The targeted agent midostaurin (PKC412), which is still in investigative stages, has received “breakthrough therapy” designation by the United States Food and Drug Administration (FDA) for the treatment of adults with acute myeloid leukemia. The breakthrough designation is intended for patients with newly diagnosed AML who test positive for the FLT3 mutation and are eligible for standard induction and consolidation chemotherapy.1

Acute myeloid leukemia (AML) is diagnosed in approximately 20,000 individuals each year in the United States. It is an aggressive leukemia, with the lowest survival rates of any acute leukemias. Standard therapy for AML has remained essentially unchanged in the past 25 years, demonstrating a clear need for novel strategies.

AML prevents certain immune cells from developing properly, leaving them in immature stages. These cancerous cells, referred to as “blasts,” are not able to fight infection as intended, and rapidly accumulate in the body. This crowds out other blood cells so that they are not able to carry out their essential functions.

Approximately one-third of patients with AML are shown to have a FLT3 mutation. This specific mutation is involved in the growth and survival of cancer cells. Patients with AML who have the FLT3 mutation have demonstrated a significantly shorter survival compared to those without the mutation.

Midostaurin, not yet approved by the FDA, is the first drug that targets the FLT3 mutation. Through binding to specific targets, midostaurin decreases the activity of FLT3 associated with cancer growth.

Breakthrough designation was instituted by the United States Food and Drug Administration (FDA) “to expedite the development and review of new medicines that treat serious or life-threatening conditions, if the therapy has demonstrated substantial improvement over an available therapy on at least one clinically significant endpoint.”

The clinical trial prompting the breakthrough designation for midostaurin was the phase III RATIFY (CALGB 10603) clinical trial, which evaluated the addition of midostaurin to standard therapy in AML.2

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The trial included patients with AML who tested positive for a FLT3 mutation. One group was treated with the addition of midostaurin to standard induction and consolidation chemotherapy, while the other group was treated with standard induction and consolidation chemotherapy plus placebo (inactive substitute). Outcomes of the two groups were directly compared.

  • The median time of overall survival was 74.4 months for the group of patients who received midostaurin/chemotherapy, compared with only 25.6 months for those who received chemotherapy/placebo.
  • Serious side effects were comparable between the two groups of patients.

The researchers concluded that the addition of midostaurin to standard induction and consolidation chemotherapy among patients with AML who have the FLT3 mutation significantly improves overall survival compared to standard therapy alone. Furthermore, the addition of midostaurin was not associated with an increase in serious side effects.

Although there is no guarantee that midostaurin will be approved by the FDA, breakthrough designation will significantly expedite the review process.


1). Novartis press release. Novartis drug PKC412 (midostaurin) receives Breakthrough Therapy designation from the FDA for newly-diagnosed FLT3-mutated acute myeloid leukemia (AML). Available at: . Accessed March 9, 2016.

2). Stone RM, et al. The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]). Presented at the 57th Annual Meeting of the American Society of Hematology.

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