Side Effect: Differentiation Syndrome

What is Differentiation Syndrome?

• Differentiation syndrome is a potentially life-threatening complication that can occur in patients undergoing treatment for certain types of cancer, such as acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL).
• It is a result of the rapid differentiation of immature immune cells, leading to the release of cytokines causing a swift and severe acute systemic inflammatory response.

What does Differentiation Syndrome look like?

Differentiation syndrome typically presents within 10-14 days of starting treatment with drugs that induce cellular differentiation.

The symptoms can vary, but commonly include:

• fever
• cough
• shortness of breath (dyspnea)
• low blood pressure (hypotension)
• acute kidney injury
• weight gain
• swelling in the arms
• legs, or neck (edema)
• fluid buildup around the lungs (pleural effusion)

The symptoms can progress rapidly, and if left untreated, differentiation syndrome can cause critical illness and even be fatal.

Who gets Differentiation Syndrome?

Patients with an elevated white blood cell count (WBC) and certain types of leukemia are at highest risk. In addition, not all anti-leukemia treatments increase the risk of differentiation syndrome, but here are some that may:

• Differentiation syndrome occurs most often in patients receiving induction therapy for APL with all-trans-retinoic acid (Tretinoin®, ATRA) or arsenic trioxide (Trisenox®, ATO).
• Certain therapies used to treat AML such as ivosidenib (Tibsovo®), enasidenib (IDHIFA®), olutasidenib (Rezlidhia®) and gilteritinib (Xospata®) can also lead to differentiation syndrome.

It is estimated that 10-25% of patients with acute promyelocytic leukemia (APL) or acute myeloid leukemia (AML) will develop differentiation syndrome when treated with the medications listed above.

How to prevent Differentiation Syndrome

Patients with AML are closely monitored for signs and symptoms during their initial treatment, known as induction therapy.

While not routinely offered to everyone, certain patients being treated for APL who are considered to be at an increased risk for differentiation syndrome may receive corticosteroids such as prednisone (Deltasone®) or dexamethasone (Decadron®) during induction therapy to provide anti-inflammatory effects to help prevent differentiation syndrome.

In some instances when the WBC is elevated, hydroxyurea (Hydrea®) may be utilized before or during therapy to help lower the WBC and lessen risk of differentiation syndrome.

How to treat Differentiation Syndrome

• Treatment for differentiation syndrome involves the prompt administration of high-dose steroids, such as dexamethasone (Decadron®), which can help to reduce inflammation and decrease symptoms.
• If symptoms are severe, therapy may need to be temporarily held until symptom resolve and additional supportive case measures such as antibiotics, mechanical ventilation, dialysis, vasopressors, and diuretics may be indicated.