Differentiation Syndrome

What is differentiation syndrome?

Differentiation syndrome is a group of severe reactions to drugs used to treat two kinds of acute leukemia, or blood cancer: (1) acute promyelocytic leukemia (APL) or (2) acute myeloid leukemia (AML). If your healthcare provider suspects differentiation syndrome, they may treat the symptoms even before confirming a diagnosis to reduce the risk of life-threatening complications.

What are differentiation agents?

Differentiation agents are a type of treatment that providers use for APL. Acute promyelocytic leukemia is more sensitive than other types of AML to agents that cause cells to mature. As a result, healthcare providers typically don’t use standard chemotherapy medications to treat APL. Instead, they use treatments called differentiation, which get their name because they help cells mature (differentiate) into normal white blood cells from the blast cell stage (or cancer cell).

Like other types of cancer treatments, these drugs cause changes in cancer cells that can slow or stop their growth. Healthcare providers may use differentiation agents alone, in combination with each other or together with chemotherapy. They can successfully treat APL. In some people with APL, however, differentiation agents can sometimes trigger potentially severe reactions.

What drugs may cause differentiation syndrome?

Differentiation agents to treat APL may cause differentiation syndrome. They include:

• All-trans-retinoic acid, or tretinoin (ATRA), a form of vitamin A.
• Arsenic trioxide (ATO), a form of arsenic.

Healthcare providers may use a group of chemotherapy drugs called isocitrate dehydrogenase (IDH) inhibitors for certain people with AML. IDH inhibitors (ivosidenib and enasidenib) can also cause differentiation syndrome. Agents such as FLT3 inhibitors can cause differentiation syndrome as well (midostaurin, gilteritinib).

People who may need IDH inhibitors include those whose cancer:

• Has come back (recurred).
• Is difficult to treat.
• Harbors a mutation that’s present (either IDH1 or IDH2 mutation).
• Can’t undergo standard chemotherapy.

Who gets differentiation syndrome?

Most people with APL have a low WBC (white blood count), but those with a high WBC have a higher risk of developing differentiation syndrome. In these cases, healthcare providers often prescribe prednisone (or dexamethasone) to decrease the risk of differentiation syndrome.

How common is differentiation syndrome?

Differentiation syndrome is a relatively rare condition. AML accounts for about only 1% of all cancers but is one of the most common types of leukemia in adults. About 1 in 250,000 people in the U.S. have acute promyelocytic leukemia.

Of the people diagnosed with AML and APL:

• People with APL who received ATRA and ATO: Up to 25% developed differentiation syndrome.
• People with AML who received IDH inhibitors: About 14% to 19% developed differentiation syndrome.

What causes differentiation syndrome?

Researchers don’t know exactly why some people react to APL treatment. Early studies suggest anticancer drugs may cause leukemia cells to rapidly release a large amount of immune system substances (cytokine release syndrome). Uncontrolled inflammation can also lead to a range of symptoms, from mild to severe.

What are the symptoms of differentiation syndrome?

Signs of differentiation syndrome in people with APL usually develop within one to two weeks after starting treatment with ATRA and/or arsenic trioxide. Symptoms may take longer if you receive IDH inhibitor treatment for AML (can happen from one day of exposure up to five to six months while on therapy).

Common symptoms include:

• Cough.
• Excess fluid buildup around your heart and lungs (pleural effusion).
• Kidney failure (renal failure).
• Low blood pressure (hypotension).
• Low level of oxygen in your blood (hypoxemia).
• Shortness of breath (dyspnea).
• Swelling (inflammation) of your arms, legs and neck.
• Unexplained fever.
• Unexplained weight gain.

What are the complications of differentiation syndrome?

Differentiation syndrome can also lead to severe conditions, such as:

• Heart failure.
• Kidney failure (renal failure).
• Lung failure.
• Bleeding from the lung (pulmonary hemorrhage).
• Pneumonia.
• Sepsis.

Talk to your healthcare provider if you experience symptoms. Call 911 immediately if you have difficulty breathing or chest pain. People with APL typically stay in the hospital for their therapy until the risk of differentiation syndrome is over.

How is differentiation syndrome diagnosed?

It’s challenging to diagnose differentiation syndrome in people with APL because many other conditions cause similar symptoms. In severe cases, healthcare providers treat symptoms as soon as they suspect differentiation syndrome — even before confirming a diagnosis.

Your healthcare provider recommends tests to confirm a diagnosis and rule out other conditions. Tests may include:

• Complete blood count (CBC).
• Chest X-ray.
• Echocardiogram.
• CT scan chest.
• Bronchoscopy.
• Bloodwork.

Is there a cure for differentiation syndrome?

Most people with acute promyelocytic leukemia can fully recover from differentiation syndrome with prompt, effective treatment. APL itself is a highly curable disease.

What is the treatment for differentiation syndrome?

Healthcare providers typically treat symptoms of differentiation syndrome with a corticosteroid or glucocorticoid such as dexamethasone. In severe cases, your healthcare provider may also recommend temporarily stopping anticancer therapies until your symptoms improve.

Most people with APL stay in the hospital until the risk of differentiation syndrome is past. If you’re being treated as an outpatient and there’s a concern for differentiation syndrome, they may decide to keep you in the hospital overnight for management or observation. Your healthcare provider works to confirm your diagnosis and effectively treat any conditions causing symptoms.

How can I reduce my risk of developing differentiation syndrome?

There isn’t anything you can do to reduce your risk of developing differentiation syndrome. If you receive chemotherapy drugs or other anticancer medications, alert your healthcare provider to any symptoms you experience. Also, know what signs/symptoms to look for (see above) and call your provider if you have concerns.

What’s the outlook for differentiation syndrome?

The outlook for differentiation syndrome is generally good for most people. In most cases, you continue anticancer therapy during or after treatment with steroids. Your healthcare team will discuss your treatment options with you.

When should I seek care for differentiation syndrome?

Talk to your healthcare provider if you experience any signs of differentiation syndrome during cancer treatment. It may be difficult for you or your provider to tell if your symptoms are due to anticancer therapy or other conditions. Prompt treatment can ease symptoms and reduce the risk of complications.

A note from Cleveland Clinic

Cancer treatment is challenging enough. It can be discouraging to find out that your treatment itself can cause side effects. Differentiation syndrome is a group of potentially life-threatening reactions to blood cancer treatments, which can resolve if identified and treated. The symptoms can worsen quickly, so your healthcare provider may treat you even before test results confirm differentiation syndrome. Prompt medical care can ease your symptoms and get you back on the road to treatment and recovery.