Case 1
A 10-year-old boy had been diagnosed with an optic chiasm pilomyxoid astrocytoma (WHO grade II, BRAF:KIAA1549 fusion-positive). Prior therapy included subtotal resection (STR), carboplatin and vinblastine, focal photon radiation to 54 Gy, and trametinib. After three months of trametinib, he experienced progressive disease (PD) and started lenalidomide in addition to trametinib. Adverse effects on this combination were limited to grade 1 rash and paronychia. He achieved 15 months of stable disease (SD) on combination therapy before experiencing PD, prompting discontinuation of this therapy.
Case 2 A 6-year-old boy had been diagnosed with an optic pathway pilomyxoid astrocytoma (WHO grade II, BRAF:KIAA1549 fusion-positive). Prior therapy included carboplatin and vinblastine, everolimus, and two courses of trametinib.
At five years of age, six months into his second course of trametinib, he experienced PD and subsequently started lenalidomide in addition to trametinib. After three months of combination therapy, magnetic resonance imaging (MRI) of the brain demonstrated a partial response. Seven months into combination therapy, trametinib and lenalidomide were held due to urgent ventriculoperitoneal shunt revision. Within 48 hours, he experienced near-complete vision bilateral loss. MRI of the brain demonstrated a left posterior watershed territory hypoxic-ischemic injury (Figure 1), with stable appearance of the optic pathway mass. Multidisciplinary stroke team evaluation did not deem the area of injury plausibly attributable to direct surgical manipulation or tumor-associated vascular compression. Echocardiogram was negative for thrombus. He discontinued trametinib and lenalidomide and started radiation therapy.
Case 3 A 11-year-old girl was diagnosed with an optic pathway pilomyxoid astrocytoma (WHO grade II, BRAF:KIAA1549 fusion-positive). Prior therapy included carboplatin and vincristine, vinblastine monotherapy, carboplatin, vinblastine and cetuximab, and focal photon radiation to 54 Gy before starting trametinib. She received 15 months of trametinib with continued gradual PD before starting on lenalidomide. After four months of combination therapy, MRI of the brain demonstrated SD. However, surveillance echocardiogram identified severe biventricular dysfunction with a left ventricular ejection fraction (LVEF) of 18%, fractional shortening of 9%, and two mural thrombi in the left ventricular apex (Figure 2); the right ventricle was also moderately depressed. Echocardiograms performed prior to lenalidomide initiation demonstrated normal biventricular function. Trametinib and lenalidomide were discontinued, and she started enoxaparin and losartan. Within two weeks, the thrombi were no longer detectable by echocardiogram, and after two months, LVEF had recovered to 53%.