I’d like to discuss here the evolving therapeutic landscape in NF1. For the past several years, the NF scientific community, including the UAB NF Research Program, has put major emphasis on conducting clinical trials for plexiform neurofibromas. Affecting upwards of 50% of people with NF1, plexiform neurofibromas are tumors that often involve multiple branches of either large or small nerves. They can be located on the surface of the body where they are easily visible or may be deep inside the body and recognized only if seen by imaging or if they cause symptoms.  Because these tumors can present serious complications and surgical removal can be complex, investigators have worked to identify drugs that can reduce the size of plexiform neurofibromas.

MEK Inhibitor-Based Treatments and FDA Approval of Selumetinib (Koselugo)

Several clinical trials have investigated the effectiveness of drugs called MEK inhibitors as potential treatments for plexiform neurofibromas. MEK is an abbreviation for one of the proteins that becomes hyperactivated in a neurofibroma when the NF1 protein is non-functional.  A medication called Selumetinib is one of the MEK inhibitor drugs that was found to be effective in shrinking some plexiform neurofibromas in clinical trials; published data, including a paper published in March in the New England Journal of Medicine have shown that 70% of study participants with NF1 and a plexiform neurofibroma who took this drug have experienced a 20% or greater reduction in tumor volume over the course of the study.

Based on these results, the FDA has recently approved Selumetinib for use in children with NF1 aged 2-18 who have inoperable plexiform neurofibromas. This is the first drug specifically approved for use with NF1 and represents a significant and exciting breakthrough in the advancement of effective therapies that improve the lives of people living with NF. Co-developed by AstraZeneca and Merck & Co., the drug will be marketed under the brand name Koselugo.  Information about the medication for both patients and physicians can be found on the Koselugo web site, and a MEK inhibitor patient information sheet can be found on the Children’s Tumor Foundation (CTF) web site

Clinical Management and Treatment of Plexiform Neurofibromas with Selumetinib and Other MEK Inhibitors

Many individuals with plexiform neurofibromas have been followed in our clinic over the years. Surgical removal of the plexiform neurofibromas in patients who do not have symptoms is usually not recommended due the risk of complications, mainly as a result of nerve and blood vessel involvement in these tumors. Surgery is reserved for cases in which important structures are affected, such as the need to relieve pressure from the tumor on the airway or spine.  Usually the tumors cannot be completely removed, and many eventually grow back after surgery.

For individuals with symptoms due to plexiform neurofibromas, the availability of MEK inhibitors, such as the newly FDA-approved Selumetinib, has opened new opportunities for treatment and underscores an important question: When is it appropriate to treat plexiform neurofibromas? The answer is that we would not treat a plexiform neurofibroma just because it is there unless one or more of the following criteria is met: the tumor is progressive; the patient is experiencing significant symptoms; or the tumor is disfiguring.

>Although MEK inhibitors may be an effective treatment option for some patients, it’s important to understand that these oral medications have potential side effects that include problems with skin, heart function, and vision, among other issues.  Because of this, patients taking MEK inhibitor drugs receive regular echocardiograms and ophthalmologic examinations, as well as blood tests, to monitor for side effects. Skin rash may include an acne-like rash or a scaling rash. Medications are available to control these side effects and often are helpful. Also, fatigue and nausea can occur in some patients. Regarding Selumetinib, information about long-range tolerance of the medication, or at what point patients can safely withdraw without risk of tumor regrowth, is still being determined.

At this time, treatment for plexiform neurofibromas is in cases where there are significant indications. However, the increasing availability of MEK inhibitors such as Selumetinib and other drugs has made treatment of these tumors an evolving issue. As we learn more about these drugs, it is possible that we might move toward treating tumors at an earlier time in their evolution; whether these drugs will prevent progression when treatment is begun early is an important but so far unanswered question.  The increasing availability of MEK inhibitors is offering exciting new avenues for effective treatment of plexiform neurofibromas, which is an encouraging and hopeful development for the NF scientific and patient communities.

