Dr. Aleksandr Itkin summarizes the possible signs and symptoms of cutaneous toxicity which can result from the use of medications used to treat melanoma.
we are back live now and our next speaker is dr it can uh he's on the staff of the scripts clinic dermatology. He has broad experience and has specific interests in uh PDT photodynamic photodynamic therapy. Uh So uh uh let's take it away. Okay thank you very very much dr bird for a kind of uh invitation. It's the third time I participate in this course. Um And I'm very honored by that. Uh we're gonna be talking today about cutaneous reactions have targeted uh immune therapy utilized and treatment of melanoma. There are no relevant relationship to disclose. Um We'll talk about background whether the medications have been involved. We will discuss cutaneous adverse reactions to immune checkpoint inhibitor therapy including skin, hair and nails. We will cover the raf map kinase pathway inhibitors and their skin reactions. And we'll talk a little about severity of the reactions and prognosis for treatment outcome uh skin reactions uh significantly affect quality of life causing pain, teaching emotional social distress distress, limit activity of daily life. Those on checkpoint therapy um have skin involvement with reactions up to 50% of the time. And that may lead to discontinuation of the life sailing Treatment and up to 20% of cases. I'd like to mention dr Allison and Doctor Honjo who received Nobel Prize in 2018 for discoveries of CTL A four MpG one molecules. That is why the treatment of uh melanoma progressed to such heights just to rehash a little bit here is an interaction between T. Cell receptor and the major history compatibility complex with antigen presenting here is an insurgent and you need a costume military molecules. So interaction between C. T. L. A. Four and B. 71 gives a inhibiting signals that kind of tells a cell too quiet down. But however if you interrupt this uh interaction uh the activating signal goes to T. Cell and it attempts to proliferate uh attack specific and pigeon on the other hand we have interaction between PG one a program death one molecule on the the surface of T cells that toxic T cell and anyone Ligon that gives an inhibiting signal interrupting this leads to uh proliferation of T cells. So this is how our checkpoint inhibitors work. And then we will cover also uh Russ be rough pathway. Um And we will also we'll talk about those medications on the right and also uh reflect on the mechanisms um that uh influence certain side effects. Okay then you say the fact um this has been already discussed that there are multiple agents. We're gonna be talking about epilepsy a map, the volume of temporal is a math. Uh in july 2020 we have another player in the market uh Pd L. One inhibitor in combination with government and and the profit from metastatic melanoma. We'll talk about the rough inhibitors and as well as T back I'll start with the most severe drug reactions talking about erythema. Multiform spectrum. Um The severity can be mild to the full skin sloughing and um checkpoint inhibitors as well as be rough inhibitors have been implicated. The take point. The point to take home is that there is a cross reaction between Morocco and the broth and ensue from attacks is all. So those who have developed uh stevens johnson m am like reaction on sulphur drugs should uh the treatment with inhibitors should be considered with great care and vice versa. Yeah. Acne form eruptions are quite common with E. G. For inhibitors and those decrease proliferation of carrots in the sights and the map chinese expression. And similarly when we use uh map kinase inhibitors uh we notice the crease and can actually carry it in a scientific application, increase in inflammatory side accounts hypothesis security in the sights thinning and abnormal epidermal differentiation, follicular rupture and popular and pastoral formation Traumatic. It will cause acne former option in 77% of the cases but a combination of giraffe and the mechanism bitters decrease it down to 10%. The eruptions agreed on scale from 1 to 5 based on body surface area and security and the treatments are similar to what we do in our clinic however, and severe uh in the severe eruptions we should be quite ready to apply systemic corticosteroids using traditional cortical steroids use um oral um um the retinoids in order to prevent uh this side effect and allow patients to continue life saving treatment. Um Mhm nail involvement is common with MAC inhibitors and the rough inhibitors here's an example of acute para nick or Nicholas is due to them. The raffle nib the ref inhibitor. Uh Nicholas is due due to topography name. Some patients will develop veronica inflammation of the nail fold. Um Those are treated with oral antibiotics. Uh If there is super infection with fungal agents and hazel's vinegar socks are good for pseudomonas species and other gram negatives, topical, super potent cortex zero. It's under occlusion, nail avulsion, final mail, major examination. Those are all treatments available for us and definitely I nd of Sibongile abscesses. Uh These side effects also may lead to those reductions and discontinuation of Antalya plastic treatment. Well um more fun. Uh more fun kind of uh side effects reactions of hair. Uh Here you have a red pigmentation of the hair. And the gentleman with adenocarcinoma of the lung treated with the volume map. We also see dignitary changes uh such as