Pediatric Ganglioglioma With a BRAF KIAA1549 Fusion

Mohamed S. Abdelbaki, MD, discusses the course of treatment he would take for a patient with pediatric ganglioglioma with a BRAF KIAA1549 fusion. 

Transcript:

My name is Mohamed Shebel Abdelbaki, I'm the director of the pediatric neuro-oncology program at Washington University School of Medicine in St. Louis. The reason that we're having this discussion today is to give an idea about how to treat a child with pediatric low-grade glioma, which is the most common pediatric brain tumor, so it would be very important for us to understand how to treat our patients with such a tumor. 

Thankfully, these are slow growing tumors that present with a longer history of symptoms and if you are able to get a complete resection of this tumor, that typically is the end of the story where the chances of the tumor coming back are very small but, in more than 50% of the cases it's not possible to achieve a complete resection. Therefore, there is a large percentage of our patients who will end up requiring systemic therapy at some time point. These are the locations that are in the middle of the brain or in the areas that are difficult for us to be able to achieve a complete resection  that may lead to surgical complications and longer-term morbidity. It would be very important to highlight that even if we do not achieve a complete resection, that's not an issue because we have therapies that we can use for these tumors and therefore, it's important to have a multidisciplinary discussion between the different disciplines that are involved in the care for a patient with pediatric low-grade glioma: neurosurgery, neurodiology, radiation oncology, neuropathology, and neuro-oncology, because if we have a tumor in a location where the resection may lead to longer-term deficits, I would rather treat this with systemic therapy rather than achieving an aggressive resection that would lead to long-term morbidities in a patient whom I expect will be a long-term survivor, and I do not want to affect their quality of life. 

After the discussion with these several disciplines, if this is a location that can be completely resected we're going to continue to follow up and observe after the resection, even if there is some tumor left, we're going to observe without doing anything extra. However, if you have performed a biopsy or a small resection, this is where you have to start systemic therapy. It used to be chemotherapy but now we have targeted therapies available, and so many of you will hear about all these targeted therapies. We have no data to say that chemotherapy is better than targeted therapy or vice versa, there are ongoing randomized control studies looking at the differences in the outcome between chemotherapy and targeted therapy, so we should not think one is better than the other. Chemotherapy, you generally have to place a central line, and it's typically given through that central line, and the patient would have to come into the hospital to get antibiotics and blood cultures and may stay for a few days if they have a fever, and it has systemic side effects. Side effects of targeted therapy varies between 1 product and the other but, it really entails skin changes, and it may entail some EKG or cardiac changes amongst other side effects. Targeted therapies are oral drugs while chemotherapy, as we've mentioned, they would have to be given through the central line. 

If we look at a scenario for a patient who's been newly diagnosed, now you're going to start therapy, you have either option, chemotherapy or targeted therapy. There are clinical trials that are looking into this, and again, we have no idea which one is better. But, if you have a patient who'd been on chemotherapy before and now the tumor has progressed, like the patient that we have in the case on the website today, and the pathology came back showing a ganglioglioma with BRAF fusion, which is the most common molecular alteration in patients with pediatric low-grade gliomas, it's not as common in gangliogliomas, where they commonly have BRAF v600E mutations, but it can happen as well in BRAF fusions, while it's the most common alteration that can happen in pilocytic astrocytoma, for example, which is the most common pediatric low-grade glioma. So you have this patient, you treated chemotherapy before, and now we have significant increase in the size of the tumor. I want to highlight one thing, which is the significant radiographic progression, we have 40% on T2 imaging. We used to assess the radiographic response based on the increase in the contrast uptake, but we're now looking into the RANO low-grade glioma criteria, that assesses the response as per the increase in the size of the tumor itself, as per the T2 flare images, for example, because the contrast uptake can go up and down on its own even without intervention, and it may not affect the whole tumor, there may be certain parts of the tumor, rather than assessing the size of the whole tumor itself on T2 images. So this is a side point that I wanted to make. 

