What is Differentiation Syndrome?

What is differentiation syndrome?

Differentiation syndrome (DS) is a rare condition that happens after treatment for certain types of acute leukemia, including acute promyelocytic leukemia (APL) and other types of acute myeloid leukemia (AML).  

Differentiation syndrome occurs shortly after treatment with certain types of medication. These include: 

• Differentiation agents
• Isocitrate dehydrogenase (IDH) inhibitors
• FLT3 inhibitors
• Menin inhibitors

Differentiation syndrome can start as soon as one day after treatment begins. It usually starts within one to three weeks, but it can start a few months after treatment. 

Differentiation syndrome can become life-threatening, so it is important that it is identified and treated early.  

What are the symptoms of differentiation syndrome?

Differentiation syndrome can look different from person to person. The symptoms may be minor at first or become severe, and they can develop quickly.  

Common symptoms of differentiation syndrome include:

• Fever
• Difficulty breathing
• Low blood pressure
• Weight gain 
• Build up of fluid around the heart and lungs
• Acute kidney injury

If any of these symptoms happen while taking a differentiation agent, IDH inhibitor, or menin inhibitor, it’s important to contact your care team right away. Differentiation syndrome is more manageable the earlier it is recognized.

What causes differentiation syndrome?

For people with AML, immature blood cells from the bone marrow or blood called blast cells do not fully develop into mature cells. Instead, the abnormal cells continue to multiply and prevent mature blood cells from functioning properly. When certain types of medication are used to treat AML, they can lead to rapid release of cytokines. Cytokines are proteins that regulate immune responses like inflammation. This can trigger differentiation syndrome.   

The medications that cause differentiation syndrome include:

Differentiation agents. These are a class of medications used to treat certain types of leukemia. They work by causing these immature white cells to mature, or differentiate, into normal functioning white blood cells. Providers use these therapies alone or in combination with other medications.Some standard differentiation agents used for treating leukemia are all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Differentiation syndrome happens to about 25% of people with AML and APL treated with ATRA and ATO.

IDH inhibitors. These medications are also used to treat AML. An IDH inhibitor is a targeted therapy that blocks certain enzymes (IDH1 and IHD2) that prevent leukemia cells from maturing. About 14% to 19% of people with AML treated with IDH inhibitors will develop differentiation syndrome.   

FLT3 inhibitors. Rarely, FLT3 inhibitors can cause differentiation syndrome. These are used to treat AML with FLT3 gene mutations. About 1% to 5% of people treated with this medication will get differentiation syndrome.

Menin inhibitors. Menin inhibitors are a new class of medication to treat AML.They can cause differentiation syndrome. Menin Inhibitors are prescribed for people who have AML with certain genetic features, such as NPM1 mutations and KMT2A rearrangements. Between 14% and 25% of people treated with menin inhibitors may develop differentiation syndrome. 

What is the treatment for differentiation syndrome?

Treatment for differentiation syndrome depends on the severity of the condition. Once differentiation syndrome has been diagnosed, the most common treatment approach is dexamethasone. This is a corticosteroid used to treat inflammation.  

If the case is more severe, your provider may recommend stopping treatment of the differentiating agent until differentiation syndrome is resolved.  

If you experience swelling, your provider may also prescribe furosemide, a diuretic used to treat fluid retention.  

Being aware of the symptoms of differentiation syndrome and communicating with your care team can help prevent serious problems and keep your treatment on track.

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Sources: 

• Differentiation Syndrome in Acute Leukemia: APL and Beyond
• Cleveland Clinic-Differentiation Syndrome 
• National Cancer Institute: Differentiation Syndrome Definition 
• Differentiating agents in the treatment of leukemia 
• HealthTree-What is AML 
• How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia 
• Efficacy and safety of IDH inhibitors in IDH-mutated
• HealthTree-Menin Inhibitors 
• OncLive-Menin Inhibitors