1. Lovell, Alexandra PharmD

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What is midostaurin?

Midostaurin is an oral multitargeted kinase inhibitor with activity against FMS-like tyrosine kinase-3 (FLT3). It inhibits both the internal tandem duplication (ITD) and the tyrosine kinase domain (TKD) FLT3 mutant kinases, as well as KIT, PDGFR, VEGFR, and protein kinase C.


How does midostaurin work?

FLT3 is a tyrosine kinase which regulates the normal growth and proliferation of CD34 hematopoietic cells. When FLT3 is mutated, this can lead to overproduction of immature blast cells. Midostaurin inhibits the autophosphorylation of FLT3, preventing the activation of cell growth signaling pathways.


What is this approved for?

Midostaurin is approved for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) with FLT3 mutations when used in combination with cytarabine and daunorubicin induction and cytarabine consolidation. It is also approved to treat adults with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).


What is the basis for this approval in AML?

Midostaurin was approved for the treatment of AML based on the RATIFY trial, an international, phase III, randomized, placebo-controlled trial in young patients with newly diagnosed AML (N Engl J Med 2017;377(5):454-464). A total of 717 patients were randomized to receive induction therapy: cytarabine 200 mg/m2 IV continuously given days 1-7 plus daunorubicin 60 mg/m2 IV days 1, 3, and 5 with either midostaurin 50 mg orally twice daily, days 8-21 or placebo. Patients who achieved complete remission received 4 cycles of consolidation with high dose cytarabine 3 g/m2 with midostaurin or placebo. Maintenance after consolidation consisted of midostaurin 50 mg orally twice daily or placebo for 12 28-day cycles. The primary endpoint was overall survival (OS).


Median OS was 74.7 months versus 25.6 months in the midostaurin group and the placebo group, respectively, with a HR for death of 0.78 (95% CI, 0.63-0.96; P=0.009). The 4-year OS was 51.4 percent in the midostaurin group compared to 44.3 percent in the placebo group. Complete remissions were seen in 58.9 percent and 53.5 percent of the midostaurin and placebo groups, respectively. Median disease-free survival was 26.7 months in the midostaurin group compared to 15.5 months in the placebo group, likely due to the lower risk of relapse with midostaurin. Anemia and rash occurred more often with midostaurin; however, there was no difference in neutrophil or platelet count recovery.


How do you administer this drug for the treatment of AML?

When treating AML, midostaurin is administered at a dose of 50 mg by mouth twice daily with food on days 8-21 of induction and consolidation cycles.


Are there any pre-medications needed?

Midostaurin has moderate to high emetic risk. A 5-HT3 receptor antagonist should be considered prior to taking midostaurin.


What are the common side effects associated with midostaurin (> or =20%)?

The most common adverse events were febrile neutropenia, nausea, vomiting, mucositis, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, and upper respiratory tract infections. Increased alanine aminotransferase, hypernatremia, and hypocalcemia were also reported.


What are the uncommon side effects associated with midostaurin (less than 10%)?

Uncommon side effects include cellulitis, fungal infections, hyperuricemia, tremor, eyelid edema, hypertension, pericardial effusion, pleural effusion, dry skin, thrombosis, and increased weight.


Are there any important drug interactions I should be aware of?

Midostaurin is primarily metabolized by CYP3A4. Coadministration with CYP3A4 inhibitors may increase midostaurin exposure, leading to increased toxicity; consider alternative therapies. If the interaction cannot be avoided, monitor patients closely, especially during the first week of therapy. Coadministration with strong CYP3A4 inducers may decrease midostaurin concentrations, leading to reduced efficacy, and should be avoided.


How do I adjust the dose in the setting of renal or hepatic insufficiency?

Mild to moderate renal or hepatic impairment did not have a significant effect on the pharmacokinetics of midostaurin and no dose adjustments are needed. Dosing has not been studied in patients with severe renal or hepatic impairment.


What should my patients know about midostaurin?

Patients should tell their health care team if they start or discontinue any medications due to drug interactions.


Women should avoid pregnancy due to the risk for embryo-fetal toxicity and should use effective contraception during treatment and at least 4 months after the last dose of midostaurin.


What else should I know about midostaurin?


* Consider regular assessments of the QTc interval if a patient is taking concomitant drugs that can prolong the QTc interval.


* Fatal cases of pulmonary toxicity have been reported with midostaurin. Patients should seek medical attention for new pulmonary symptoms due to the risk of interstitial lung disease or pneumonitis.


What useful links are available regarding midostaurin for the treatment of AML?


* Highlights of Prescribing Information:


* FDA Approval Announcement:


Any ongoing clinical trials related to midostaurin?

Midostaurin is being studied for other AML populations including FLT3-negative, core-binding factor, minimal residual disease positivity, and in patients who cannot tolerate intensive chemotherapy. More information is available about these clinical trials at


ALEXANDRA LOVELL, PHARMD, is a Clinical Pharmacy Specialist in the Leukemia Department at MD Anderson Cancer Center in Houston, and serves as an author for the Pharmacy Forum column. JANELLE E. MANN, PHARMD, BCOP, is the Manager of Clinical Pharmacy Services and practices as an Ambulatory Clinical Oncology Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., She serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.

Alexandra Lovell, Ph... - Click to enlarge in new windowAlexandra Lovell, PharmD. Alexandra Lovell, PharmD
Janelle E. Mann, Pha... - Click to enlarge in new windowJanelle E. Mann, PharmD, BCOP. Janelle E. Mann, PharmD, BCOP
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