All About Gilteritinib

What is flit 3 positive AML? Flit 3 positive AML is AML where the patient has a mut or the patient's disease has a mutation in flit 3. So flit 3 mutations are found in about 30% of patients with acute myoid leukemia. The reason it's important to know if you have a flip 3 mutation is because there are specific targeted therapies that can target the flip 3 mutation and that can potentially lead to improved outcomes if you have this particular mutation. What is guiltritin?

Guiltritin is a is a very potent targeted inhibitor of mutant flit 3. And um just to cut to the chase in a big randomized control trial that looked at patients with relapse and refractory acute myoid leukemia that had a mutation either uh they had a mutation in flip 3. It was proven that giving guilt nib led to improved survival over giving standard chemotherapy. And that's important because guiltib is also an oral medication that is easy to take has very few side effects. So, you know, if you have a drug that number one um is better in terms of survival um and that drug also doesn't have bad side effects, that's a winner in in my view and in the view of many or probably all of my patients. How does guiltridden work to treat flip 3 positive AML? In order to understand how guiltridden works, you need to understand what happens when you don't have guiltridden when you just have the flip 3 mutation. So when you just have a flip 3 mutation in your AML cells, what it does is it essentially turns a switch on in those AML cells to tell them to constantly divide. It's kind of like if you had a light switch that you just couldn't turn off. There was a short circuit and you couldn't get it to go off. So how do you get it to go off? Then you need to come up with a way to block that switch from being activated. What guiltib does is it blocks the activation of that abnormal switch and that keeps the cells from dividing and dividing and dividing causes those cells to differentiate and die and that's how the leukemia goes into remission. When during a course of treatment is guiltridden used to treat flit 3 positive AML. Guiltrib is now being used only in the setting of relapsed and refractory acute myo leukemia. That's where it's um approved. Relapse and refractory means that you had leukemia, you got treatment and the treatment didn't work or you had leukemia, you got treatment, the leukemia went into remission but then it came back uh down the road. So that's where guilt nib is currently approved. Um there are some exciting clinical studies that are looking at the use of guilt nib in combination with chemotherapy for newly diagnosed acute milo leukemia. You know whenever you have a good drug that's being used in the relapse and refractory setting, you know, we don't want to keep it there. We want to give our best drugs at the very beginning of treatment. So this clinical trial is looking to see does guiltitib in combination with chemotherapy work better than chemotherapy in combination with what's called a first generation or a less potent flip 3 inhibitor called midostorin. Who are the most appropriate patients to receive guiltib? So guilt is appropriate for anyone with a flip 3 mutation who has relapse and refractory AML. I mean that is what a patient in 2022 should get. That is what a patient should get. That is the standard of care. There are clinical trials that are investigating guilt nib in combination with other agents for relapse and refractory AML. I always um encourage my patients to seek out a clinical trial because clinical trials um work to try to do better than the current standard of care. But a clinical trial that's that you might be interested in for flip 3 mutant AML should be one that incorporates guilt written into that trial. How is guiltritin administered? Uh guiltritin is an oral agent that is given uh once daily. Easy to take just like taking a Tylenol. Uh no no big side effects. What are the common side effects of guiltritin and how are these side effects typically managed? Guiltritib is approved in the United States for patients with relatory flit 3 mutated acute myoid leukemia based on the results of the adnal trot. In general I believe um guiltritib is well tolerated by patients with uh very little GI toxicity. The major toxicity I observe in my own patients is myosuppression which is manageable. What research is being done with guiltritin to make this therapy more effective? So investigators are evaluating the use of a flip inhibitor with other targeted therapies, intensive chemotherapy and imunotherrapeutic approaches. So for example the use of gelitnib with um the bcl2 inhibitor venettolax has shown an 80% response rate in patients with relapse refractory flip-free mutated acute myoid leukemia. It's also being evaluated in combination with intensive chemotherapy compared to intensive chemotherapy with mitoin in patients with flip 3 mutated AML that are previously untreated. And of course other um inhibitors will be um developed with flit 3 inhibitors. For example um nucleophosma mutations quite commonly occur with flit 3 ITD mutations. Menin inhibitors have shown single agent activity in patients with acute myoid leukemia with nucleophosin or npm1 mutations and clinical trials are being designed and some have already started with menin inhibitors in combination with a flip 3 inhibitor such as guiltitanib in patients with relapse refractory AML that have both a flip 3 and a nucleophos mutation. Are there other flit 3 inhibitors in development? What may make these better than guiltritin? Flit 3 is a uh one of the three most common mutations that are found in acute myoid leukemia and are part of leukemagenesis. And so it makes sense that multiple uh inhibitors have been developed that target [ __ ] 3 and in general have shown single agent activity. I think the it's fair to say that the three [ __ ] three inhibitors that are the furthest along in clinical develop in acute mywayia are guiltitart

and krenolanib. Now these are all second generation more specific and more potent flit three inhibitors compared to drugs like the first generation mitoin which is already approved. And so those um flit 3 inhibitors are being uh all of them are being uh studied in combinations with chemotherapy, other targeted inhibitors such as BCL2 inhibitor venettolax with less intensive therapies such as the hypomethylating agents and with imunotherrapeutic approaches. At this year's congress e-ha 2022, I am presenting the results of a quantum first study where we show that the addition of quizardinib a second generation type 2 inhibitor flip 3 ITD has shown a survival benefit compared to placebo in patients up to the age of 75 with flip 3 ITD mutated acute myoid leukemia. So there are definitely other flip three inhibitors in development. There's a drug called quizardnip that is being the results of a clinical trial are being presented at this this year's e-honing. I think it's being presented tomorrow. That's a study of quizardnib in combination with chemotherapy. Um we'll have to see what the results of that trial are. Um in terms of whether anything is better than guilt nib, I'm not sure. I think geltib is very potent. Um I I'm I'm not sure there's anything that's that's actually better out there that's being investigated. I think the question is going to be is the efficacy of guiltridden in combination with chemotherapy going to be similar to the efficacy of a drug like quizardib with chemotherapy. Can guiltritin cure AML? The admin trial showed an improvement in the median survival of patients treated with um gelaritin from about 5 to 6 months to uh 9 months. Now very few patients were still receiving guiltritin after 2 years and that shouldn't be unexpected since flip-free mutations especially the ITV mutation is a late event in chemogenesis. So I think it would be unlikely that a single agent such as guiltrit would be effective as a more prolonged maintenance therapy in patients. I think it's highly unlikely that any flip 3 inhibitor as a single agent would be curative for acute myoid leukemia. As we know this is a very heterogeneous disease. The median number of mutations in patients is four and flit 3 mutations especially the ITD are late events in leukemagenesis. So by just targeting flit 3 uh with an inhibitor I think it's highly unlikely that we'll get prolonged remissions with single agent therapy. And so we really do need to stress and focus on combinations with chemotherapies either intensive such as 7 and three and hydrocyerine or less intensive therapies in order to see a benefit of flit 3 inhibition or in the future imunotherapies as well in combination with um flit 3 inhibitors such as guiltritin. Can a patient develop resistance to guiltinib? Resistance um can occur with any flit 3 inhibitor um that we use in the clinic. In terms of guiltritinib, we do see u resistance develop. Now since guiltritin is a type 1 inhibitor and it inhibits both the flip 3 ITD and the TKD mutation, when patients progress um on guiltritin, they typically do not have a flip 3 ITD or TKD mutation. However, um other mutations develop and the most commonly identified mutation in those patients are mutations in RAS.