Graft-versus-Host Disease: How it Affects Skin

Transcript of Presentation:

(00:01): Jordan Sexton: Introduction. Good afternoon and good morning, and welcome to the workshop Graft-versus-Host Disease: How It Affects Skin. My name is Jordan Sexton, and I'll be your moderator for this workshop.

(00:10): Before we begin, I'd like to thank Incyte Corporation, whose support helped make this workshop possible.

(00:15): It's now my pleasure to introduce today's speaker, Dr. Alina Markova. Dr. Markova is an Associate Professor of Dermatology at Weill Cornell Medical College. She is also the co-director of the Multidisciplinary GVHD Clinic at Memorial Sloan Kettering Cancer Center in New York City.

(00:32): Dr. Markova specializes in treating skin conditions that develop after a bone marrow or stem cell transplant. Her outpatient clinical practice is devoted to helping people affected by graft-versus-host disease (GVHD) of the skin. She also specializes in treating people who develop skin, hair, and nail conditions as a side effect of cancer treatment, and people with cancerous wounds. Please join me in welcoming Dr. Markova.

(00:58): Dr. Alina Markova: Overview of Talk. Thank you so much for the kind introduction. It’s my pleasure to spend the next hour with you to review how GVHD affects the skin, hair, and nails.

(01:13): Our objectives for this session are to understand the various ways that chronic graft-versus-host disease can affect the skin, hair, and nails. We're going to review the timeline of manifestations of chronic GVHD on the skin, hair, and nails, and we're going to describe how cutaneous chronic graft-versus-host disease affects activities of daily living. Lastly, we're going to summarize pharmacologic and non-pharmacologic therapies that can help patients who have cutaneous graft-versus-host disease.

(01:45): Graft-versus-host-disease (GVHD) of the skin can be acute or chronic. As some of you may know, there are two main presentations of skin GVHD. In the first approximately 100 days after transplant, a patient may develop a rash that is often considered acute graft-versus-host disease. Later, after the transplant, a patient may develop different types of rashes and skin changes that may be considered chronic graft-versus-host disease.

(02:13): While there's a typical timeline of developing acute GVHD in the first 100 days, and chronic GVHD later than that, the way we diagnose the type of rash and the type of GVHD is based on the features of the skin, and not exclusively based on the timeline. So chronic graft-versus-host disease sometimes can happen before 100 days, though rarely, and acute graft-versus-host disease can occur after 100 days and not infrequently.

(02:51): Acute GVHD of  the skin typically occurs in the first 100 days post-transplant, but can also occur later. s. As I mentioned, acute GVHD presents typically in the first 100 days. It presents as pink, flat patches and smaller areas called macules that can be raised at times. It can be itchy, or it can be very minimally symptomatic. It can affect all parts of the body, and it can evolve. It can start first on the face, upper chest, or arms, and can progress to the rest of the body. Very rarely, acute GVHD can blister. As you can see in this patient on this slide, there are blisters developing, and that is typically painful.

(03:32): The way we determine the severity of acute GVHD of the skin is by the percentage of skin involved.  A stage 0 GVHD is 0% body surface area involved. Stage 1 of acute GVHD involves less than 25% of the body surface area. We only count the areas that are involved, not the areas that are spared in between the involved areas. Stage 2 acute GVHD involves 25-50% of the body surface area of the total skin surface, and stage 3 involves over 50%. Stage 4 occurs once a patient has over 50% skin involvement and then blister formation on at least over 5%. So, a rash on 50% or more, and blistering with over 5% of that is considered stage 4.

(04:28): Acute GVHD of the skin may be treated with topical or systemic therapist depending on its severity. Acute GVHD of the skin, while it's oftentimes stage 1 and even sometimes stage 2, can be exclusively managed with topical therapies. Later stages and more refractory stage 2 disease may require systemic therapies.

(04:46): Topical therapies for GVHD of the skin that can be helpful are topical steroids, topical calcineurin inhibitors, and narrowband UVB phototherapy. The top two can come as creams or different vehicles which I'll review in the next slide.

(05:05): The topical steroids are typically anti-inflammatory medications that have certain side effects like skin thinning but can be very effective. Topical calcineurin inhibitors are also anti-inflammatory without the side effects of skin thinning, but can be greasy, and some patients can have a burning sensation. Phototherapy is a lovely addition that can target the whole skin, but it does require visits three times a week to a local dermatology practice to receive the phototherapy, which may also be associated with a copay.

(05:40): Topicals, topical steroids, or even topical calcineurin inhibitors come in different vehicles. A vehicle is the formulation of the medication. Different formulations can be associated with different strengths of the same topical steroid and they can also have different benefits.

(06:02): While solutions, sprays, gels, and foams are easy to apply, they do contain alcohol.  If there is any broken skin, these can have a burning sensation from the alcohol. Creams, oils, and ointments are greasier - and they can be very effective and soothe broken skin - but in areas where there's hair-bearing (any hairy sites or extensive application requirements) the creams and ointments can be challenging.

