Differentiation Syndrome

Differentiation syndrome is a group of severe reactions to drugs used to treat acute myeloid leukemia (AML). It’s most commonly linked to drug treatments for an AML subtype called acute promyelocytic leukemia (APL).

The drugs used to treat APL are extremely effective, curing up to 9 in 10 people with APL. But in some people, they trigger the potentially life-threatening symptoms associated with differentiation syndrome. 

This is why your healthcare team will keep a close watch on you in the hospital if you’re receiving drug therapies known to put people at risk. They’ll provide treatment at the first signs of differentiation syndrome to keep you safe.

What drugs may cause differentiation syndrome?

The most common drug therapies tied to this condition are called differentiation agents. They’re named after how they work. They fight cancer by getting cancerous blast cells to mature (differentiate) into normal white blood cells.

These drug therapies are:

• All-trans-retinoic acid (ATRA)
• Arsenic trioxide (ATO)

Up to 1 in 5 people with acute promyelocytic leukemia (APL) treated with ATRA or ATO develop differentiation syndrome.

Less often, drugs used to treat acute myeloid leukemia that’s not APL can cause differentiation syndrome. These drugs include:

• IDH inhibitors, like enasidenib, ivosidenib and olutasidenib
• Menin inhibitors, like bleximenib, enzomenib, revumenib and ziftomenib
• FLT3 inhibitors, like gilteritinib and quizartinib

Symptoms of differentiation syndrome

Signs and symptoms can progress fast once they start. They include:

• Fever
• Shortness of breath or trouble breathing
• Extreme weight gain from fluid retention (more than 11 pounds, or 5 kilograms)
• Fluid buildup around your heart and lungs
• Swelling in your arms, legs or neck
• Low blood pressure
• Kidney failure

Symptoms usually start within seven to 12 days after starting treatment with ATRA and/or ATO. Severe forms of the syndrome usually start closer to the one-week mark, while more moderate forms often show up closer to two weeks.

But there’s no set timeline. Depending on the drug type, symptoms can start anywhere from a few days to months after treatment begins.

​Differentiation syndrome causes

Researchers don’t know exactly why some people react to APL treatment. But studies suggest these anticancer drugs may cause leukemia cells to release a large amount of immune system substances called cytokines. They trigger damaging inflammation throughout your body. This is called cytokine release syndrome.

The damage can extend to blood vessels, causing fluid to leak out. This is called capillary leak syndrome. Signs of this syndrome, like low blood pressure and fluid buildup, happen as a result.

Risk factors

Most people with APL have a low white blood cell count (WBC). But those with a high WBC have a higher risk of developing differentiation syndrome.

In these cases, healthcare providers may prescribe a corticosteroid, like prednisone or dexamethasone, to decrease the risk of differentiation syndrome. These meds calm inflammation in your body.

How doctors diagnose this condition

Differentiation syndrome is a medical emergency that requires immediate treatment. This is why healthcare providers treat symptoms if they suspect you have it — even before confirming a diagnosis.

Tests used to diagnose it include:

• Blood tests: Your provider will check your blood cell counts. They’ll look for substances in your blood that may mean there’s organ damage.
• Imaging: They’ll take chest X-rays and, in some cases, CT scans to check for issues in your lungs. You may need an echocardiogram to check your heart.

Differentiation syndrome severity

Healthcare providers classify the condition’s severity based on the number of signs or symptoms a person has:

• Indeterminate: Up to two
• Moderate: Three
• Severe: Four or more

Severe differentiation syndrome may also mean that you’re showing signs of life-threatening complications, like organ failure.

Care teams act fast to prevent differentiation syndrome from becoming severe.

How is differentiation syndrome treated?

At the first sign of this condition, healthcare providers often give a corticosteroid, like dexamethasone, every 12 hours. Once symptoms start to go away, your provider may taper your dose.

In severe cases, you may need to stop anticancer therapy until your symptoms improve. But most people can continue ATRA/ATO while getting treatment for differentiation syndrome.

Depending on your situation, you may also need:

• Diuretics to manage fluid imbalances
• Blood products to boost low blood cells or platelets
• Oxygen support

Recovery time

Most people start to notice major improvements within 12 to 24 hours of starting corticosteroids.

When should I see my healthcare provider?

People with APL typically stay in the hospital for their therapy until the risk of differentiation syndrome is over. If you’re being treated as an outpatient and there’s a concern for differentiation syndrome, your provider may decide to keep you in the hospital overnight for observation.

Let your healthcare provider know if you’re having symptoms.

If you’re at home and having symptoms like a fever, chest pain or difficulty breathing, call 911 or your local emergency number immediately.

What is the prognosis for differentiation syndrome?

The outlook is excellent. Most people fully recover with prompt treatment. The mortality rate from differentiation syndrome during APL treatment is 1%. This means that 99 out of 100 people survive this severe reaction. Acute promyelocytic leukemia itself is a highly curable disease.