Acute Myeloid Leukemia — IDH1/2-Mutant

Sequencing for IDH1/2-mutant acute myeloid leukemia: frontline therapy split by fitness for intensive induction (intensive 7+3, or an IDH1-targeted ivosidenib + azacitidine vs venetoclax-based lower-intensity regimen), then relapsed/refractory therapy targeted to the IDH subtype (ivosidenib for IDH1, enasidenib for IDH2) with a non-cross-resistant salvage for prior ivosidenib exposure, then clinical trial or allogeneic transplant.

Fitness for intensive induction chemotherapy?

1L: Intensive induction (cytarabine + daunorubicin, "7+3")

For fit patients (younger, good performance status, acceptable organ function). Standard 7+3 induction followed by consolidation; proceed to allogeneic transplant based on risk. IDH inhibitors may be incorporated in trials or maintenance settings.

Lower-intensity regimen selection (unfit for intensive induction)

1L: Ivosidenib + azacitidine (IDH1-targeted)

For newly diagnosed IDH1-mutant AML in patients unfit for intensive chemotherapy; AGILE showed superior event-free and overall survival versus azacitidine alone. Monitor for differentiation syndrome, QTc prolongation, and tumor lysis.

Evidence: AGILE

1L: Venetoclax + azacitidine

Active regardless of IDH status and a standard lower-intensity option for unfit patients. Requires tumor-lysis prophylaxis and a venetoclax ramp-up; manage prolonged cytopenias with dose/schedule adjustments.

IDH mutation subtype at relapse/refractory (no prior IDH inhibitor)

2L: Ivosidenib (IDH1-mutant, no prior IDH1 inhibitor)

Single-agent ivosidenib for relapsed/refractory IDH1-mutant AML in patients not previously exposed to an IDH1 inhibitor. Watch for differentiation syndrome, QTc prolongation, and leukocytosis.

2L: Enasidenib (IDH2-mutant)

Single-agent enasidenib for relapsed/refractory IDH2-mutant AML. Watch for differentiation syndrome and indirect hyperbilirubinemia.

2L: Non-cross-resistant salvage (venetoclax + azacitidine) after frontline ivosidenib

For IDH1-mutant patients who already received frontline ivosidenib + azacitidine: switch to a non-cross-resistant regimen (venetoclax-based, if not already used) or a clinical trial rather than repeating the same IDH1 inhibitor.

3L+: Clinical trial or allogeneic hematopoietic cell transplant

Consolidate responders with allogeneic transplant where feasible; otherwise prioritize a clinical trial. Best supportive care for patients ineligible for further therapy.