All About Midostaurin

What is midostorin? What are the most common side effects of mitosin? So, mitoin is an oral chemotherapy agent. Uh, it specifically comes under the umbrella of targeted therapy because it targets a mutation found in roughly 30% of cases with acute my leukemia. that mutation is flit 3 either ITD which is internal tandem duplication or TKD which is tyrrosin kindness domain so around 30% of patients with AML will have this mutation and midtorin is an oral agent targeting this mutation specifically we don't know if it works for other mutations but it is approved in AML only for patients harboring the flit 3 mutation what led to the approval was a randomized phase three study in which patients younger than 60 years of age who had a flit 3 mutation were randomized to receive intensive chemotherapy which is standard of care with 7 days of citarabine and 3 days of anthroyc and patients were then given midostorin versus placebo. So the comparison was 7 + 3 plus midostorin versus 7 plus 3 plus placebo. Midostorin was given at a flat dose of 50 milligrams twice a day starting at day 8 and continuing through day 21 of chemotherapy and then it was added for uh during consolidation chemotherapy as well. The primary endpoint of the study was to show overall survival benefit with the addition of midostorin to standard chemotherapy and the study did meet its primary endpoint and there was a survival benefit for patients who had received midostorin compared to those who were receiving placebo. Now there are different ways to look at how much that survival benefit was because a lot of patients went to transplant as well. But broadly speaking after four years of therapy patients who took midostorin had a roughly 6 to9% chance of living longer than those who had not received midtorrin therapy. Some of the common side effects associated with mitoin were GI toxicity such as nausea, vomiting, diarrhea, the elevation of liver enzymes and needs to be monitored very closely when giving with other fungal medicines or other infection preventing medicines as well. How are these side effects managed? Usually you give supportive measure medicines for the GI side effects like anti-nausea medicines, anti- diarrhea medicines. Sometimes you would hold a medicine for a little while, patients would feel better and then restart the midtorrin. And um as far as interactions with other medicines were concerned, you would ideally want to use other supportive medicines from a different class which would have the minimum interaction with my daughter. What is the difference between a first generation and second generation flit 3 inhibitors broadly speaking? So flit 3 inhibitors are becoming more and more selective as you go generation by generation meaning that the earlier flit 3 inhibitors so there was saraphanib there's midostorin now there's guiltitib that's fd approved there's kartneib which was recently published and was a positive phase three study so these are all frit three inhibitors the the more novel the agent the more specific they are meaning that agents approved before had more targets in addition to just split three. Now those targets may not be mutations found in AML but they were just other targets that the medicine would cover meaning that had a chance of leaving leading to offtarget toxicity or more side effects. So a very simple way of saying is that the earlier TKIS would have been more of a dirty TKI meaning broadly covering several targets and this could mean that you know whether that led to increased efficacy through some unknown mechanism yes but that also could mean that it could lead to more toxicity as well and uh so the novel TKI are more flit 3 specific they also have their own side effects of course but these mainly target flit 3 so they may not have too many offtarget toxicities and may just have regular milosuppression or which is low blood counts and other toxicities but they may not be effective for other mutations like let's say some of the earlier fit three inhibitors were. How can a patient tell if mitoin has successfully eliminated their AML cells? When you treat people with um midostorin there are different ways to capture response. So you know the basic response is whether they've achieved remission meaning there's no there no more blast in the bone marrow and the person has recovered their white cells red cells and platelets uh and there's no evidence of disease by sensitive tests such as flowcytometry so you could do an assay to look for frit 3 which is called lucostrat which is a PCR basically and that's how you initially diagnose the mutation at the time of diagnosis either through PCR or NGS PCR being a little more sensitive than NGS So you can use this assay to see if the FRI 3 mutation has gone or whether it is present at a low level which we would call measurable resolute disease or MRD positivity. So we think we know that patients who are MRD negative tend to do better than those who are MRD positive in terms of relapse and overall survival. So yes there it does go away but we now have very sensitive tests for example 10 to the^ minus 6 like looking at almost a million cells or more and trying to find leukemia cells from those cell from those total number of cells. So we see where there's complete absence of leukemia or bad cells and then we see that there's a small presence and a small presence may predict for poor outcomes compared to complete absence of leukemia cells. Who should take midostorin and how is it administered? So the current standard is that midostorin is approved as frontline therapy for patients with AML. So newly diagnosed patients with acute myo leukemia harboring a frit three mutation. Whereas the current indication for gilaritin is for patients with relapsed or refractory acute milo leukemia with a fit three mutation. So one is approved in the frontline setting whereas the other one is approved in the relapse and refractory setting. So patients with acute miler leukemia who have a flit 3 ITD or TKD mutation and are also considered fit to receive intensive chemotherapy are the patients where you would use mitoin in combination with intensive chemotherapy. So you know the actual study that led to mitoin approval had patients younger than 60 years old. In general practice people above 60 are also uh consider like we would also give them mitoin if we thought they were fit for intensive chemotherapy. Some factors that go into determining the fitness of a person for intensity of treatment is age co-orbidities as well as what their performance status was probably not at the time of diagnosis but let's say 2 to four weeks prior to the diagnosis. So even if they were let's say 65 had minimum co-orbidities were healthy were doing fine before the diagnosis of AML you could consider treating them with intensive chemotherapy plus mid torrent by the same token you know if you have someone who's young but let's say has too many co-orbidities such as um congestive heart failure coronary artery disease chronic kidney disease then you may not even consider giving them intensive chemotherapy and may consider using a less