Pediatric Pilocytic Astrocytoma With a KIAA1549:BRAF Fusion

Shubin Shahab, MD, Emory University, Atlanta, Georgia, discusses the course of treatment he would take for a patient with pediatric pilocytic astrocytoma with a KIAA1549:BRAF fusion.

Transcript: 

Hi, my name is Shubin Shahab, I'm a pediatric neuro-oncologist at Children's Health Care Atlanta, Emory University, and I’m an instructor in pediatric oncology. The case that I'm going to be talking about today is a patient with a low-grade glioma that I treated a few years ago. 

This was a 5 year old female who presented to us with a couple of months of progressive headaches as well as emesis. By the time she presented, she had been experiencing daily headaches for 4 days as well as 1 day of dysconjugate gaze which prompted the parents to take her to an emergency room. A head CT done at this emergency room revealed a suprasellar mass with obstructive hydrocephalus. The patient was then transferred to our hospital for urgent neurosurgical evaluation, and at that time MRI revealed a T2 hyperintense, predominantly solid, suprasellar mass measuring 4.3 by 3.5 centimeters, pretty big for a 5 year old, located just posterior to the optic chiasm. She underwent a subtotal resection and was discharged after her hydrocephalus resolved with planned outpatient oncology follow-up. We did consult on her while she was inpatient, and we were just waiting on the pathology. When pathology came back, it revealed a pilocytic astrocytoma, which is the most common type of pediatric low-grade glioma that we take care of, with a KIAA1549: BRAF fusion which is also the most common type of molecular alteration that is seen in pediatric low-grade glioma. She did not have any other molecular abnormality and given that she had a partial resection, we knew that she needed further therapy. We offered several chemotherapy options at this point, we offered her a combination of carboplatin and vincristine, a combination of a 4-drug regimen called TPCV, which stands for thioguanine, procarbazine, lomustine, and vincristine, as well as monotherapy with vinblastine. We also discussed a clinical trial option, however this family was about an hour and a half away from our hospital, so that would have been a very difficult option for them. At that time, there was a national shortage of vincristine so after discussion, the decision was made to proceed with weekly vinblastine therapy, which could be initiated at our center but then could be continued at the local center that would be much more convenient for the family.

She tolerated the vinblastine pretty well, completed a whole year of treatment without significant toxicity, and end of therapy scans demonstrated improved tumor bulk however, at a 3-month follow-up visit, off therapy scans demonstrated regrowth of her tumor. We had further discussions about additional treatment options, and we decided to proceed with irinotecan plus bevacizumab. Initially, the patient was only started on irinotecan because we had a discussion with neurosurgery, and it wasn't decided whether she was going to need further neurosurgical evaluation. When neurosurgery cleared her, we started her on bevacizumab. She did receive her first dose, but after her second dose she developed malignant hypertension and had to be emergently treated at the ICU with an antihypertensive drip. When she recovered, we had to stop this regimen and we had to switch her to another regimen. 

At this time, the decision was made to treat her with carboplatin and vincristine per the CCG-A9952 study. She initially tolerated this regimen pretty well however, over time developed what was thought to be an allergic reaction to carboplatin which did not resolve despite giving her pre-medications as well as discussions with other support groups, including a psychologist, so treatment was discontinued after 8 months of this carbo-vincristine regimen and the decision was made to switch her to vinblastine one more time to complete her 1 year of treatment. 

Unfortunately, the patient had developed severe anxiety to chemotherapy in general at this point and she could not finish her vinblastine regimen either and treatment had to be stopped a few weeks before her completion of 12 months. Surveillance imaging and visual exams at this point were stable and remained stable for over a year off therapy however, an 18 month off therapy scan demonstrated regrowth of her tumor and she started developing some visual symptoms. She was found to have papilledema on exam as well as hydrocephalus. At this point she underwent a ventriculoperitoneal shunt placement and we discussed treatment options again with the family. 

Because of her severe anxiety to chemotherapy, we offered her oral regimens including MEK inhibitors and RAF inhibitors and the family decided that go with a MEK inhibitor at this point, so we started her on trametinib. Given her prior history of hypertension, we decided to start her on a lower dose, so we started around half a milligram per day of trametinib which was ultimately increased to 1 mg daily after 3 months. She remains on this dose to this day and so far, her only toxicities have been grade 1 including some facial rash, which results with clindamycin, shas had some CPK elevation, as well as creatinine elevation, which have been mild to date, as well as some mild upper extremity edema, and some loose stools. Our MRI at 3 months, since starting trametinib, has been actually showing that she has responded to this treatment. She continues to be closely followed with cardiology, because of her hypertension, endocrinology, neurosurgery, as well as ophthalmology because of prior papilledema. 

The question I had was in addition to measuring tumor burden by neuroimaging, what other monitoring can be an early warning sign for progression in this case? The options are imbalance, visual equity changes, swallowing difficulty, or cognitive decline. Just like other pediatric brain tumors, the symptoms depend on where the tumor is located, and in this case, because the tumor is located so close to the optic chiasm, the sign that we are worried about is visual equity changes and this is actually a pretty common sign to monitor for pediatric low-grade glioma. There's been multiple recent studies and a pediatric working group recommendation that visual equity be monitored and functional outcomes be monitored closely for patients with a low-grade glioma. This is done in our center in consultation with pediatric neuro-ophthalmologists, but this is of critical importance because sometimes you may not pick up changes in MRI scans early enough however, you may notice visual equity changes in an ophthalmology exam. Even in clinical trials now it is recommended that this functional outcome be incorporated as an outcome measure in addition to looking at MRI changes that are monitored by radiology. 

This case illustrates not necessarily the most common type of outcome for pediatric low-grade glioma, but certainly a very typical course for patients with pediatric low-grade glioma, which is often this relapsing remitting course with intermittent episodes where they do respond to the treatment that we offer, but then often we have to retreat them. When I see patients with pediatric low-grade glioma, there's a significant proportion of patients that respond very well to their initial treatment, which often is surgical resection, but then there's also the significant fraction of patients that either cannot have a full complete resection because of the location of the tumor or they experience relapse early on and then have this type of course where they have to be treated with repeated courses of treatment. I think this case is very important for learners to understand what a typical case of pediatric low-grade glioma could look like and how we have to approach these cases. 

The other important thing that I wanted to mention is that it is really an important team approach that is needed for these patients. You have to partner with neurosurgeons, ophthalmologists, endocrinologists, as well as sometimes other specialists, like in this case cardiology, because of the medications we give them because of the locations of the tumors, so really it takes a village for these types of cases.