(06:37): Certain medications like the topical calcineurin inhibitors such as tacrolimus and pimecrolimus only come as creams or ointments. So not every medication is available in every vehicle, but if you prefer a certain type of vehicle, you can always ask your oncologist or your dermatologist to try to prescribe the same topical in a different vehicle.

(07:04): For example, solutions and sprays are nice to apply to the scalp. These are easier to use to part the hair - if there is hair - and apply to the scalp. If the hair is very dry, tightly wound, or curly, oils are nice for the scalp as well. Gels and foams can also be used. For areas such as the face, creams may be preferred.

(07:33): Typically, for localized therapy of acute graft-versus-host disease of the skin, we start with applying topical steroids twice daily and/or topical calcineurin inhibitors twice daily. Most of our treatments are applied just twice daily. More than that can lead to additional side effects without additional benefit.

(07:54): Phototherapy is another option for treating acute GVHD of the skin. If this treatment is inadequate, we can recommend narrowband ultraviolet B phototherapy, which is just like a medical tanning bed that's a safer version, or systemic therapy as per the bone marrow transplant team. And there is an approved therapy for acute GVHD called ruxolitinib (Rituxan), which is a JAK1/2 inhibitor, and it's also taken twice daily.

(08:22): If you are interested in phototherapy, the easiest way to find a phototherapy center near you - it does not have to be at your cancer center or your BMT practice – it can be somewhere closer - is to go to the American Academy of Dermatology website. Search Find a Dermatologist or just add “/fad”. Enter your location with your zip code, city, or state. Select Phototherapy in the second column under Procedures, and it will provide a list of local dermatologists who offer phototherapy.

(09:01): Another option would be to call your insurance and inquire as to which dermatologists who offer phototherapy are located near you. You can also find out about your copay. Some insurances do charge a copay for every phototherapy visit, and of course this can quickly add up.  Be aware and ask that question as this may impact your decision as to whether you want phototherapy.

(09:29): There are two types of chronic GVHD of the skin: non-scarring or scarring (sclerotic). Now that I've covered acute GVHD, I'm going to move on to chronic GVHD. Chronic GVHD has two main phenotypes or presentations. One is the non-scarring variant or non-sclerotic variant, and the other is a scarring or sclerotic variant.

(09:51): One presentation of the non-scarring variant is called lichenoid chronic graft-versus-host disease. This presents as purplish bumps on the skin that can be red and scaly, and they can affect the back of the neck and the chest. They can have a little bit of this lacy pattern as you can see on the neck in this patient on this slide, and they can be quite extensive. You can see in this patient generalized purplish, whitish plaques across the hands and palms with little normal skin retained.

(10:29): This can involve the lips, can appear pinkish and purplish on darker skin as well, and can be very extensive on the chest.

(10:41): You can see when lichen planus-like GVHD affects the distal fingers and the palms, a patient may develop white little bumps and loss of the fingertip anatomy. That can be very sensitive and uncomfortable. There are things we would do topically to help manage that, such as the topical therapies previously discussed for acute GVHD.

(11:05): Topical therapies that we offer for chronic GVHD that's non-scarring are very similar to the topical therapies for acute GVHD. We typically discuss topical steroids, topical calcineurin inhibitors, and narrowband UVB phototherapy for more generalized disease. Of course,  

(11:22) if the topicals are inadequate, we would always discuss with our BMT colleagues to consider adding an additional line of therapy while still maintaining the topical use. An additional line of therapy that's approved for chronic GVHD includes ibrutinib (Imbruvica), ruxolitinib (Rituxan), belumosudil (Rezurock), and most recently axatilimab (Niktimvo).

(11:50): Sclerotic (scarring) chronic GVHD of the skin often can occur in a variety of places on the skin. Moving on to the scarring type of GVHD or sclerotic GVHD. Sclerotic GVHD may present with these white plaques, oftentimes at areas of trauma. We see these over the underarm area, over old port sites, old surgical sites, or old bone marrow biopsies. These can affect areas of prior radiation. So, an area that previously had radiation may have a very tight plaque there that appears with the onset of the sclerotic GVHD.

(12:26): Other areas where sclerotic GVHD may appear are areas of common trauma. When patients wear bras or pants, these can appear at the points of light frequent trauma – so at the waistband and at the bra lines.

(12:49): Sclerotic GVHD unfortunately can progress and be quite extensive, leading to reduced range of motion without even having joint graft-versus-host disease. Patients can have extensive sclerotic plaques on their arms, on their chest, or abdomen that may limit their ability to take a deep breath or to eat a big or normal-sized meal. And on the legs, these can lead to progressive tightness and then ulceration or wounds on the legs. It is important to try to treat these with systemic therapies, as topical therapies may have limited efficacy for scarring chronic graft-versus-host disease.

(13:34): We often perform a photographic range of motion to assess patients and determine whether their tightness in the skin or joints is affecting their range of motion. We don't make patients perform every procedure or every position. We just ask them to perform the rightmost ones, so the 7, 7. 7, 4, on the right slide of the slide, and then we scale them and see how far they can get. And normal is expected as the three 7s and the 4. That's the baseline for the patient. We monitor how they are affected by GVHD with respect to their range of motion. And then after they are started on systemic therapies, we can monitor for improvement - but this can be a very reassuring score as patients improve on systemic therapy.