Vitiligo. Here is a patient of mine and dr Bolen dr Bolen and mine. And here's a similar patient from journal American Academy of Dermatology Published in 2017. Both have equal type of vitiligo and vitiligo was shown to be a good prognostic factor, both in treatment with a single agent. Uh checkpoint inhibitor capitalism. Up as well as in combination with Xrt Nicola Mabon Xrt Up to 5% of melanoma patients treated with EU will develop this Allegra. Here's a case of 55 year old woman with Melanoma have left me that most in 1987. It was metastatic left inguinal fold in 2014. Uh This lady developed uh multiple metastases throughout her body. Was treated with Pepe lima map for infusions and then uh the volume map. She did well. She developed a single four local vitiligo, this is her natural color and she's done Great. Um last time I saw her sometime in the middle of 2020, be rough inhibitors have been reported to cause textural changes. Here's the kinky hair and patients treated with the broken hip. The same class of drugs was implicated in scaling and hair cost formation. Uh This would be treatable in the same way as separate dermatitis of the scalp with salicylic acid catalytic agent as well as topical steroids. And key to Canada's oil shampoo induction was of squamous nia plasm. And though there is a range from hypertrophic actinic keratosis to eruptive squamous cell carcinomas, eruptive care, atomic and formas. And the rough agents uh induce it. And like them. And have been 25% of the cases the paraffin and 7% of the cases. And it seems that our ass mutation, the mutant Russ is responsible. So even when you apply um be rough inhibitor is not all activated be with mutant rats. Not all activated. Be rough molecules will be inhibited and demoralization of those lead to propagation to activation of the pathway. And that causes tumor growth. Now there has been also report uh co administration of map uh bureau of inhibitors and MAC inhibitors decrease character in a city near Plasm. Uh the case uh there have been reported several cases of PT one inhibitor causing eruptive character become famous. And as you can see this is in the sun exposed area. We constantly have patients like this who even without the presence of uh checkpoint inhibitor would develop multiple uh squamous cell carcinomas in the sun exposed area when they have inflammatory processes like stasis dermatitis, for example. And I think this is the mechanism you just increase inflammation in the area and suddenly the mutate cells would undergo further uh probably very chilly, probably positive plastic changes creating multiple squamous cell carcinomas. Um induction of Milan acidic near Plaza have been reported with fear of inhibitors. And this is uh related to uh new mutation in receptor interacting protein. Chinese three. This is a Syrian three named Kinney's that is important in induction of apoptosis. And so it's been shown that induction of new primary melanoma during the rough and tumble to Sweden was reported in um Five out of 468 patients in Phase 2 3 trials. And in various online publications. So, I've had patients who did just that in my practice as well. Uh This is a recent publication from N. Y. U. 617 patients. They were looking at severe skin toxicity versus mild skin toxicity and its relation to uh survival benefit. And it's been shown that if you look at the severe or mild skin toxicity both of those were beneficial for patients survival. Looking at the graphs however, when a severe toxicity uh well when when the data was adjusted for time from the initiation of treatment to the skin event, a city of existing city taxes were not associated with progression free survival. Yeah, inflammatory german close. This is what we deal on a constant basis with these patients because those are in case of C. T. L. A. For uh inhibitors uh inhibitory dilemma mob are reporting up to 70% of the haze cases and providers. The example is Russia's neutrophils. Dermatitis is a huge generalized example was postural Asus um alopecia areata variants protagonist, hilarious as well as um uh their motto, my side is for the sensitivity reactions for the asian dermatitis like dermatitis etcetera. Uh Here is uh can we go back to slides one more, Here is the patient of mine and dr Bolen. He had metastatic melanoma into lymph node in his Hogzilla. He was treated with epilepsy a map for that and he had developed this extremely critical female patches throughout his trunk and proximal extremities. We were unable to relieve his suffering even with 60 mg of predniSONE daily. After two months of trying to taper corticosteroids. I started looking at his medications and found that he was on calcium channel blocker for his blood pressure. I decided to to stop this medication. And within six weeks we were able to um 60 minutes to two months we stopped his oral predniSONE. I looked at some literature and I found uh interesting foreign government releasing essay. So you combine occipital Renault which is a marker for al appearing over the metabolite of Allah pernod with anti PD L. One antibody and peripheral blood, blood money, nuclear cells. And then you count how many of those cells release gamma interferon, some similar to how we do 24 on tv test. And then you can look at the percentage of self that released government front and say okay this patient will be allergic to gallop urinal. What if we have a whole set of uh lab tests for most common groups of medications? Anti diabetic lipid uh