What is the role of Ivosidenib (Ivosidenib, Idhifa) in the treatment of Acute Myeloid Leukemia (AML)?

Role of Ivosidenib in Acute Myeloid Leukemia (AML) Treatment

Ivosidenib is FDA-approved for IDH1-mutated AML as both first-line therapy for older/unfit patients and for relapsed/refractory disease, offering targeted treatment with significant survival benefits compared to conventional therapy. 1, 2

Mechanism of Action and Indications

Ivosidenib (Tibsovo) is a small molecule inhibitor that specifically targets the mutant isocitrate dehydrogenase 1 (IDH1) enzyme. IDH1 mutations occur in approximately 6-10% of AML cases, with R132H and R132C being the most common substitutions 2.

FDA-Approved Indications:

• Newly diagnosed AML: For patients ≥75 years old or with comorbidities precluding intensive induction chemotherapy who have IDH1 mutations 3
• Relapsed/refractory AML: For adult patients with IDH1-mutated disease 4

Efficacy Data

Newly Diagnosed AML

• Monotherapy: 41.2% CR/CRh rate and 58.8% overall response rate in older patients unfit for intensive chemotherapy 3, 5
• With azacitidine: 78.3% overall response rate and 60.9% complete remission rate, with 12-month survival estimate of 82.0% 6
• Median overall survival: 12.6 months as monotherapy in newly diagnosed elderly patients 5

Relapsed/Refractory AML

• CR/CRh rate: 30.4% with median duration of response of 8.2 months 7
• Complete remission rate: 21.6% with median duration of 9.3 months 7
• Overall response rate: 41.6% with median duration of 6.5 months 7

Combination with Intensive Chemotherapy

• In newly diagnosed patients receiving ivosidenib with intensive chemotherapy, CR rate was 55% and CR/CRi/CRp rate was 72% 8
• 39% of patients achieved IDH1 mutation clearance and 80% became negative for measurable residual disease by flow cytometry 8

Molecular Response

• IDH1 mutation clearance observed in:
  • 71.4% of patients achieving CR with ivosidenib plus azacitidine 6
  • 21% of patients with CR/CRh in relapsed/refractory setting 7
  • 39% of patients receiving combination with intensive chemotherapy 8

Adverse Effects and Monitoring

Common Adverse Events

• Febrile neutropenia (25.2-28.5% of patients) 3
• Pneumonia (14.7% of patients) 3
• QT interval prolongation (mean increase of 17 msec) 2
• Differentiation syndrome (18% of patients) 1, 7

Differentiation Syndrome

• Presents with fever, acute respiratory distress, pulmonary infiltrates, pleural/pericardial effusion, hyperleukocytosis, or renal impairment 3, 1
• May mimic infection, requiring careful differential diagnosis 1
• Management includes corticosteroids and hydroxyurea if hyperleukocytosis develops 3, 1

Drug Interactions

• Ivosidenib is predominantly metabolized by CYP3A4 3, 2
• Strong CYP3A4 inhibitors (including triazole antifungals) increase ivosidenib exposure 3, 1
• Dose reduction to 250 mg daily recommended if strong CYP3A4 inhibitors must be used 1

QT Prolongation

• Regular ECG monitoring required, especially with concomitant QT-prolonging medications 1, 2
• Maintain normal electrolyte levels, particularly magnesium (>2.0 mg/dL) 1

Treatment Algorithm for IDH1-Mutated AML

1. Test for IDH1 mutation in all newly diagnosed AML patients
2. For older patients (≥75 years) or those unfit for intensive chemotherapy:
   • Ivosidenib 500 mg daily as monotherapy OR
   • Ivosidenib 500 mg daily plus azacitidine 75 mg/m² days 1-7 of 28-day cycle (preferred based on higher response rates) 6
3. For younger/fit patients with newly diagnosed disease:
   • Consider ivosidenib 500 mg daily combined with standard induction chemotherapy 8
4. For relapsed/refractory disease:
   • Ivosidenib 500 mg daily as monotherapy 7, 4
5. Monitoring during treatment:
   • Weekly CBC for first month, biweekly for second month, then monthly 1
   • ECG monitoring for QT prolongation (baseline and at least monthly) 1, 2
   • Regular assessment for differentiation syndrome 3, 1
   • Magnesium levels weekly initially, then biweekly once stabilized 1

Clinical Pearls and Pitfalls

• Differentiation syndrome can mimic infection - maintain high suspicion and initiate corticosteroids promptly if suspected 3, 1
• QT prolongation risk increases with hypomagnesemia and concomitant QT-prolonging medications 1, 2
• Drug interactions with CYP3A4 inhibitors (especially triazole antifungals) require careful medication review 3, 1
• Transfusion independence can be achieved in 35-43% of previously transfusion-dependent patients 7, 5
• Molecular monitoring for IDH1 mutation clearance provides valuable prognostic information 6, 7, 8

Ivosidenib represents a significant advancement in targeted therapy for AML, offering improved outcomes for patients with IDH1 mutations compared to conventional chemotherapy alone, particularly in older patients or those with relapsed/refractory disease.