(14:23): Wounds may develop within sclerotic GVHD, and as you can see there are ulcers on the back of the foot here and on the belly. These can be very uncomfortable and get secondarily infected. They develop in a setting of involvement - a scarring involvement of the skin from the GVHD whereby the skin cannot heal and it remains with an open wound. To treat these wounds in addition to good wound care is really to treat the underlying sclerotic GVHD, typically with these systemic therapies.

(15:02): Scarring GDHD of the skin usually requires systemic therapy rather than topical treatments. The topical therapies for chronic scarring GVHD - the topical steroids and topical calcineurin inhibitors are typically minimally effective. The scarring in the skin is quite deep, and so we typically minimally use topicals in sclerotic GVHD or scarring GVHD. We only use topicals if a patient is having symptoms.

(15:25): For example, if a patient is having itch, or pain, or inflammation that they feel is uncomfortable, we might use a topical therapy to reduce those symptoms. But ultimately, it's not going to change the course of the GVHD without a systemic therapy.

(15:42): Several systemic therapies have been approved for sclerotic GVHD of the skin. I mentioned, wound care is paramount to reduce risk for infections, especially when patients are on immunocompromising systemic therapies for their GVHD. When there is any sclerotic GVHD, systemic therapies should be considered. As I mentioned, the approved systemic therapies in order of approval - as may have been mentioned in other talks throughout this workshop - are ibrutinib (Imbruvica), ruxolitinib (Rituxan), belumosudil (Rezurock), and most recently axatilimab (Niktimvo).

(16:16): Extracorporeal photopheresis (ECP) is also used in both acute and chronic graft-versus-host disease. This is where the blood is removed and exposed to something that's a psoralen - a medication that sensitizes the blood to light. Then it's reinfused into the patient in a process that allows decreased inflammation in the blood and ultimately decreased inflammation in the skin.

(16:45): UVA1 phototherapy is a light application just like the other light therapy I shared, but the wavelength penetrates deeper and allows for potential improvement in sclerotic or scarring graft-versus-host disease.

(17:03): Stretch marks may occur with prolonged systemic steroid use for sclerotic GVHD of the skin and require additional treatments. Stretch marks may develop with prolonged systemic steroid use, especially in children who undergo bone marrow transplant around the pubertal time. These stretch marks can be really extensive and sometimes break down. We do offer some therapies, although it's very challenging to effectively treat stretch marks.

(17:25): The main ways that we treat stretch marks are therapies that include topical tretinoin, which is a vitamin A derivative cream oftentimes used for acne. This improves early stretch marks as you can see in the images to the right. It reduces the length and width of stretch marks. We usually start this every other night - just a very, very thin layer. As patients tolerate this cream more, we increase to nightly.

(17:55): The limitations of using this therapy are that patients may experience dryness, pinkness, or skin peeling with the treatment. We start slowly with this application every other night, and then we move on. We support this by adding moisturizers as well, to combat the dryness. We typically avoid using topical steroids on stretch marks because topical steroids can further thin the skin and create wounds within the stretch marks. In areas of stretch marks, we typically discourage using topical steroids.

(18:30): Stretch marks may also be treated with a laser. There are two main laser types that are used for stretch marks - one targets the redness and the pinkness. That’s typically a pulsed dye laser - or PDL laser - that effectively can treat the red blood cells passing through the little blood vessels in the stretch marks, and remove the red color for those patients who are bothered by the red. This can be done depending on how extensive - even in one treatment, a patient may experience significant improvement - but additional treatments may be necessary depending on how extensive the stretch marks are.

(19:12): If a patient is bothered by the texture - where the stretch marks indent in, or indent or pouch out - the available lasers oftentimes include lasers that are called fractional CO2 lasers or Er:YAG lasers. These types of lasers make microscopic holes in the skin that create a stimulus for collagen to rebuild and strengthen the skin again. This one does have a little bit of a recovery time where the skin may have a little bit of crusting and need wound care for a week or so to recover. The pulsed dye laser can have bruising but no skin opening, so the recovery time is a little bit shorter.

(19:59): A CO2 laser, as you can see in this picture, can have a positive effect on even late stage stretch marks. In the left side of both columns, you can see that this is after a CO2 laser. The stretch marks improved after several treatments. The one limiting factor is that lasers are rarely covered for medical purposes, so the cost of the laser treatments is oftentimes out of pocket.

(20:28): Microneedling is another approach for stretch marks. It can be safe and effective. In this one study, a patient with stretch marks had over 50% improvement after two treatments - with transient pinkness being the main side effect. This is oftentimes less expensive than a laser treatment. I would recommend seeing a dermatologist or a plastic surgeon who is familiar with the safe application of these invasive treatments.

(21:01): A question that oftentimes comes up is: how do you wash your skin when you have skin GVHD? Given how often patients are generally washing their hands to prevent their risk for infections, or to reduce their risk for infections, the guidance we typically provide is to still wash your hands to prevent infections. Dry your hands with a clean towel but leave some water on your hands. Immediately after washing your hands, apply a fragrance-free moisturizer.

