RATIFY: What the Leukemia Trial Found

A mutation worth testing for

Acute myeloid leukemia moves fast. NCI says this type of cancer usually gets worse quickly if it is not treated.

About 30 percent of adults with newly diagnosed AML carry a mutation in a gene called FLT3. Roughly three-quarters of those are internal tandem duplications, which the trial authors note carry a poor prognosis because of a high relapse rate. FLT3 makes a receptor on the surface of blood-forming cells. When it is mutated, it stays switched on and keeps telling the cell to multiply.

Midostaurin is an oral kinase inhibitor that blocks it. RATIFY asked whether adding it to standard chemotherapy would help people live longer.

How the trial worked

Investigators screened 3,277 adults aged 18 to 59 with newly diagnosed AML for FLT3 mutations. Of those, 717 with a mutation were randomly assigned: 360 to midostaurin, 357 to placebo.

Everyone received the same standard chemotherapy. Induction with daunorubicin and cytarabine, then consolidation with high-dose cytarabine. Those still in remission afterwards entered a maintenance phase on midostaurin or placebo.

Randomization was stratified by the type of FLT3 change. A point mutation in the tyrosine kinase domain, called TKD, was one group. An internal tandem duplication, called ITD, was split into high and low, depending on the ratio of mutant to normal copies. There were 214 ITD-high, 341 ITD-low and 162 TKD.

Allogeneic stem cell transplant was allowed. The primary endpoint was overall survival.

What it found

Overall survival was significantly longer with midostaurin. The hazard ratio for death was 0.78, with a one-sided p of 0.009. Event-free survival also improved, with the same hazard ratio and a one-sided p of 0.002.

Median overall survival was 74.7 months with midostaurin and 25.6 months with placebo. That gap looks enormous, and here the trialists themselves supply the caution.

They wrote that the difference in medians may be large because of inflection points on the survival curves, and that the hazard ratio of 0.78 more accurately reflects the size of the benefit.

The four-year overall survival rate makes the same point in plainer terms: 51.4 percent against 44.3 percent. About seven percentage points.

Complete remission rates were 58.9 percent and 53.5 percent, a difference that was not statistically significant. The benefit was consistent across all three FLT3 subtypes, and severe adverse events occurred at similar rates in both groups.

FDA approved midostaurin, sold as Rydapt, on April 28, 2017 under priority review.

Why the medians mislead

This is worth a paragraph on its own, because the same trap appears in most cancer headlines.

A median is the point where half the group has had the event. When a survival curve is steep in one place and flat in another, small shifts in the curve can move that halfway point by years without changing very many people's outcomes.

A hazard ratio compares the rate of events across the whole follow-up period instead. A survival rate at a fixed time, like four years, compares two actual proportions.

When those three measures disagree in size, the median is usually the one exaggerating. Our page on trial endpoints sets out what each one measures.

What it changed in practice

Two things.

First, midostaurin became part of standard treatment for people with FLT3-mutated AML who are fit for intensive chemotherapy.

Second, and more broadly, it made rapid FLT3 testing at diagnosis necessary. The result only applies to people who carry the mutation, and treatment for AML starts within days. A test that takes three weeks is no use. Our page on FLT3 and NPM1 mutations covers what the report says.

When to get checked

NCI is direct that the early signs of AML can look like flu. Check with a doctor for:

• Weakness or feeling tired.
• Fever.
• Infection.
• Paleness, or loss of normal skin color.
• Bleeding, or easy bruising.

The combination is what matters. Fatigue plus bruising plus a fever that will not clear, arriving over a few weeks, is different from any one of them alone. AML moves fast enough that a same-week blood count is reasonable.

There is no screening test for leukemia in the general population. Diagnosis begins with a complete blood count, then bone marrow tests and genetic testing. Our page on acute myeloid leukemia covers what follows.

The group picture

SEER figures describe the whole United States population, across all ages and all subtypes of AML.

Five-year relative survival is 33.4 percent for cases from 2016 to 2022. An estimated 22,720 new cases and 11,500 deaths are projected for 2026. The median age at diagnosis is 70.

That last number matters for reading this trial.

What to keep in perspective

• RATIFY enrolled adults aged 18 to 59 who were fit for intensive chemotherapy. The median age at AML diagnosis is 70. The result does not extend to older or less fit patients.
• The result applies only to people whose leukemia carries a FLT3 mutation. Without it, the drug has no target.
• The p-values are one-sided, which is a less conservative test than the two-sided kind.
• Stem cell transplant was permitted and used, which makes it harder to attribute the whole benefit to the drug alone.
• Trial participants meet specific criteria, so findings may not describe everyone with this cancer.

Sources

• Stone RM et al., Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation, N Engl J Med 2017 — PubMed Central full text via NCBI E-utilities — https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=pmc&id=5754190&rettype=xml
• ClinicalTrials.gov API v2, NCT00651261 — https://clinicaltrials.gov/api/v2/studies/NCT00651261
• FDA Drugs@FDA, midostaurin (Rydapt, NDA 207997) — https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=207997
• NCI PDQ, Acute Myeloid Leukemia Treatment (Patient Version) — https://www.cancer.gov/types/leukemia/patient/adult-aml-treatment-pdq
• SEER Cancer Stat Facts, Acute Myeloid Leukemia — https://seer.cancer.gov/statfacts/html/amyl.html

How this article was prepared

An AI-assisted editorial system helped prepare this page. No named medical reviewer has reviewed it unless one is listed.

The National Cancer Information Foundation publishes Cancer Explained. This page is for learning. It is not medical advice and does not suggest a test or treatment.

See an error, old source, or unclear wording? Tell us.