How Belzutifan Treats VHL
- Belzutifan was FDA-approved for certain Von Hippel-Lindau (VHL) disease patients in August 2021, and offers hope for some fighting the disease.
- Two of the main side effects of belzutifan are a low oxygen saturation in the blood and a decrease in hemoglobin which can lead to anemia.
- One of our experts says he doesn’t recommend the “wonderful alternative” of belzutifan to everyone. But the fact that it allows patients with VHL-related tumors to be treated with means other than surgery is “probably one of the greatest” things he’s experienced working with VHL patients.
Understanding Von Hippel-Lindau (VHL) Disease
VHL is a rare genetic disease that can cause cysts or tumors based in the blood vessels to form in many organs throughout the body. It occurs in about one in every 36,000 people and happens when someone has a mutation of the VHL gene – a tumor suppressor gene.Read More
But not all people who develop the disease have it in the family. In this case, the person has developed a de novo mutation – a genetic alteration that is present for the first time in one family member as a result of a randomly-occurring variant (or mutation) in a germ cell (egg or sperm) of one of the parents, or a variant that arises in the fertilized egg itself during early embryogenesis.
“So, that’s thought to be a mutation that may have even occurred in the womb or earlier on. And then that starts a cycle where it can be passed on,” Dr. Craig Rogers, Chair of Urology, Henry Ford Health and head of the VHL team there, said in an interview with SurvivorNet.
VHL can cause many tumors and cysts or even just one, and these manifestations of the disease can be cancerous or benign (noncancerous). These tumors and cysts can be found in places like:
- The brain/spine
- The eyes
- The adrenal glands
- The kidneys
- The pancreas
- The inner ear
- The reproductive organs
That being said, below are some of the signs of the disease that can occur when tumors and cysts (both cancerous and noncancerous) form in different parts of the body:
- Blindness from tumors in the retina of the eye.
- Balance issues and weaknesses of different parts of the body from tumors in the brain.
- Impaired hearing or balance issues from tumors of the inner ear called endolymphatic sac tumors (ELST).
- High blood pressure, episodes of racing heartbeat palpitations, nausea, headaches, vision changes, sweating and turning pale from poheochromocytoma tumors of the adrenal gland.
- A little bit of blood in the urine (hematuria) from cancerous kidney tumors (renal cell carcinoma).
VHL: No ‘Cure,’ But Lots of Hope
Von Hippel-Lindau disease currently does not have a cure.
“We have not discovered [a cure] yet, and we are striving,” Dr. Rogers said. “And so we’re hoping that cure comes soon … Right now our main goals are to identify patients with VHL and to closely monitor them for these tumors, so we can pick up on tumors that are going to become a problem and either remove them or start medication to suppress them.”
Dr. Rogers also added that there has been significant progress when it comes to treating the disease recently.
A New Treatment Option: Belzutifan
One of the most exciting recent advancements in the world of VHL treatment has been the FDA approval of the drug belzutifan on August 13, 2021, for adult VHL patients who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery.
Dr. Rogers says the research on VHL-associated RCC that prompted this approval was positive.
“They did see a positive response in terms of either tumor shrinking or just delaying progression,” he explained. “Still, it’s not a cure. It’s not like the tumors are gonna go away, but if it buys you time, that’s still a win.
“This may just be the tip of the iceberg for other medications that come out.”
SurvivorNet also spoke with Dr. Tobias Else, an endocrinologist who leads the Comprehensive Clinical Care Center for Von Hippel-Lindau disease at the University of Michigan Health Rogel Cancer Center, to better understand this treatment option and look into pros and cons of trying the drug.
Dr. Else said that the study into belzutifan was promising since “most tumor shrunk.”
“They stayed small and adverse events were tolerable, right. So if you talk about a cancer drug, and you don’t have any severe side effects, that is pretty amazing,” he said.
Side Effects of Belzutifan
Dr. Else said the main side effects of the drug include:
- A low oxygen saturation in the blood.
- A decrease in hemoglobin – a protein in your red blood cells that carries oxygen to your body’s organs and tissues and transports carbon dioxide from your organs and tissues back to your lungs.
- Lower than normal hemoglobin levels = a low red blood cell count (anemia).
“The simple reason for that is that the way this drug molecularly works is actually it kind of stops the body sensing or signaling that there is not enough oxygen around,” Dr. Else said of these prominent side effects. “And so it is actually something that is totally expected with this drug that these two things happen.
