Midostaurin

Midostaurin is an oral anticancer medicine belonging to the multikinase inhibitor class. It blocks the activity of several protein kinases, particularly FMS-like tyrosine kinase 3 (FLT3) and KIT, which can contribute to abnormal cell growth and survival. In acute myeloid leukemia (AML), certain FLT3 gene mutations drive the growth of malignant blood cells. By inhibiting FLT3 signalling, midostaurin can help reduce the survival and proliferation of these abnormal cells. Its activity against KIT is relevant to selected systemic mast cell disorders, in which abnormal mast cells accumulate in tissues and organs. Midostaurin is supplied as oral capsules and is taken with food according to the prescribed schedule. It is used with standard chemotherapy for eligible adults with newly diagnosed FLT3-mutation-positive AML and as a single agent for adults with aggressive systemic mastocytosis, systemic mastocytosis associated with a haematological neoplasm, or mast cell leukaemia, subject to local regulatory approval. Treatment requires specialist oversight because side effects can affect the gastrointestinal system, blood counts, lungs, and other organs. Genetic testing, review of concurrent medicines, and appropriate clinical and laboratory monitoring help determine whether treatment is suitable and support safer use.

Midostaurin was developed as a multikinase inhibitor with activity against FLT3 and KIT, among other kinases. Its development in AML focused on patients whose leukaemia carries an activating FLT3 mutation, while its activity against KIT supported evaluation in advanced systemic mast cell disorders. The United States Food and Drug Administration (FDA) approved midostaurin in April 2017 for adults with newly diagnosed FLT3-mutation-positive AML in combination with chemotherapy and for adults with certain advanced systemic mastocytosis subtypes. The European Commission granted marketing authorisation in the European Union on 18 September 2017. The AML indication was supported by the RATIFY trial, which evaluated midostaurin alongside standard chemotherapy. Evidence for advanced systemic mastocytosis included clinical studies assessing response and disease-related outcomes in patients with limited treatment options. Approval status, eligible patient groups, and authorised uses can differ by country, so the current local prescribing information should be checked before treatment.

Midostaurin is indicated for adults with newly diagnosed acute myeloid leukemia (AML) that tests positive for a FLT3 mutation, in combination with standard induction chemotherapy containing daunorubicin and cytarabine, followed by consolidation chemotherapy containing high-dose cytarabine. For patients who achieve complete remission, maintenance treatment may be used according to the applicable prescribing information and treatment plan. Midostaurin is not indicated as single-agent induction treatment for AML. It is also indicated as monotherapy for adults with aggressive systemic mastocytosis, systemic mastocytosis associated with a haematological neoplasm, and mast cell leukaemia. These disorders involve abnormal mast-cell accumulation and may affect multiple organs. Selection for AML treatment requires confirmation of FLT3 mutation status using an appropriate validated test. The decision to use midostaurin should consider the specific diagnosis, disease characteristics, prior treatment, overall health, and locally approved indications.

Midostaurin is taken orally as 25 mg capsules with food, generally twice daily at approximately 12-hour intervals. For FLT3-mutation-positive AML, the usual dose is 50 mg twice daily on days 8 through 21 of each induction and consolidation chemotherapy cycle. Subsequent maintenance treatment may be given according to the approved regimen and specialist treatment plan. For aggressive systemic mastocytosis, systemic mastocytosis associated with a haematological neoplasm, and mast cell leukaemia, the usual adult dose is 100 mg twice daily, continued until disease progression or unacceptable toxicity. Antiemetic medication may be prescribed to help manage nausea and vomiting. Capsules should be swallowed according to the product instructions and should not be opened or crushed. If a dose is missed or vomited, patients should follow the prescribing instructions rather than taking an additional replacement dose. Dose interruptions or reductions may be necessary because of adverse effects or interactions. Treatment should be managed by a specialist familiar with the relevant disease and current prescribing information.

Common side effects vary according to the condition being treated and whether midostaurin is combined with chemotherapy. In patients receiving treatment for AML, reported effects include nausea, vomiting, mouth sores or mucositis, headache, muscle and joint pain, small skin spots caused by bleeding, nosebleeds, fever associated with low white blood cell counts, and infections. Changes in blood glucose and heart electrical activity may also occur. In patients treated for advanced systemic mastocytosis, common effects include nausea, vomiting, diarrhoea, abdominal discomfort, swelling, fatigue, headache, musculoskeletal pain, constipation, fever, and shortness of breath. Some symptoms may be related to chemotherapy or the underlying disease rather than midostaurin alone. Supportive treatment, including antiemetics and appropriate monitoring, can help manage certain adverse effects. Patients should report persistent vomiting, worsening diarrhoea, unusual bleeding, fever, or new respiratory symptoms promptly.

Midostaurin can cause serious adverse effects, including interstitial lung disease or pneumonitis, which may be life-threatening or fatal. New or worsening cough, breathlessness, or other unexplained respiratory symptoms require prompt medical assessment, and treatment should be discontinued when drug-related pulmonary toxicity is suspected without an infectious explanation, in accordance with prescribing guidance. Severe allergic reactions can occur, and the medicine may cause harm to an unborn baby. In patients receiving chemotherapy for AML, severe infections, febrile neutropenia, low platelet counts, and other blood-related complications require close attention. Gastrointestinal bleeding and significant abnormalities in heart rhythm measurements may also occur. Patients should be monitored for signs of infection, bleeding, breathing difficulties, and other serious reactions. Treatment interruption, dose reduction, or discontinuation may be required depending on the nature and severity of toxicity. Midostaurin should not be used in patients with known hypersensitivity to the medicine or its ingredients.

Before starting midostaurin, clinicians should review the patient's medical history, current medicines, blood counts, liver and kidney function, and relevant cardiovascular and respiratory conditions. FLT3 mutation testing is necessary when considering treatment for AML. Pregnancy status should be assessed in patients who could become pregnant. Midostaurin may cause fetal harm; effective contraception is advised during treatment and for four months after the final dose for patients of reproductive potential and for male patients with partners who could become pregnant, according to prescribing information. Strong CYP3A4 inhibitors, including certain azole antifungals, may increase midostaurin exposure and the risk of toxicity, while strong CYP3A4 inducers may reduce its effectiveness. Medication review is essential before adding or stopping prescription medicines, over-the-counter products, or herbal supplements. Particular attention should be paid to medicines that can prolong the QT interval, and electrocardiogram monitoring may be appropriate. Patients should not start or stop interacting medicines without consulting their treating clinician.

Confirm the diagnosis and relevant biomarker results before treatment, particularly FLT3 mutation status in AML. Coordinate midostaurin with the planned chemotherapy schedule and verify the intended dose, administration days, and treatment phase. Review the full medication list for CYP3A4 interactions and assess whether electrocardiogram monitoring or electrolyte correction is needed. Establish baseline blood counts, liver and kidney function, and respiratory status, with follow-up assessments based on the disease, treatment combination, and clinical condition. Provide anticipatory counselling about nausea, vomiting, diarrhoea, infection symptoms, unusual bleeding, and respiratory warning signs. Ensure that patients understand how to take capsules with food and what to do if a dose is missed or vomited. Check pregnancy prevention requirements and discuss potential fetal risks where relevant. Pharmacists should follow product-specific storage and handling instructions and confirm any dose changes with the oncology team. Regularly assess treatment response and tolerability, and promptly evaluate symptoms that may require supportive care, dose modification, or discontinuation.