RATIFY – Midostaurin for AML

Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation.

Stone RM, Mandrekar SJ, Sanford BL, et al.

N Engl J Med. 2017 Aug 3;377(5):454-464. [Full Text]

Summary by Harrison Winters

Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with large cytogenetic and mutational heterogeneity. Recent advances on the various genes implicated in the pathogenesis of AML have allowed for the development of new targeted therapies.

One mutation in a protein known to modulate cellular differentiation and proliferation in AML is FLT3 (fms-related tyrosine kinase 3 gene). This mutation confers a poor prognosis in patients and is present in approximately 30% of adults with newly diagnosed AML [1]. RATIFY was a phase 3 trial designed to evaluate the effectiveness of a targeted FLT3 inhibitor, midostaurin, in addition to standard chemotherapy, in patients with newly diagnosed FLT3+ AML. The results of this landmark clinical trial went on to support US FDA approval of midostaurin in addition to standard and consolidation chemotherapy for the treatment of newly diagnosed FLT3-mutated AML.

Patient Population and Design

Patients 18 to 59 years old who had newly diagnosed AML and had not previously received chemotherapy were screened for FLT3 mutations. Those with the FLT3 mutation were enrolled if they met other inclusion criteria including: a bilirubin level < 2.5 times the upper limit of normal and the absence of other major coexisting illnesses.

Treatment groups for those with AML + FLT3 mutation were standard chemotherapy plus either midostaurin or placebo. Standard chemotherapy was defined as: Induction (Daunorubicin/Cytarabine) and Consolidation (High-Dose Cytarabine). Patients were randomized to each treatment group in a double blinded fashion. Randomization was stratified according to FLT3 mutation subtype: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed.

Outcomes and Safety Measures

The primary outcome was overall survival, defined as the time from randomization to death from any cause. There were numerous secondary outcomes: (1) event free survival, defined as the time from randomization to relapse, death from any cause, or failure to achieve complete remission on or before 60 days of protocol therapy initiation, (2) disease free survival, defined as the time from complete remission to relapse or death from any cause, (3) complete response rate, percentage of participants who achieved a complete response, (4) overall survival, censoring participants who receive a stem cell transplant at the time of the transplant.

Adverse events were tracked with an emphasis on Grade 3, 4, or 5 adverse events.

  • Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL.
  • Grade 4: Life-threatening consequences; urgent intervention indicated.
  • Grade 5: Death related to AE.


A total of 717 patients from 17 countries were enrolled. The median age was 47.9 years old; 55.5% were female; 11% were a race other than White/Caucasian. Transplantation was common, with 57% undergoing transplantation at some point during the disease course. It was performed during the first complete remission in similarly in both groups: 28.1% of midostaurin patients and in 22.7% of the placebo group (P = 0.10).

The primary outcome of overall survival was significantly longer in the midostaurin group: 74.7 months (95% CI, 31.5-NR) versus 25.6 months in the placebo group (95% CI, 18.6-42.9), HR 0.78 [95% CI, 0.63 to 0.96; P =0.0009].

Midostaurin also had favorable results in multiple secondary outcome. Event free survival: 8.2 months (95% CI, 5.4-10.7) midostaurin compared to 3.0 months (95% CI, 1.9-5.9) placebo; P = 0.0002. Disease free survival: 26.7 months (95% CI, 19.4-NR) midostaurin versus 15.5 months (95% CI, 11.3-23.5) placebo; P=0.01. Complete response rate: 68% midostaurin versus 61% placebo; p=0.04.

On the other hand. overall survival after censoring participants who received a stem cell transplant at the time of the transplant was similar : 63.7% in the midostaurin group and 55.7% in the placebo group; p=0.08.


The results from the RATIFY trial demonstrated the clinical efficacy of using midostaurin in addition to standard chemotherapy for FLT3 mutant AML. Specifically, the addition of midostaurin resulted in a overall survival that was significantly longer in the midostaurin group, with a 22% lower relative risk and 7% lower absolute risk of death in patients diagnosed with FLT3 mutant AML at 4 years. Additionally, midostaurin had a statistically significant effect on the complete response rate, event free survival, and disease free survival, illustrating a meaningful advantage of this drug on achieving complete response and maintaining remission when compared to placebo. Furthermore, overall survival was longer in the midostaurin group among patients with two predominant subtypes of FLT3 mutations, demonstrating applicability to at least two genotypes. The therapy was relatively well tolerated.  Significant toxicities included anemia, rash, and nausea.

An important observation made in this trial was the number of patients who underwent stem cell transplantation following the first remission (57% across both treatment arms), which emerged as a leading treatment of FLT3 mutant AML after the trial started. While the overall survival rate was higher in the midostaurin group when compared to placebo in patients who underwent transplant, this data did not reach statistical significance. It is unclear whether early transplant may have limited exposure to midostaurin and thus diminished its effect.  It is also possible that the survival rate was higher in the midostaurin group as more patients in this group received transplant within the first documented complete response; however, this data did not reach statistical significance [2]. The role of midostaurin after transplant therefore remains unclear.

After RATIFY was published, another type of FLT3 inhibitor known as gilteritinib, which is more selective than midostaurin for FLT3, was approved by the FDA to treat relapsed or refractory cases of FLT3 mutant AML [3].  Interestingly, midostaurin was not shown to confer an effect on survival or remission rates for patients with relapsed or refractory disease [2]. Currently, a phase II clinical trial is underway to directly compare gilteritinib and midostaurin in the treatment of newly diagnosed AML, further advancing our knowledge on how to best treat this type of aggressive leukemia.

F: Follow upUp to 10 years
R: RandomizationYes, stratified by FLT3 subtype
I: Intention to treatYes
S: Similar at baselineFemale sex 51.7% midostaurin vs. 59.4% placebo group
B: BlindingYes
E: Equal treatmentYes
S: Source (funding)National Cancer Institute and Novartis
  1. Daver, N., Schlenk, R. F., Russell, N. H., & Levis, M. J. (2019). Targeting FLT3 mutations in AML: review of current knowledge and evidenceLeukemia33(2), 299-312.
  2. Keiffer, G., Aderhold, K. L., & Palmisiano, N. D. (2020). Upfront Treatment of FLT3-Mutated AML: A Look Back at the RATIFY Trial and BeyondFrontiers in Oncology10.
  3. Perl, A. E., Martinelli, G., Cortes, J. E., Neubauer, A., Berman, E., Paolini, S., … & Levis, M. J. (2019). Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AMLNew England Journal of Medicine381(18), 1728-1740.