intense approach. approach in which case uh they would not be candidates for my distortion therapy. It's given orally. It's uh for the induction cycle for example uh it is started at day number eight it is started at a dose of uh usually 50 milligs twice a day and it is given for a total of 14 days. So from day 8 to day 21 during induction and similarly for 14 days per cycle of consolidation chemotherapy. Now once consolidation finishes if a patient proceeds to transplant that's fine then they come off a midtorin when they if they don't proceed to transplant there is some data you could use midostorin maintenance but that's not as mainstream as there other agents now approved for maintenance such as oral aocidine so in that scenario where they don't proceed to transplant one can consider keeping them on midtorin if they tolerated it but um that wouldn't be considered standard of care at many centers So while it's being given with induction and consolidation, it's used with other drugs. But as uh if if you were to use it at maintenance, you'd probably use it as monotherapy. So you know in the for example in induction, it is given with 7 plus 3 which is the standard induction backbone in the United States and in consolidation it'd be given with something we call hideac or highdose scarabine. Uh so those are the common drugs it's combined with. Can midostorin cure AML? So you know midostorin can help in curing AML for a subset of patients. Now how is that? So you know so for patients with flit 3 mutation ITD they're considered um by the they're considered more intermediate to high-risisk patients. So we know that perhaps chemo by itself isn't sufficient to uh keep them in remission for a long time and most of these patients would benefit from consolidation with a stem cell transplant down the line. Uh midtorrin may help in getting these patients into a deep remission and then allowing these patients to proceed to transplant in a deep remission which could ultimately cure a subset of these patients. So it could you could think of it as a bridge to cure but um it would be hard to say that by itself it would cure leukemia. There is a lot of research being done to improve the outcomes of patients with AML with the flit 3 mutation. So for example um so gilto which is already approved in relapse refractory setting. Uh a lot of these flit 3 inhibitors are being used as postransplant maintenance. And then just recently there was a positive study leading to a survival benefit with another fit three inhibitor called kartib uh compared to placebo. Things are improving by finding novel agents which are even uh more effective than already approved agents and hopefully with a side effect profile that is much more tolerable. Who should take mitoin and how is it administered? So the current standard is that midostorin is approved as frontline therapy for patients with AML. So newly diagnosed patients with acute myo leukemia harboring a fit three mutation. Whereas the current indication for guiltitib is for patients with relapsed or refractory acute milo leukemia with a fritri mutation. So one is approved in the frontline setting whereas the other one is approved in the relapse and refractory setting. So patients with acute miler leukemia who have a flit 3 ITD or TKD mutation and are also considered fit to receive intensive chemotherapy are the patients where you would use mitoin in combination with intensive chemotherapy. So you know the actual study that led to mitoin approval had patients younger than 60 years old. In general practice, people above 60 are also uh consider like we would also give them mitoin if we thought they were fit for intensive chemotherapy. Some factors that go into determining the fitness of a person for intensity of treatment is age co-orbidities as well as what their performance status was probably not at the time of diagnosis but let's say 2 to four weeks prior to the diagnosis. So even if they were let's say 65 had minimum co-orbidities were healthy were doing fine before the diagnosis of AML you could consider treating them with intensive chemotherapy plus mid torin by the same token you know if you have someone who's young but let's say has too many co-orbidities such as um congestive heart failure coronary artery disease chronic kidney disease then you may not even consider giving them intensive chemotherapy and may consider using a less intense approach in which case uh they would not be candidates for my destroying therapy. It's given orally. It's uh for the induction cycle for example uh it is started at day number eight it is started at a dose of uh usually 50 milligs twice a day and it is given for a total of 14 days. So from day 8 to day 21 during induction and similarly for 14 days per cycle of consolidation chemotherapy. Now once consolidation finishes if a patient proceeds to transplant that's fine then they come off a midtorin when they if they don't proceed to transplant there is some data you could use midostorinant maintenance but that's not as mainstream as there other agents now approved for maintenance such as oral aocyodine. So in that scenario where they don't proceed to transplant, one can consider keeping them on midtorrin if they tolerated it. But um that wouldn't be considered standard of care at many centers. Right? So while it's being given with induction and consolidation, it's used with other drugs. But as uh if if you were to use it at maintenance, you'd probably use it as monotherapy. So you know in the for example in induction it is given with 7 plus 3 which is the standard induction backbone in the United States and in consolidation it'd be given with something we call highac or highdosese citarabene. Uh so those are the common drugs it's combined with can mitoin cure you know midostorin can help in curing AML for a subset of patients. Now how is that? So you know so for patients with flit 3 mutation ITD they're considered um by the they're considered more intermediate to high-risisk patients. So we know that perhaps chemo by itself isn't sufficient to uh keep them in remission for a long time and most of these patients would benefit from consolidation with a stem cell transplant down the line. uh midtoin may help in getting these patients into a deep remission and then allowing these patients to proceed to transplant in a deep remission which could ultimately cure a subset of these patients. So it could you could think of it as a bridge to cure but um it would be hard to say that by itself it would cure leukemia. There is a lot of research being done to improve the outcomes of patients with AML with the flit 3 mutation. So for example u so gilitiv which is already approved in relapse refractory setting uh a lot of these flit three inhibitors are being used as post-transplant maintenance and then just recently there was a positive study leading to a survival benefit with another fit three inhibitor called kart nibib uh compared to placebo things are improving by finding novel agents which are even uh more effective than already approved agents and hopefully with a side effect profile that is Much more tolerable.