uh lowering drugs, uh blood pressure medications and and test the patient right before we introduce checkpoint inhibitors uh to see if they would react to their own medication. So this was a uh reaction to drug to blood pressure, drug induced by introduction of epidemic mud. Uh the pt one inhibitory spam bro and the volume ab also uh causing significant amount of uh inflammatory Dermot Asus and uh with keratitis and like annoyed reactions and examiners, dermatitis. Being at the top of the list as well as its like here is a bulletin for God this gentleman had bullets configuration of his new causal surfaces mostly. He did have large bullet on um medial surfaces of his thighs and arms. Um He was not able to eat, was not able to swallow because of the severe involvement of his oral because I'm probably um some portion of his software. He responded very well to treatment with predniSONE and re taxi madam infusion. Uh this this patient was treated for a lung carcinoma and um it remained quite stationary for several years and he never restarted checkpoint inhibitors after that. Here is the most severe boost in February that I've seen when I saw this lady. First time. This is already half recovered. You can see those hypo pigmented patches where Bull I worked. Her body was covered 70% with July. Um she was treated with temporal is a mark for metastatic renal cell carcinoma as well as um cns remind you of parasite toma that was locally advanced. Um after she responded nicely to systemic predniSONE and the fusion of riTUXimab. But three months later her oncologist and outside oncologist decided that she needs repeat treatment with checkpoint inhibitor. She was placed on the volume map and her bullets. And for good rickard and this is the second recurrence of her bullets that go ahead as I showed you inflammatory dermatologists are the markers a good prognosis. This is a lady with metastatic merkel cell carcinoma. So she presented with one skin nodule on the lower leg and multiple in Transit metastases that all were positive for merkel cell carcinoma. She had two large lymph nodes in the right uh inguinal fold. Um it took some time for Dr. Bolin to persuade this 87 year old lady to start temporal is a map and she developed a very mild erythema, this populus innocuous throughout her skin, some with periodic she did great with her metastatic disease. So everything resolved at least for the time that I followed this lady, here's an example of like annoyed vermouth Asus uh economic dermatitis. So like in planet of the souls extremely painful condition and this gentleman also he had the piano mucosa involved. He was treated with temporal is a mob for land carcinoma that was stopped. He recovered very nicely with topical corticosteroids and the inclusion and then re introduction of a different protocol involved in the volume map. Rickard. His brush on plant of surfaces. Vasculitis can be used by immune checkpoint inhibitors and um this review from clinical rheumatology describes predominantly lost large cell vasculitis. Vasculitis of nervous system that needs to be suspected. Now they also noted since PT one inhibitors C. T. L. A for inhibitors induced vasculitis. Them the drugs that cause the opposite effect on the same uh in the same pathways maybe uh maybe discovered for the future treatment of idiopathic rescue abilities. Here's an example from Jack Casey Creek case reports, the patient presented with non palpable corporate that was diagnosed pathologies. Look aside the plastic vasculitis but also had abdominal pain, nausea, vomiting, diarrhea and die on ct scan. Dilated bowel loops with about will and Emma consistent with our vascular haters. This is an example of uh in my view sub acute cutaneous lupus rash. Although pathology head interface dermatitis with increased music deposition suggestive of both photo toxic reaction all lupus. This lady was positive for his stone and I I looked back at her medications. She was exposed to prochlorperazine within a month or two of initiation of capitalism app she did actually grade her lung cancer ST stable or even decreased in size. And she did well with systemic and topical corticosteroids. Doesn't Okay, can we go for it? Okay. Uh the vic um those who treat with T Vac know that after about five months of treatments average nine treatment, you may start seeing new nodules arising at the areas of regret, cutaneous metastases or in transit metastases. Uh Those lesions must do biopsy because in many cases uh since those virus, the politic HSV has also GM CSF production built into it. Uh they induce granuloma granulomas and in places of resolved metastatic disease. So that needs to be checked by biopsy and this is my life last light. I hope I I did my presentation on time. Um There are many new combinations of therapies that are becoming mainline. And if you look at the kinetics of uh toxicity of those drugs, the skin is the first window into toxicity for those patients. Everything else comes later, G. I. Liver culinary etcetera. So skin provides us with unique opportunity to initiate treatment of cutaneous toxicity as soon as possible and will allow to save a lot more patients. As you can see, the combinations do have a survival advantage. And uh that's pretty much it for my presentation. I would be happy to answer all the questions. Thank you. Thank you Alexandra. There was a very nice presentation and as with the other speakers, we will forge the questions to you to answer next week.