(21:30): When possible, we also recommend using a bar soap to wash your hands. Bar soaps have less additions that can dry out the skin. Foaming agents oftentimes can be irritating and can dry out the skin, so bar soaps are the gentlest soaps that you can use for your hands.

(21:48): We encourage the same in the shower. Use a gentle fragrance-free soap or cleanser - ideally a bar soap - and keep the showers relatively short. Twenty minutes is quite a long shower. Shower less than 20 minutes using lukewarm water – for either a bath or shower. Avoid any antibacterial soaps - particularly those with triclosan - because those can take off the natural oils on the skin and further dry out the skin. All soaps are antibacterial by removing the bacteria, so you do not need to additionally have antibacterial ingredients.

(22:26): Another question that frequently comes up with patients is:  what's the order of my skin products when I have GVHD? How do I apply all the different products I want to use?  The first is always going to be to apply your medicated cream or ointment onto the skin. That's because you want the medication to have direct contact with the skin. After that is applied and absorbed - if it's a medicated liquid or lotion - and you want an extra moisturizer, apply the extra moisturizer on top of the medicated topical. On top of that, you can add a sunscreen. Lastly, you would apply makeup.

(23:08): For most patients, if they are going to use both a moisturizer and a sunscreen, I strongly recommend using a moisturizer with sunscreen so you can simplify your regimen. Makeup can also actually combine all three. Many makeup products nowadays have CC cream options, etc., where they basically are a moisturizer, sunscreen, and makeup combined into one. Those are oftentimes much easier to apply than having three separate topicals. But generally, that is the order, whether you do a medicated topical, then sunscreen, and makeup, or just medicated cream and then makeup. All of those are appropriate - but always use medicated first.

(23:48): How do you choose a moisturizer when you have skin GVHD? Generally, we recommend choosing an ointment or a cream - something that you scoop. Anything with a pump bottle is typically more of a lotion that can contain some alcohol and cause burning on the skin. It typically does not moisturize quite as well as an ointment or cream.

(24:08): We recommend applying something like petroleum jelly or another type of fragrance-free moisturizing cream that your care team may recommend when the skin is still damp. After you get out of the shower, the best time to apply moisturizer is right when your skin is damp because it'll lock in that moisture on the skin and keep it moist. We also recommend sealing in the moisture by covering any moisturized hands and feet with cotton gloves or nitrile gloves or socks to seal in the moisture, and that can give those painful hands some additional relief.

(24:45): Choosing sunblocks can be challenging. There are so many options available, so we will review two main categories of sunscreens. One is the chemical and one is the mineral.

(24:57): Chemical sunscreens with ingredients like octinoxate, oxybenzone, or avobenzone are easier to spread on the skin. Look at the back of your sunscreen bottle for these ingredients. They come in water-resistant options. They can work well if you do not have sensitive skin. They oftentimes work better in patients with darker skin because they don't leave a white glaze on the skin, but they can cause some allergies.

(25:26): We oftentimes recommend mineral sunblocks which have the ingredients zinc oxide or titanium dioxide. These are thicker, whiter, and they may not rub into the skin as easily. These are a better choice however, for sensitive skin.

(25:45): How do we sun-protect when patients have GVHD? We always recommend applying sunblock 20 minutes before you go outside. Choose a broad spectrum sun protection factor of 30 and above.

(26:00): Wear clothing that protects your skin from the sun. While sunblock is great, nothing is better than not having to reapply the creams in the first place. Wear ultraviolet protective factor clothing - UPF clothing. These are available at most sports stores, and there are some online brands that offer UPF clothing. This clothing reduces how much sunblock you have to use.

(26:26): For example, if a patient wears a long sleeve UPF clothing with a long skirt or long pants, the sunblock only needs to be applied to the face and hands that are exposed. A wide brim cap can be worn. We strongly recommend wide brim caps, especially if there is hair thinning, since the scalp is no longer protected. The scalp is a really high-risk site for skin cancer, because there's very thin skin there. Skin cancers can become aggressive on the scalp.

(26:59): We typically recommend that you avoid the sun between the peak hours - between 10:00 AM and 4:00 PM - but we still encourage patients to go outside and enjoy their lives outside. You've survived so much going through the transplant and now living as a survivor with graft-versus-host disease. We want you to enjoy your life outdoors, but we recommend doing it in a smart way by protecting yourself so that the risks for skin cancer and GVHD flares are minimized.

(27:34): Using makeup when you have skin GVHD is another question that comes up frequently. Social events do come up. Patients oftentimes would like to resume using makeup to feel more like themselves when they go back to work. We recommend using fragrance-free products made for sensitive skin when possible, avoiding products that are natural or unpreserved because they may contain germs. Try one product at a time every few days. You may have new allergies even to products you previously used, so it's really important to have a stepwise approach when adding products back in. It's okay to use makeup to cover a rash if the skin is not broken and a concealer to cover any dark or light spots.

