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. Patients were then given midostaurin versus placebo. So the comparison was 7+3 plus midostaurin versus 7+3 plus placebo. Midostaurin was given a flat dose of 50 mg twice a day, starting at day eight and continuing through day 21 of chemotherapy. It was also added during consolidation chemotherapy. 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 receiving placebo.
There are different ways to look at how much that survival benefit was, because many patients went to transplant as well. 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. These need to be monitored very closely, especially when giving with other fungal medicines or infection-preventing medications. Side effects are usually managed with supportive measures and medicines for GI symptoms, like anti-nausea and anti-diarrhea medications. Sometimes a medicine may be held temporarily until the patient feels better, and then restarted. For interactions with other medicines, supportive drugs from a different class are preferred to minimize interactions with midostaurin.
What is the difference between first-generation and second-generation FLT3 inhibitors? Broadly speaking, FLT3 inhibitors are becoming more selective with each generation. Earlier FLT3 inhibitors, like sorafenib and midostaurin, were less specific and targeted multiple proteins in addition to FLT3. Newer agents like gilteritinib and quizartinib are more specific to FLT3, which reduces off-target toxicities but may not work for other mutations. Early inhibitors were “dirty” TKIs, meaning they affected multiple targets, which could increase efficacy in unknown ways but also increased side effects. The novel TKIs mainly target FLT3 and mainly cause myelosuppression or low blood counts, without too many off-target effects.
How can a patient tell if midostaurin has successfully eliminated their AML cells? Response is measured by remission status—no blasts in the bone marrow, recovery of white cells, red cells, and platelets, and no disease evidence in sensitive tests like flow cytometry. Molecular assays, such as LeukoStrat PCR, can detect the FLT3 mutation at diagnosis and track it over time. Measurable residual disease (MRD) testing detects very low levels of AML cells. MRD-negative patients generally have better outcomes in terms of relapse and overall survival.
Who should take midostaurin and how is it administered? Midostaurin is approved as front-line therapy for newly diagnosed AML patients with FLT3 mutations who are fit for intensive chemotherapy. Gilteritinib, by contrast, is approved for relapsed or refractory AML with FLT3 mutations. Fitness for intensive chemotherapy depends on age, comorbidities, and performance status, usually assessed 2–4 weeks prior to diagnosis. Midostaurin is given orally, typically starting on day eight of induction at 50 mg twice daily for 14 days, continuing for 14 days per consolidation cycle. If the patient proceeds to transplant, midostaurin is stopped. In cases where transplant is not pursued, it can be considered as maintenance, though this is not standard at many centers. During induction, midostaurin is combined with 7+3 (cytarabine plus an anthracycline), and during consolidation, with HiDAC (high-dose cytarabine).
Can midostaurin cure AML? Midostaurin can help achieve remission and serve as a bridge to transplant for patients with FLT3-ITD mutations, who are considered intermediate- to high-risk. While it contributes to deep remission, by itself it is unlikely to cure AML. Most patients benefit from consolidation with stem cell transplant. Ongoing research is improving outcomes with newer FLT3 inhibitors, including quizartinib, which has shown a survival benefit in recent studies. Novel agents are being developed to be even more effective with better tolerability.