular apoptosis, and remodeling of myocytes may also rely on normal MAPK function.
This is the first report of trametinib used concomitantly with lenalidomide; thus, no pharmacodynamic data is available for the combination. Although the side effect profiles for each agent are unique, MEK inhibitor-induced cardiotoxicity combined with the prothrombotic properties of immunomodulatory agents may additively contribute to the risk for thrombosis in patients treated with trametinib and lenalidomide concurrently. Given the severe thromboembolic events experienced by these patients treated with concomitant trametinib and lenalidomide, this combination requires further investigation, and we urge caution if used concurrently.