(28:23): Here is some additional guidance about makeup. It applies to all patients, but certainly a patient with an increased risk for infection. Throw out your older products and buy new ones regularly. Replace mascaras every few months. Replace eyeshadow every year and foundation every one to two years. Replace lipstick and blushes every one to two years. You can replace these more frequently if you so choose, but at the minimum, try to replace them in this way.

(28:53): GVHD of the skin may cause nail changes and require nail hardeners, steroid injections, or systemic therapy. I'm going to move on to nail changes, which is another feature of GVHD that can be quite asymptomatic. Patients with GVHD may develop ridges along the nails, as well as some lifting of the nail plate and peeling of the nails. Patients may experience complete nail loss, and this can be very uncomfortable. Sometimes the nails will snag on the clothing, so we recommend certain things to try to improve the symptoms.

(29:24): First and foremost, we advise the use of nail hardeners. We recommend two common brands available over the counter: Sally Hansen Hard as Nails or Nailtek. These really coat the nail and make it stronger and can be applied every night to facilitate protecting the nail. Oral biotin may be taken daily to support hardening of the nails as well. For significant inflammation of the nail, we recommend applying a high-potency topical steroid that can be used nightly. Apply to the nail bed and the nail folds - the area from where the nail is coming out.

(30:06): In patients who have scarring or complete loss of the nail or are approaching that, we sometimes perform steroid injections into the nail folds, which can be quite painful. So most often if the nails are significantly affected, we really do recommend systemic therapy for GVHD to treat the nails. The nails do improve with systemic therapy.

(30:28): We'll cover hair loss after transplant. Patients may experience hair loss after transplant for a variety of reasons. The most common is what we call anagen effluvium. This is hair loss in the first six months after chemotherapy. It affects about 90% of the hair on the scalp, and it typically regrows in the several months after transplant. This will regrow on its own, but there are some things we can do to expedite the regrowth.

(30:57): Rarely, patients will experience persistent chemotherapy-induced alopecia. This is hair loss lasting over six months after the chemotherapy.  We offer certain therapies to support this.

(31:10): Additionally, patients may have GVHD-associated hair loss that can occur as part of chronic GVHD. This can be scarring or non-scarring. Patients may also have hair loss from other conditions such as a decreased nutritional state, or thyroid changes. All of this can contribute to hair loss. We like to evaluate patients for their thyroid function and their nutritional nutrients - vitamins and minerals - to make sure that patients have adequate stores to support hair regrowth.

(31:44): As you can see in this patient, hair loss can be non-scarring, so a patient can regrow the hair. There's no scale. There's no loss of the hair follicle. Or it can be scarring where a patient loses hair follicles, and the scalp becomes a little bit shinier. Hair regrowth in those areas may not be possible. It's important to know the type of hair loss the patient has - whether it's scarring or non-scarring.

(32:11): Minoxidil can be an effective treatment for hair loss associated with GVHD of the skin.  If there's any inflammation in the scalp, we recommend using a topical steroid. If there's any hair thinning, we typically add either topical or oral minoxidil. Most patients prefer using oral minoxidil or oral Rogaine, which is a historical antihypertensive. But in the dermatology setting, it's used at very low dosages that do not typically affect blood pressure and helps with hair growth by prolonging the growing phase of the hair and by thickening the hair.

(32:44): There is another treatment that we use if the patient has no inflammation so we won’t use topical steroids - but we will use either topical or oral minoxidil. We'll use oral finasteride or oral spironolactone. These are all available hair therapies.

(33:01): If there's scarring, we'll still add minoxidil to increase the density, and if there's active inflammation, we would prescribe topical steroids and also discuss systemic therapy for the GVHD. But if the scarring is old and the GVHD is well controlled and essentially inactive, then we may recommend hair transplant.

(33:25): We also typically add a topical antifungal shampoo called ketoconazole shampoo applied to the scalp three times a week. This can also thicken the hair even when used off-label for just hair thickening and not a fungal etiology.

(33:42): This was a study of women with breast cancer treated with minoxidil, showing where the minoxidil shortened the period of baldness by an average of 50 days. It does not prevent alopecia, but it can support faster regrowth.

(33:56): Minoxidil may help reduce the periods of scarring GVHD by increasing the background hair density. It cannot regrow scarred-over hairs, but it can make the existing hair thicker and reduce how thin it appears.

(34:12): Minoxidil takes at least six months to work and its peak effect is at 12 months. Then it plateaus and generally keeps the patient’s hair stable. The patient may not have additional significant regrowth beyond that, but the hair loss is less than it would be if the patient was not on minoxidil.

(34:34): Hair care comes up often in patients who have graft-versus-host disease. We typically recommend washing and conditioning the hair every two to four days, although that may change depending on the hair type, ethnicity, and common washing and conditioning practices. The most frequent washing we recommend is every two to four days, but it can be less frequent because the natural oils stay on the hair, which is helpful.

(35:00): We recommend using a shampoo and a cream rinse or hair conditioner. When you brush or comb your hair, start at the end, use a soft bristle brush, a comb, or your fingers. Use over-the-counter antifungal shampoo for dandruff scale. This can also increase the hair thickness.