“Occasionally, patients will need transfusions or other treatments for the anemia for the low red blood cell count … or they might experience some tiredness, fatigue, sometimes shortness of breath, but usually that actually becomes better once they’re on the drug for three or four months. Then it kind of levels out at a new normal, and a lot of patients will have no severe ongoing side effects from that drug.”
Who Should Be Using Belzutifan?
Dr. Else says there’s a “whole spectrum” of opinions within the community of physicians who treat VHL disease, meaning that some doctors use it more conservatively than others.
“We’re still trying to learn how to best use this drug,” Dr. Rogers explained. “How long do you give it? Do you give it intermittently? Is it just for kidney tumors? Can you give it for others? So, there will need to be other clinical trials that address that question.”
Some feel the “preferable side effect profile,” according to Dr. Else, is reason enough to put anyone with a VHL diagnosis on belzutifan to prevent any kind of future tumor development before they’ve even developed a problematic tumor or cyst. But Dr. Else made a point to say this type of prescribing is not what the drug was approved for. The approval was specifically for, again, adult patients with VHL who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery.
“I think that’s not a conclusion you can draw from the study because that was actually treating patients with a diagnosis of tumors related to VHL, so those were patients with VHL who already had developed a tumor,” Dr. Else said.
Some doctors take a more conservative approach to prescribing belzutifan.
“You will find people who say … we’ve been doing pretty well with surgeries and surveillance. So, once that is not an option anymore, that’s when we’re going to use this new drug,” Dr. Else said.
In Dr. Else’s opinion, “the truth lies somewhere in between.” He also admits he falls “more on the conservative side,” though there are certainly instances where there’s a “clear cut indication for [him] to use belzutifan.”
“If a patient has a diagnosis of prior renal cell cancers and had removal, for example, of one kidney and has a tiny little piece of another kidney left and any further surgery would mean that they will be developing kidney failure and would be committed to dialysis, I think then obviously, surgery is not an option,” Dr. Else said. “So, those would be the patients where we would definitely use a drug like the drug belzutifan.”
Another example he gave was if someone had a hemangioblastoma – a benign (noncancerous) tumor made up of nests of blood vessels in the brain or spine – located in the spine and the neurosurgeon says they can remove it with surgery, but there’s a chance the patient will be left with paraplegia or quadriplegia, then belzutifan could be just the right thing.
Similarly, if someone has a tumor of the eye and their ophthalmologist says surgery is possible but there’s a high chance for resulting blindness, then belzutifan could also be a great option to try. Dr. Else says he’ll often turn to something like belzutifan when “the traditional options fail.”
Dr. Else says there are also other reasons to look into belzutifan as an option. One reason: since the clinical trial on which the FDA approval was based showed that people who were frequently having surgeries for VHL were no longer needing them after taking the drug, some people might just be sick of having surgeries or not want the risks associated with their surgery options.
Still, there are always reasons to proceed with caution when looking into belzutifan. Below, are some considerations from Dr. Else:
- Anemia concerns: “A patient with baseline anemia… we’d probably not necessarily treat them with a drug that leads to further critical reduction of those levels.”
- Fertility concerns: “We don’t know what the effects on fertility of this drug is. We also know that it’s not compatible with pregnancy at all… You cannot be pregnant with this drug; it will lead to an abortion.”
- We don’t know the longterm effects: “We don’t know whether there is something that we just discover in 10 years that is irreversible. And because we have usually good therapies otherwise, I think that’s something which patients just simply need to know about.”
- It’s unclear if VHL-related tumors will eventually stop responding to belzutifan: “We know how the tumors react in two years, three years, four years. But we don’t know whether after six, seven years of treatments the patient or the tumor might not actually respond to belzutifan anymore and it might become actually even more difficult to treat.”
- Potential impacts of monitoring kidney tumors: When monitoring renal cell carcinoma of the kidney, doctors generally consider 3cm to be a “cut off” for a size that would generally necessitate surgical removal. “That cut off… is that the same for tumors you’re treating with belzutifan? We just simply don’t know,” Dr. Else said.
Even though “there’s a lot of unanswered questions” and Dr. Else won’t use this drug for every VHL patient, he still considers it a “wonderful alternative.”
“I think the opportunity that we can treat patients with VHL-related tumors with other means than surgery is probably one of the greatest, greatest things that I’ve experienced during my professional life working with patients with VHL,” he said.
“And, as always,” he added, “I think patients are the leaders in this game … This is something which they make the decisions [about].”
Questions To Ask Your Doctor
- Is belzutifan a potentially good treatment option for me?
- What kind of side effects should I be prepared for if I start taking belzutifan?
- What longterm impacts should I consider when it comes to belzutifan?