What is differentiation syndrome in patients taking enasidenib (Idhifa, idh2 inhibitor) and how is it diagnosed and treated?

Differentiation Syndrome in Enasidenib-Treated Patients

Differentiation syndrome (DS) is a potentially fatal complication occurring in approximately 10-19% of patients treated with enasidenib, requiring immediate recognition and treatment with systemic corticosteroids. 1, 2, 3

What is Differentiation Syndrome?

Differentiation syndrome is a severe adverse reaction that occurs when IDH inhibitors like enasidenib promote rapid differentiation of leukemic myeloblasts, leading to a systemic inflammatory response. 4, 2

Key clinical manifestations include: 4, 1

• Fever (very common)
• Dyspnea and acute respiratory distress (most frequent symptom, 80.6% of cases) 3
• Pulmonary infiltrates (73.1% of cases) 3
• Pleural or pericardial effusions
• Rapid weight gain or peripheral edema
• Hypoxia
• Hyperleukocytosis (present in 61% of enasidenib-associated DS cases) 5
• Renal impairment
• Multi-organ dysfunction or failure

Critical timing: The median time to onset is 19-32 days after starting enasidenib (range: 1-129 days), though it can occur at any point during treatment. 2, 5, 3

Diagnosis

DS should be suspected immediately when any combination of the above symptoms appears in a patient receiving enasidenib. 1, 2 The diagnosis is clinical and does not require waiting for confirmatory testing.

Important diagnostic pitfall: DS can mimic infection, making differentiation challenging. 4 The presence of fever, pulmonary infiltrates, and respiratory distress may initially suggest pneumonia or sepsis, but the constellation of symptoms (especially with concurrent weight gain, effusions, or rapid leukocytosis) should raise suspicion for DS. 4

Risk factors for developing DS: 3

• Higher baseline bone marrow blast percentage (≥48% associated with increased risk)
• Higher peripheral blood blast count (≥15%)
• Elevated lactate dehydrogenase levels
• Fewer prior anticancer regimens (median 1 vs 2 in those without DS) 2
• Patients with ≥20% bone marrow blasts at baseline are at higher risk 2

Standard diagnostic workup should include: 4

• Standard evaluation for neutropenic fever and infections in AML patients (to rule out infectious etiology)
• Chest imaging to assess for pulmonary infiltrates and effusions
• Assessment of renal and hepatic function
• Complete blood count with differential to evaluate for leukocytosis

Treatment

Initiate systemic corticosteroids immediately upon suspicion of DS—do not wait for diagnostic confirmation. 1, 2 This is the cornerstone of DS management and is emphasized in the FDA black box warning. 1

Specific treatment algorithm: 2, 3

1. Start dexamethasone 10 mg IV twice daily immediately when DS is suspected 2

   • 88.1% of patients with DS received systemic steroids 3
   • Continue until complete resolution of symptoms
   • Taper corticosteroids gradually after symptom resolution

2. Hemodynamic monitoring should be initiated for all suspected DS cases 1

3. Enasidenib management: 2, 3

   • Temporary interruption of enasidenib is required in 45.5% of cases 2
   • Hold enasidenib for patients with severe or life-threatening DS
   • Permanent discontinuation is rarely necessary 2
   • Enasidenib can typically be resumed once symptoms resolve with corticosteroid therapy

4. Supportive care measures: 2

   • Hydroxyurea for management of concurrent hyperleukocytosis (present in 39-61% of DS cases) 4, 2, 5
   • Oxygen support and respiratory management as needed
   • Diuretics for fluid overload/effusions if indicated
   • ICU admission for severe cases with multi-organ dysfunction

Important clinical note: Grade ≥3 DS occurs in approximately 66-68% of identified DS cases, with a 5-6% fatality rate. 5 Early recognition and aggressive treatment with corticosteroids are essential to prevent mortality. 1, 2

Response to treatment: Most patients respond well to corticosteroids, and DS can be effectively managed without permanent discontinuation of enasidenib. 2, 3 However, patients who develop DS have lower complete remission rates (18%) compared to those without DS (25-36%). 5

Prophylaxis consideration: While not universally recommended, some centers consider prophylactic corticosteroids for high-risk patients (those with high blast counts or elevated LDH), though this lacks strong evidence-based support. 6