(35:23): We also recommend certain powders that can camouflage hair thinning. There are pigmented concealing powders that can be applied to the hair, and they come in different colors. They can come as a powder, a lotion, or a spray.

(35:35): In this slide, you can see the patient on the left before using the powder, and then right after, it can really fill in. They attach to the hair themselves or cover the scalp and can provide a fill-in of the scalp that masks the hair thinning.

(35:51): Hair transplantation is only used once the GVHD of the skin is inactive. The main advantage is that it's effective and permanent, but it is performed under local anesthesia, so it does not require operating room time, but there is pain associated with the numbing. There's risk for scalp swelling, bleeding, and minor infections. There's a risk of unnatural-looking hair, and there is a scar from wherever the hair is removed. It is expensive as it is not covered by insurance.

(36:23): Micropigmentation is another option to create the appearance of hair follicles. This is almost like tattooing the scalp to recreate hair density. It's relatively permanent. It resembles pores on the scalp, but there is a small risk of infection from the procedure. Some patients may be allergic to the pigment. Natural hair must be dyed to match the pigment if it's growing in addition to the pigment that's being placed, and that may need touch-ups over time.

(36:55): In summary, acute graft-versus-host disease of the skin presents as a maculopapular rash – so a pink-red, scaly rash that may or may not be itchy. Chronic graft-versus-host disease may affect the skin, hair, or nails and has two main forms, scarring and non-scarring, and they require different treatments.

(37:15): Many treatments are available that can improve your quality of life. Notify your care team if you develop any signs or symptoms of skin, hair, or nail GVHD.

(37:27): Especially now with telehealth and photos being so readily available, absolutely always document any new rashes, new skin symptoms, and hair nail symptoms with photos. Take them, send them to your provider, and ask for help. Ask for a referral if you want specialized care. There are clinicians who can help you with these symptoms, and I strongly recommend reaching out and asking for help.

(37:54): Even though the skin may not seem important, or the hair or nails may not seem important, it is important for you to feel like yourself and maintain your quality of life. This is important to clinicians, and we want to help you with it.

(38:11): I want to thank you. On the screen, that's our Memorial Sloan Kettering Cancer Center in the center, and that's our outpatient building. I am happy to take any questions. Thank you so much.

Question and Answer Session:

Jordan Sexton (38:21): Jordan Sexton: Wonderful. Thank you very much, Dr. Markova. This was an excellent presentation. We are now going to begin the question and answer session.

(38:27): The first question I have for you is from someone who says their daughter is constantly itchy and has reddish white bumps and patches since having the stem cell transplant six years ago. What do you suggest she use to relieve the itching?

(38:58): Dr. Alina Markova: That's a really, really great question and something I'll add in a future module. When there are skin changes accompanied by itch, the most important thing is to first treat the inflammation and the redness in the skin that's causing the itch. A patient with skin changes typically benefits from either a topical steroid or a topical calcineurin inhibitor at the very least, and that can help some of the itch symptoms. But if a patient has significant itch, and the topical steroids are inadequate, and the patient is starting systemic therapy for any sort of generalized rash, we also typically add oral medications for the itch.

(39:41): Some patients start with medications such as over-the-counter diphenhydramine or Benadryl, but we can also add medications such as hydroxyzine, which is another type of antihistamine that can sometimes work better for itch. One of our favorite medications that works for itch - this works in the nerve that contributes to itch approved for neuropathy - is pregabalin (Lyrica). Pregabalin is a gabapentinoid and it can be very effective for itch. It can make patients drowsy, so we typically start at night, and then we increase with a morning dose. Patients usually take a dose twice a day as multiple different dosages. The dose can be tailored for the size of the patient.

(40:23): Another off-label medication we sometimes use for itch is called aprepitant - that's used for chemo-induced nausea - but also works on the itch pathway. So, there are many different medications that can help with itch, but understanding why the patient is having itch is important. If it's itch with rash, targeting the rash is the key.

(40:43): Jordan Sexton: Excellent. What's the reason to apply sunscreen 20 minutes before going outside?

(40:50): Dr. Alina Markova: That's a great question. It is because it is not effective immediately and particularly with chemical sunscreens, they have to interact with your skin. Whereas the mineral blockers work almost immediately, the chemical sunscreens do not.

(41:06): Jordan Sexton: Good deal. For systemic therapies, can you combine pharmaceuticals like belumosudil (Rezurock®), ruxolitinib (Jakafi®), sirolimus(Rapimune®), and axatilimab (Noktimvo™) at the same time? If so, how would the provider determine which one is effective? Additionally, are there diagnostic tools to identify the cause or pathology of a particular type of GVHD to help determine the best treatment?

(41:32): Dr.  Alina Markova: That's a great question. We are combining all those therapies in one patient, but rarely are these added at one time. Typically, a patient may be on a GVHD prophylactic therapy such as the sirolimus (Rapamune) and then develop GVHD. When a patient develops chronic GVHD, a first-line therapy may be added oftentimes with systemic steroids.

