On April 28, 2017, the Food and Drug Administration (FDA) approved a new drug for the treatment of acute myeloid leukemia (AML) –Midostaurin (generic name: midostaurin, trade name: Rydapt, manufactured by Novartis). It is an oral multitargeted kinase inhibitor for the treatment of adult patients with newly diagnosed acute myeloid leukemia carrying the FLT3 mutation.
In parallel, the FDA also approved the FLT3 Mutation Assay (LeukoStrat CDx FLT3 Mutation Assay, manufactured by Invivoscribe Technologies) as a companion diagnostic for patients with acute myeloid leukemia by detecting The LeukoStrat CDx FLT3 Mutation Assay, manufactured by Invivoscribe Technologies, is used as a companion diagnostic to screen patients with acute myeloid leukemia for mutations in the FLT3 gene that are suitable for midostaurin therapy.
In addition, midostaurin is approved for the treatment of adult patients with certain types of rare blood disorders, including aggressive systemic mastocytosis (ASM), systemic mastocytosis with hematologic neoplasia (SM-AHN), and mast cell leukemia (MCL).
Midostaurin is the first targeted therapy approved in combination with chemotherapy for the treatment of AML and the first major breakthrough in AML in more than 20 years.
What is FLT3-mutated acute myeloid leukemia?
Acute myeloid leukemia is a rapidly progressive cancer with an excess of white blood cells in the blood and bone marrow. About 30% of acute myeloid leukemias carry the FLT3 mutation.
FLT3 is known as FMS-like tyrosine kinase 3, also known as CD135. in vivo, when the FLT3 ligand binds to the FLT3 receptor, it leads to FLT3 receptor dimerization or autophosphorylation, signaling downstream, inhibition of tumor cell apoptosis, and stimulation of tumor cell proliferation and differentiation. Therefore, FLT3 mutation in AML predicts a short remission period and easy relapse of the disease. And once acute myeloid leukemia relapses, the survival of patients becomes very short.
What is midostaurin?
Midostaurin, a direct derivative of indolocarbazole and astaxanthin, is a multikinase inhibitor that targets multiple proteins in cells and blocks several cell growth-promoting enzymes to exert anti-tumor effects.
In acute myeloid leukemia, midostaurin targets the FLT3 mutation in addition to serine/threonine protein kinase C, VEGFR-2, c-KIT, and PDGFRα/β receptors, all mutations associated with acute myeloid leukemia. In addition, in aggressive SM, midostaurin targets a protein called KIT D816V.
When targeting the FLT3 antigen, midostaurin competes with the FLT3 ligand to bind the FLT3 receptor, thereby blocking the FLT3 signaling pathway, accelerating tumor apoptosis, and promoting cancer cell differentiation for therapeutic effect.
Evidence of efficacy: 22% reduction in risk of death
The approval of midostaurin was based primarily on an international multicenter phase III clinical trial, the results of which were presented by investigators at the American Society of Hematology (ASH) 2015 Annual Meeting. The study included 717 patients aged 18 to 60 years with newly diagnosed FLT3 mutation-positive acute myeloid leukemia who were randomly assigned to either midostaurin + standard chemotherapy (zofranil + cytarabine) or placebo + standard chemotherapy.
Results showed that midostaurin reduced the risk of death by 23% compared with placebo. Four years after diagnosis, more than half (51.4%) of patients treated with midostaurin were still alive. After treatment, a similar proportion of patients in both groups were able to undergo stem cell transplantation, and the time required for treatment was similar.
Adverse effects: need to be alert for lung injury
Common side effects of midostaurin in patients with acute myeloid leukemia include febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, nosebleeds, device-related infections, hyperglycemia, and upper respiratory tract infections.
This medication should not be used in patients who are allergic to other ingredients in the medication, and should not be taken by pregnant or breastfeeding women.
Interstitial lung disease, some of it fatal, has occurred in patients treated with midostaurin monotherapy or in combination with chemotherapy, and the FDA recommends that physicians monitor and discontinue midostaurin if patients show signs or symptoms of lung injury.
How do I use midostaurin?
According to the approved product insert, the recommended use and dosage of midostaurin is as follows:
- Recommended dosing: 50 mg of midostaurin orally twice daily on days 8 through 21 for induction therapy and 50 mg of midostaurin orally twice daily on days 8 through 21 for consolidation therapy with high doses of cytarabine and midostaurin.
- Antiemetics may be given prophylactically to reduce nausea and vomiting prior to oral treatment with this drug.
With advances in genetic testing technology, AML is no longer seen as a single disease, but as a group of diseases with different genetic mutations. Hypothetically, two patients with acute myeloid leukemia may have the same leukemia when viewed under a microscope, but at the genetic level, they have completely different genetic mutations and clinical features and do not require the same treatment.
While midostaurin is not yet available in China, it and other targeted drugs that target mutations associated with acute myeloid leukemia represent the future of precision therapy for acute myeloid leukemia.