Role of Telemedicine in the UAB NF Clinic

To slow the spread of COVID-19 and protect our patients, our NF Clinic is currently seeing patients for routine visits using telemedicine. We’ve found that telemedicine works well to address specific patient concerns, arrange diagnostic testing, and discuss the results of imaging and other diagnostic tests. We can do a limited physical exam by telemedicine, but in some cases it is necessary to perform a face-to-face examination.  We hope that our clinic will open soon for regular visits, but in the meantime, telemedicine has been a helpful approach for dealing with some issues.  In the future we expect that we will continue to use telemedicine for some purposes, for example to return results of testing for patients who live a long distance from our site.  We had been interested in integrating telemedicine into our clinic for a while, and the pandemic has facilitated and accelerated this process. Our hope is that our patients will benefit over the long term from the convenience and accessibility that telemedicine can provide.

As the world grapples with the challenge of the novel coronavirus, I have received many inquiries related to the risks associated with viral infection in individuals with NF. Three of the most common questions are: 1) Are individuals with NF at greater risk for being infected with the virus; 2) does the virus lead to more severe illness in those with NF; and 3) if an NF patient is being treated with medication or on a clinical trial, does this pose a special risk?  In thinking about these questions, we need, of course, to remember that NF is really a term that covers three distinct conditions – NF1, NF2, and schwannomatosis, that might raise different issues regarding the viral infection.  Second, this is obviously new and uncharted territory – anything we say about risks of coronavirus infection is based on the limited recent knowledge of this new disorder and general experience regarding individuals with NF who develop other viral illnesses.  There is a lot left to be learned about coronavirus, and about infectious disease risks in NF in general.

Susceptibility to Coronavirus Infection

The reassuring news is that I’m not aware of any evidence that persons with any form of NF are at greater risk of viral infection compared to those who do not have NF.  I haven’t seen evidence of any generalized immune problems in persons with NF, and I haven’t noticed that those with NF are more susceptible to typical viruses such as common colds and flu, for example. However, if an individual with NF has medical problems that requires seeing a physician more often, this could increase human contact and could therefore increase the risk of exposure to the virus. My recommendation at this time is that people with NF should follow the same guidelines issued by the CDC (www.coronavirus.gov) and NIH (www.nih.gov/coronavirus), which include avoiding exposure to groups of more than 10 people and self-isolating at home as much as possible.    

Risk of Complications of Coronavirus Infection

Regarding the question of outcomes of people with NF who contract the virus, there are no data as of yet related to this issue. To my knowledge, it has also not been studied whether common colds or flu are more severe in individuals with NF, although the ability to fight infection in people with NF does not seem to be impaired.

It is possible that individuals with NF who have specific medical problems might be at greater risk of complications of coronavirus infection.  For example, those who have severe scoliosis (curvature of the spine) or large plexiform neurofibromas in the chest cavity, might already have impaired lung function.  In these individuals, one might expect that the lung manifestations of coronavirus infection could be exacerbated.  In addition, there is a subset of people with NF1, usually older adults, who develop chronic lung disease that can impair lung function. We don’t know how common these lung manifestations are; I’ve personally seen this just a few times in the many years I’ve been following patients with NF1, but it’s possible that milder versions are more common and have escaped notice.   This condition usually presents as respiratory distress upon exertion, and subsequent testing of lung function reveals impairment, along with visible changes on imaging of the lungs.  Again, one might imagine that a person with NF1 who has impaired lung function to begin with might be at increased risk of coronavirus complications.   There are no data on this point, however.  Additional studies are needed to determine the frequency of this lung manifestation and how COVID-19 impacts NF patients with this condition.

Risk to Patients on Treatment or in a Clinical Trial

There are some individuals with NF who are currently being treated for a complication of NF or are enrolled in a clinical trial of an investigational medication.  Given that there are many different types of medications being used, I suggest that these individuals should discuss any risks with the physician who is managing their treatment or participation in the trial.   Some types of medications, especially those used to treat malignancies, might impair the immune system and therefore could confer increased risk of infection, whereas others do not affect the immune system.  There is also the risk associated with frequent visits to the clinic, and therefore exposure to the virus.   As much as possible, we’re trying to work with patients by using telemedicine to minimize exposure; also, for those on clinical trials, we are trying to work with local physicians to reduce the need to travel to a specialized clinic.