(41:55): If a patient progresses on systemic steroids, something like ruxolitinib (Rituxan) may be added next. Ruxolitinib typically takes about two months to start to see a response in chronic graft-versus-host disease - somewhere from two to two and a half months. If a patient is not improving at that time, or progressing despite being on the full dose ruxolitinib, typically another medication is added. That can be the belumosudil or the axatilimab. Then, if a patient has some sort of partial response to the ruxolitinib, or partial response to the belumosudil, but still has pretty active disease, a third agent can be added such as axatilimab.

(42:34): But if a patient is on, for example, ruxolitinib for several months without improvement, then oftentimes that medication will be discontinued, and the patient will be switched to a different medication in lieu of adding medications - in order to minimize the polypharmacy or the total number of medications a patient has.

(42:55): Some of the ways we decide which treatments to use - and a BMT physician is the one who's prescribing these - it is oftentimes based on what insurance may approve. Sometimes insurances have therapeutic ladders that we need to go through.

(43:09): Other treatments are known to work better in sclerotic or non-sclerotic GVHD. We generally know that ruxolitinib and belumosudil are effective for acute and both types of chronic GVHD. Axatilimab has shown to have great improvements in sclerotic GVHD. So, we try to target, but we're still learning as to which drugs work best for which type of GVHD.

(43:36): As far as the other question about diagnosis - in chronic GVHD, a skin biopsy may be used, especially if it's non-sclerotic or non-scarring GVHD, to make sure that the patient has chronic graft-versus-host disease and not another type of rash such as eczema or psoriasis. It's not always required. It's often not required because the GVHD is often easier to clinically diagnose.

(44:00): For sclerotic GVHD or scarring GVHD, we rarely need to biopsy because it's clinically diagnostic, and GVHD is ultimately a clinical diagnosis. But if there's something in the differential - some other type of process - a biopsy may be helpful. But primarily it's in the non-scarring chronic GVHD variant.

(44:21): Jordan Sexton:  You mentioned the name of the shampoo earlier. Could you please repeat the name of it and spell it if you can?

(44:27): Dr. Alina Markova: Yes, it's ketoconazole shampoo. It’s the fourth bullet here on the slide - prescription ketoconazole shampoo. It's an antifungal shampoo. I think the brand name is typically called Nizoral, and it can be applied to the scalp. A patient would then use their own shampoo afterwards, because this one is just a medication to the scalp. It’s lathered on for about a couple of minutes and then rinsed off, and then normal hair care is resumed.

(44:58): Jordan Sexton:  Could GVHD of the skin be caused by any medications or certain foods? If so, can you give any examples?

(45:09): Dr. Alina Markova: There are no foods that I’m aware of that have been associated with graft-versus-host disease. As for medications, treatments such as donor lymphocyte infusion can cause and flare GVHD. In certain patients who are very sensitive to immune stimulation, other immune stimuli can cause GVHD flares, such as exposure to a virus, or exposure to a vaccination. Sometimes, if the patient is very sensitive to this, they'll notice that anytime they have a cold or an upper respiratory infection, their GVHD flares a little bit. The same thing can happen in the setting of a vaccine. But otherwise, most medications have not been associated with GVHD. Worse exacerbations, though, certainly tapering or reducing GVHD immunosuppression, can cause a GVHD flare.

(46:06): Jordan Sexton: Good deal. Do you have any advice or information about skin GVHD looking like cellulite?

(46:14): Dr. Alina Markova: Yes, absolutely. In patients with early scarring GVHD, the GVHD may present like new areas of cellulite relatively quickly developing oftentimes in the inner arms or on the inner thighs, and it can feel firm and appear very quickly. Unlike regular cellulite, which can develop over many months, this appears much more quickly and continues to progress. So, this is a sign of sclerotic GVHD and it merits an evaluation by a bone marrow transplant physician and or a dermatologist.

(46:54): Jordan Sexton: Good deal. Do you have suggestions when chronic GVHD affects the fascia and the fingers become less flexible long-term?

(47:03): Dr. Alina Markova: That's very challenging. When it's active, again, the systemic therapies for GVHD are key. We partner very closely with our physiatrists or rehab medicine doctors because they can give exercises and stretches for the fingers and for other joints that are affected by fascial graft-versus-host disease. Sometimes they even prepare splints to help stretch out the fingers. If the tightness is largely not just from the fascia, but more from the skin tightness, we can even do CO2 laser to try to soften up that tightness and increase range of motion. That is also done as well.

(47:46): Jordan Sexton: Is there anything that can be done to repair thin skin as a result of steroids?

(47:53): Dr. Alina Markova: Unfortunately, it's very challenging to repair thin skin. The approaches are largely related to using the tretinoin cream that I previously mentioned for the stretch marks, as well as CO2 laser can be used in focal areas - but the generalized thinness - it's really hard to recover. The main thing is really time and avoiding additional topical steroids.

(48:23): Jordan Sexton: What is myofascial treatment and is it effective for skin GVHD?

(48:31): Dr. Alina Markova: Myofascial treatment is typically something that our physiatrists discuss with our patients because it's deeper to the skin, so I would defer to them on that. It doesn't target the skin itself. It targets the deeper fascia, and so I would defer to them. On the skin it’s not a skin targeting treatment, so it would not help skin GVHD, but it could help the fascial deep component of GVHD - but not the skin itself.