In a case like this, how would you treat, would you treat with carboplatin vincristine? I think since you have significant radiographic progression, I think this shows us that probably carboplatin vincristine doesn't work. Would you start a type 1 BRAF inhibitor? This is an extremely important point that I would like to highlight– when you have a BRAF fusion, you cannot use a type 1 BRAF inhibitor, which is in this case dabrafenib or other type 1 BRAF inhibitors, for example like vemurafenib. You cannot use a type 1 BRAF inhibitor because it would cause paradoxical activation of the tumor. You would use a type 1 BRAF inhibitor in patients with BRAF V600E mutation, and there is an FDA approval for patients with BRAF V600E low-grade gliomas to use dabrafenib and trametinib, which is a MEK inhibitor. While you cannot use that combination in patients with BRAF fusion, this is an extremely important point, and that's why we have this in the choice of BRAF fusion and whether you would select a type 1 BRAF inhibitor or not, because you should not use a type 1 BRAF inhibitor in patients with BRAF fusion. I think this is an extremely important point that we want to continue to highlight. What can you use for BRAF fusions? You can use chemotherapy, different chemotherapy options, we have vinblastine here as an option, you can use an MEK inhibitor because it would work in patients with BRAF fusions. You cannot use a type 1 BRAF inhibitor, like dabrafenib in patients with BRAF fusions, and you can use a Pan RAF inhibitor like tovorafenib, which has been recently FDA approved over the past few weeks in April, 2024. These are the options that you would have for this patient. Observation with serial imaging, without any further intervention, this may be an option if let's say, that we finished therapy for a patient and the child is doing really well from a clinical standpoint, and there is a 2% to 5% increase in the size of the tumor, I would continue to observe with serial imaging without further intervention unless there is significant radiographic progression, which we typically say more than 25% increase in the size of the tumor or clinical progression. In a case like ours that we're discussing today, I would not continue the carboplatin vincristine  because there is a significant increase in the size of the tumor. I would not do observation with serial imaging since there had been a significant increase in the size of the tumor. I would not start the type 1 BRAF inhibitor because it would cause paradoxical activation in cases with BRAF fusions. I think doing, a MEK inhibitor or a pen-RAF inhibitor like tovorafenib, a MEK inhibitor trametinib or selumetinib, or starting a different chemotherapy option– I think all of these are viable options in this case.

To summarize, if you have a patient with a low-grade glioma in a location that's resectable, great, we should move forward with this after a multidisciplinary discussion, making sure that we are not going to cause harm or affect the long-term quality of life for this patient. Why? Because as we see from the case, we have several options that we can use for patients, either in the newly diagnosed setting or the recurrent setting. It would be very important for us if we're not able to achieve that complete resection when the tumor is in a location that would be difficult for us to do this with a biopsy or some resection, like a partial resection, for example, or some debulking, we're going to follow that up with any of the therapies that we've discussed today. I think it's very important to highlight for the families that these are slow growing tumors, if we cannot resect them. This is like a chronic disease where we continue following up your child for a long period of time and that you have to come in for serial imaging. The tumor may grow and stop growing at certain time points, we try to leave radiation therapy as the last resort, so radiation therapy is an option, but we try to make it as the last resort for our patients, and again highlighting the importance of the multiple options– we have no idea which option is better than the other and this is why we're performing or conducting clinical trials to compare chemotherapy and targeted therapy. We highlighted that you can use a type 1 BRAF inhibitor like dabrafenib in patients with BRAF V600E mutations, you cannot use them in patients with BRAF fusions, and there is an FDA approval for dabrafenib and trametinib in patients with BRAF V600E low -grade gliomas. You can use tovorafenib for patients at recurrence for patients with BRAF fusions or BRAF V600E mutations, or you can use MEK inhibitors like selumetinib and trametinib for patients with BRAF V600E mutations or BRAF fusions, and then the different chemotherapy options that most of us are aware of.