Conclusion

This is a difficult time for everyone, and having NF adds an additional dimension for concern.  For now, the best advice is to follow guidance issued for everyone to minimize exposure to the virus; I would also recommend that persons with NF be in touch with their NF specialist if particular questions arise related to their condition.  Last week, Dr. Scott Plotkin (Massachusetts General Hospital) and I participated in a global video chat on coronavirus infection and NF organized by the Children’s Tumor Foundation.  A recording of this presentation can be found at https://www.ctf.org/news/coronavirus-covid-19-update

With the start of a new year, I’d like to discuss the topic of precision medicine, which is reshaping traditional approaches to disease treatment and prevention and opening new possibilities for the treatment of NF. Precision medicine is also sometimes referred to as personalized or individualized medicine.  Many clinicians, however, prefer to use the term precision medicine because the terms personalized or individualized medicine imply that previous medical approaches have not been personalized. Medicine has always been personalized in treating people as individuals, but we now have powerful new approaches that vastly increase our ability to make a difference in a person’s health. 

Precision Medicine Tools

Precision medicine uses a variety of tools that help to identify the underlying mechanisms of disease and provide specific information about the most effective treatment. Traditional medical approaches develop strategies for a group or cohort of patients with a common clinical presentation, whereas precision medicine evaluates the impact of lifestyle, environment, and genetics on a person’s health. Precision medicine takes advantage of many advances in medical science, and especially of developments in imaging and in genomics. In the past, the diagnosis of tumors was based on inference from a clinical exam because imaging tools to detect a tumor were not available. Today, when clinical symptoms are present, advanced imaging such as CT or MRI can provide vivid and clear pictures of a tumor.

Genomics evaluates an individual’s genetic information through DNA sequencing of the genome. Genome sequencing can reveal the underlying causes of disease by identifying specific genetic alterations, or mutations. Understanding the genetic drivers of disease and tumors enables the development of more precisely targeted treatments that can minimize side effects and maximize benefits. For example, tumors are driven by an accumulation of genetic changes that drive the cancer cells to divide rapidly and spread throughout the body. Traditional cancer treatments, such as chemotherapy, kill all the rapidly dividing cells in the body, resulting in side effects such as nausea, vomiting, and hair loss.  Also, the tumors eventually develop resistance to treatment by acquiring further genetic mutations. Genomic medicine-based treatment approaches more precisely target the underlying mechanism driving the growth of a tumor. Because this targeted approach only affects the tumor cells and not healthy cells in the body, side effects should be minimized. The hope is to develop treatments that target multiple mechanisms simultaneously so that tumors are unable to develop resistance in response to treatment. 

An additional treatment challenge that can be addressed by precision medicine relates to individual patient responses to a particular medication. For a medication to be utilized effectively by the body, it must be absorbed, distributed, interact with its target, and then be metabolized and excreted. Each of these steps is controlled by an individual’s genetic make-up and can lead to a medicine not being metabolized quickly enough to achieve an optimal therapeutic effect, or accumulating so quickly as to cause side effects. Genomic medicine provides information that allows the choice and dosage of a medication to be customized to an individual’s genetic profile so that therapeutic benefits can be maximized and side effects minimized.

Precision Medicine in NF Treatment 

The discovery of the NF gene in 1990 revealed the underlying mechanism of NF that involves the activity of the Ras/MAPK cellular signaling pathway. This pathway, which is hyperactive in individuals with NF, helps to control cell growth and division. Precision medicine treatments have focused on blocking the activity of this pathway with inhibitors of the components of the pathway.  Using inhibitors to one of the components of the pathway called MEK, this approach has achieved success in shrinking plexiform neurofibromas. We are learning that the environment between tumor cells and surrounding cells is also important, and new drugs are in development to target this component of tumor growth. Advances in imaging have also enabled tumors to be detected earlier and targeted more effectively.

Another precision medicine-based approach is focused on restoring function to a mutated gene or gene product, or editing out the mutation entirely. An advantage of this approach to treatment of NF1 is that restoring function to the mutated gene might result in fewer side effects than drug treatments that block Ras signaling. Research on this approach is underway at UAB, though the challenges lie in targeting therapeutics to the right cells as well as precisely correcting the mutation or its effects on the protein.  We are hopeful that progress our scientists make in this area will eventually result in new treatments, that, together with other approaches such as the use of MEK inhibitors, will significantly improve quality of life for those who deal with NF.