(49:02): Jordan Sexton: Will fingernails ever grow back to normal after GVHD?

(49:08): Dr. Alina Markova: That is a great question. It depends on the type of GVHD changes a patient has in their fingernails. For a patient who has a splitting of the nails after chemotherapy - fingernails after that regrow in six months, and toenails in about a year and a half to two years. For GVHD that's non-scarring, the nails typically regrow. They may not be as strong as they were originally, but they do regrow. When there’s scarring, it depends on the extent of scarring. If there is extensive scarring and the stem cells that produce the nail that are right where the nail fold is, are damaged, then the nail may never regrow normally.

(49:51): Jordan Sexton: This question is from a person who was diagnosed with chemo-induced alopecia a few years after transplant, and their hair is very thin and sparse now. What do you think of shampoos, conditioners, and scalp serums like Vegamour to grow or activate more follicles in hair?

(50:06): Dr. Alina Markova: That's a great question. If there's diffuse thinning from chemotherapy, the most effective therapies are adding oral minoxidil, oral spironolactone, oral finasteride, or oral dutasteride (and oftentimes a combination of therapies), as well as adding the ketoconazole shampoo. And do a nutritional workup to make sure all of your nutrients are adequate to promote hair growth, and that the thyroid function is adequate.

(50:36):  Most of the advertised over-the-counter shampoos are typically very expensive (but with minimal effective ingredients or some of the ingredients at low dosages) and will have some minimal, minimal efficacy - but not nearly compared to the systemic therapies by mouth. So, when there's extensive hair thinning, we really encourage using the oral minoxidil as a starting point and then using hair powders as well.

(51:07): Jordan Sexton: Okay. The next question is from someone who is four years post-transplant and would like to be outside more. They're usually covered from head to toe due to GVHD, and they're wondering if they'll ever be able to go to the pool or the beach again.

(51:24): Dr. Alina Markova: That's really, really tough. Yes, absolutely. As I mentioned, we encourage going outside. You can go to the pool, you can go to the beach, but we typically recommend wearing a rash guard - a long sleeve UPF rash guard. They even make swim pants and a wide brim hat. Then all that needs to be reapplied is the face and hands. That’s really the safest way.

(51:50): Of course, you can go to the pool or the beach at less sunny times as well, like start of the day or end of the day. At that point, you might not really need the swim pants, but I would still recommend wearing the long sleeve rash guard to really protect the skin. But yes, go. Just wear the gear. We recommend that not just to GVHD patients. We recommend the same to patients with a history of melanoma or very fair skinned patients who are at high risk of skin cancer. There are many brands that make cute swimsuits and rash guards at this point, so they can be fashionable as well.

(52:35): Jordan Sexton: What kind of doctor would be the one to prescribe ketoconazole shampoo? Sorry, the one you mentioned earlier.  

(52:43): Dr. Alina Markova: Yeah, ketoconazole.

(52:45): Jordan Sexton: Would that be a dermatologist?

(52:47): Dr. Alina Markova: It could be a dermatologist. It could be a primary care doctor, or a BMT physician. It's a low-risk medication and is oftentimes prescribed just for dandruff of the scalp. So really anyone can prescribe it.

(53:02): Jordan Sexton: One person has a follow-up question with regards to oral medications. Can they be stopped? I don't know which ones in general they may be referring to.

(53:14): Dr. Alina Markova: If it's related to hair - the oral medications for hair loss. If the hair loss is related to a remote insult - whether that's GVHD that's already controlled or chemotherapy - and the hair regrows to a point where the patient is happy, then they can be stopped. If the hair loss is related to hormonal changes after transplant, and then if the oral medications for hair loss are stopped, the patient is likely to continue to suffer from that hormonal etiology of the hair loss and continue to have hair shedding. In those cases, we do not typically stop the medications, and we continue. If it's oral systemic therapies for GVHD, it really depends on whether the patient's GVHD is controlled - and those are tapered off very slowly.

(54:06): Jordan Sexton: I think we have five minutes left, so we'll be taking our last question now.  This person has become heat intolerant since their transplant. And when they wear lotion, especially cream-based ones, it feels like it's trapping heat in their body. Do you have any suggestions on what to use that lets their skin breathe while it's hydrating?

(54:28): Dr. Alina Markova: That's a challenging scenario, and many of our patients will experience either inability to sweat or sweating too much, and sensitivity to their sweat, like itching or burning when they do sweat. That oftentimes does improve over the years after transplant.

(54:49): There are some gel-based moisturizers and patients can find those to be more soothing. Another one - they're called gel creams - but they're gel-based. Another option that some patients like is Aquaphor spray, which is an emollient - but it's a petrolatum spray. It's cooling when you spray it on like a sunblock, but it moisturizes. So that's another potential option.

(55:20): Jordan Sexton:  Closing. Thank you very much, Dr. Markova, on behalf of BMT InfoNet and our partners. I think this was a fantastic and informative presentation. And thank you to the audience for your excellent questions. Please contact BMT InfoNet if we can help you in any way. Thank you.