EU Approves Midostaurin for AML, Advanced Systemic Mastocytosis


The European Commission has approved midostaurin (Rydapt) for adults with newly diagnosed FLT3-positive acute myeloid leukemia and advanced systemic mastocytosis.

Bruno Strigini, CEO

The European Commission has approved midostaurin (Rydapt) for adults with newly diagnosed FLT3-positive acute myeloid leukemia (AML) and advanced systemic mastocytosis (SM), including aggressive systemic mastocytosis (SM), SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia.

Midostaurin is approved for AML in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation, and then as maintenance monotherapy for patients achieving a complete response. For patients with SM, the drug is approved as a monotherapy.

Midostaurin is now available for patients in all 28 EU member states, plus Iceland, Liechtenstein, and Norway. The FDA approved the drug for these indications in April.

Study results published in the New England Journal of Medicine showed that midostaurin was associated with a 23% reduced risk of death in patients with AML.1 The drug induced an overall response rate of 59.6% (95% CI, 48.6-69.8%) in patients with SM.2

“Novartis is proud that we can deliver Rydapt, a breakthrough medicine, to patients with serious and hard-to-treat diseases where there are few treatment options,” Bruno Strigini, CEO, Novartis Oncology, the manufacturer of midostaurin, said in a statement. “For patients with FLT3-mutated AML, there have been no meaningful advancements in more than 25 years and with Rydapt they now have a targeted medicine that could significantly extend their lives.”

The European Medicines Agency’s Committee for Medicinal Products for Human Use issued a positive opinion on midostaurin in July based on phase III results from the RATIFY trial in AML and 2 single-arm, open-label studies of patients with SM. In RATIFY, the median overall survival (OS) was 74.7 months for the combination versus 25.6 months for placebo (hazard ratio [HR], 0.77; 95% CI, 0.63-0.95; one-sided P = .0078).

In RATIFY, also known as CALGB 10603, 717 patients with newly diagnosed FLT3-mutant AML were randomized to standard induction and consolidation chemotherapy plus midostaurin (n = 360) or placebo (n = 357). Hydroxyurea was allowed for up to 5 days prior to beginning therapy, while FLT3 test results were obtained.

During induction therapy, 60 mg/m2 daunorubicin was administered on days 1 to 3 along with 200 mg/m2 cytarabine on days 1 to 7. Oral midostaurin was administered at 50 mg twice daily on days 8 to 22. If patients achieved a complete remission, patients received consolidation therapy with 3 g/m2 cytarabine, plus either placebo or midostaurin. After 4 cycles of consolidation, patients continued on maintenance therapy with either midostaurin or placebo for up to 1 year.

The most frequent adverse reactions (≥30%) associated with midostaurin were febrile neutropenia, nausea, exfoliative dermatitis, vomiting, headache, petechiae, and pyrexia. The most frequent Grade 3/4 adverse reaction (≥5%) was febrile neutropenia, lymphopenia, device-related infection, exfoliative dermatitis, hyperglycemia and nausea

For advanced SM, the approval is based on two single-arm open-label multicenter trials, including the open-label phase II CPKC412D2201 study. Patients (n =116) were assigned to twice-daily 100 mg oral midostaurin. Eighty-nine patinets with mastocytosis-related organ damage were eligible for inclusion in the primary efficacy population; 16 had aggressive systemic mastocytosis, 57 had systemic mastocytosis with an associated hematologic neoplasm, and 16 had mast-cell leukemia. The primary outcome was the best overall response.

The study used an adapted Fleming two-stage design. The planned sample size for stage 1 was 40 patients. If efficacy was declared, an extension phase would be initiated in which 40 additional patients would be enrolled. According to the study protocol, the primary analysis required at least 12 months of patient follow-up, which corresponded to a data-cutoff date of July 9, 2013.

The response rate for the primary efficacy population (n = 89) was 60% (95% CI, 49-70; P <.001), with 45% having a major response and 15% having a partial response.

Median OS was 28.7 months, and the median progression-free survival was 14.1 months. Among the 16 patients with mast-cell leukemia, the median OS was 9.4 months (95% CI, 7.5-not estimated).

In advanced SM, the most frequent adverse reactions were nausea (79%), vomiting (66%), and diarrhea (54%). The most frequent Grade 3/4 adverse reactions were fatigue, sepsis, pneumonia, febrile neutropenia and diarrhea.

Of the 116 patients in the intention-to-treat population, 84 (72%) discontinued treatment and 32 (28%) were receiving ongoing treatment at the time of data cutoff.


  1. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017;377(5):454-464.
  2. Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med. 2016; 374(26):2530-2541.
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