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.