Who should take Midostaurin and how is it administered?

What is midostaurin?

What are the most common side effects of midostaurin?

So midostaurin is an oral chemotherapy agent. It specifically comes under the umbrella of targeted therapy because it targets a mutation found in roughly 30% of cases with acute myeloid leukemia. That mutation is FLT3 either ITD, which is internal tandem duplication, or TKD, which is tyrosine kinase domain. So around 30% of patients with AML will have this mutation. And midostaurin 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 FLT3 mutation. What led to the approval was a randomized phase three study in which patients younger than 60 years of age, who had a FLT3 mutation, were randomized to receive intensive chemotherapy, which is standard of care, with seven days of cytarabine and three days of an anthracycline. And patients were then given midostaurin versus placebo.

So the comparison was 7+3 plus midostaurin versus 7+3 plus placebo. Midostaurin was given as a flat dose of 50mg twice a day, starting at day eight and continuing through day 21 of chemotherapy. And then it was added for consolidation chemotherapy as well. The primary endpoint of the study was to show overall survival benefit with the addition of midostaurin to standard chemotherapy.

And the study did meet its primary endpoint. There was a survival benefit for patients who had received midostaurin 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 midostaurin had a roughly 6 to 9% chance of living longer than those who had not received midostaurin therapy.

Some of the common side effects associated with midostaurin were GI toxicities, such as nausea, vomiting, diarrhea, and elevation of liver enzymes. It 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?

So in general, usually, you give supportive measures and medicines for the GI side effects, like anti-nausea medicines and anti-diarrhea medicines. Sometimes you would hold the medicine for a little while. Patients would feel better and then restart the midostaurin. And as far as interactions with other medicines were concerned, you'd ideally want to use other supportive medicines from a different class, which would have the minimum interaction with midostaurin.

What is the difference between the first generation and second generation FLT3 inhibitors?

Broadly speaking, FLT3 inhibitors are becoming more and more selective as you go generation by generation. Meaning that the earlier FLT3 inhibitors, such as sorafenib, midostaurin, and gilteritinib, are less specific and target additional molecules beyond FLT3. The more novel agents, like quizartinib, are more specific to FLT3, meaning they tend to have fewer off-target effects.

The earlier FLT3 inhibitors had more targets in addition to FLT3, which may have led to more side effects due to off-target activity. A simple way of saying this is that the earlier TKIs were more "dirty" TKIs, meaning they covered several targets. This could have increased efficacy through unknown mechanisms, but also increased toxicity. The newer TKIs, being more FLT3-specific, typically have fewer off-target toxicities, though they still may cause myelosuppression (low blood counts) and other side effects.

How is midostaurin used to treat AML? Can midostaurin get rid of the FLT3 mutation?

That's a very good question. When you treat people with midostaurin, there are different ways to capture response. So you know, the basic responses—whether they achieve remission, meaning there's no more blast in the bone marrow and the person has recovered their white cells, red cells, and platelets, and there's no evidence of disease by sensitive tests such as flow cytometry.

You could do an assay, such as LeukoStrat, a PCR test, to look for FLT3, which is how you initially diagnose the mutation at the time of diagnosis, either through PCR or NGS (next-generation sequencing), with PCR being a little more sensitive than NGS. You can use this assay to see if the FLT3 mutation has gone or whether it's present at a low level, which we would call measurable residual disease (MRD) positivity.

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, the mutation can go away, but we now have very sensitive tests, for example, looking at ten to the power of minus six (a million cells or more) and trying to find leukemia cells among those cells. We see whether there's complete absence of leukemia cells or a small presence, and even a small presence may predict for poor outcomes compared to a complete absence of leukemia cells.