Teaching pack: Acute myeloid leukaemia

Acute myeloid leukaemia is a cancer of immature myeloid cells that floods the marrow and blood within weeks. It is defined molecularly: WHO 2022 and ICC 2022 classify by driver genetics, and ELN 2022 assigns favourable, intermediate, or adverse risk from NPM1, CEBPA, core-binding-factor fusions, FLT3, TP53, KMT2A, and myelodysplasia-related mutations. Median age at diagnosis is 68, and outcomes diverge sharply by age and fitness.

Treatment split into two paradigms. Fit patients receive intensive 7+3 induction (unchanged since 1973) with a targeted add-on chosen by genetics: midostaurin or quizartinib for FLT3, gemtuzumab ozogamicin for CD33+ favourable and intermediate risk, CPX-351 for secondary AML, then high-dose cytarabine consolidation and allogeneic transplant for adverse or MRD-positive disease. Unfit patients, once offered only supportive care, now receive venetoclax with azacitidine (VIALE-A) or, since May 2026, an all-oral regimen with decitabine-cedazuridine; IDH1-mutated patients may receive ivosidenib-azacitidine (AGILE). Relapse is treated by genotype: gilteritinib (FLT3), ivosidenib, olutasidenib or enasidenib (IDH), and the new menin inhibitors revumenib and ziftomenib (NPM1-mutated or KMT2A-rearranged), with transplant as the consolidating cure.

• Menin inhibitors.
• Venetoclax combinations.
• Genotype-directed induction: FLT3 inhibitors (two positive phase 3 trials), gemtuzumab for CD33+ favourable/intermediate risk, CPX-351 for secondary AML.
• Venetoclax + hypomethylating agent made unfit AML treatable, and since May 2026 the regimen can be fully oral.
• Menin inhibitors (revumenib 2024/2025, ziftomenib 2025) opened NPM1-mutated and KMT2A-rearranged leukaemia, ~40% of adult AML, to a new drug class within one year.
• MRD by flow and molecular methods now guides transplant, maintenance, and pre-emptive therapy; ELN 2021 MRD standards are in routine use.

1. 1948First chemotherapy remissions in leukaemia
2. 19737+3 regimen
3. 19737+3 induction defined
4. 1977First allogeneic transplants cure refractory leukaemia
5. 1988ATRA induces differentiation in APL
6. 2000Gemtuzumab: first ADC
7. 2000Gemtuzumab ozogamicin, the first ADC
8. 2004Azacitidine approved (MDS)
9. 2012ALFA-0701 rescues gemtuzumab
10. 2017Midostaurin, enasidenib, gemtuzumab re-approval

• Revumenib (product)
• Venetoclax (product)
• Ziftomenib (product)
• Menin inhibitor + venetoclax + azacitidine (pairing)
• myeloMATCH (trial)
• Gilteritinib (product)
• Quizartinib (product)
• Decitabine + cedazuridine (oral) (product)
• CPX-351 (liposomal daunorubicin-cytarabine) (product)
• BH3 profiling (functional apoptosis testing) (technology)
• NGS-based MRD (clonoSEQ and molecular MRD) (technology)
• MRD-guided transplant decisions in intermediate-risk AML (idea)

• QuANTUM-First (phase 3, n=539): Overall survival (median): 31.9 months vs 15.1 months, HR 0.776
• RATIFY (CALGB 10603) (phase 3, n=717): Overall survival (median): 74.7 months vs 25.6 months, HR 0.78
• ADMIRAL (phase 3, n=371): Overall survival (median): 9.3 months vs 5.6 months, HR 0.64
• VIALE-A (phase 3, n=431): Overall survival (median): 14.7 months vs 9.6 months, HR 0.66
• ALFA-0701 (phase 3, n=271): Event-free survival (median): 17.3 months vs 9.5 months, HR 0.56
• CPX-351 Study 301 (phase 3, n=309): Overall survival (median): 9.56 months vs 5.95 months, HR 0.69

• TP53-mutant AML remains lethal.
• Older patients.
• TP53-mutated and complex-karyotype AML: no class has improved survival; magrolimab (CD47) and eprenetapopt (p53 reactivator) both failed in phase 3.
• Relapse after allogeneic transplant remains the leading cause of death; which maintenance (FLT3, menin, azacitidine) helps whom is unresolved.
• Menin-inhibitor resistance through MEN1 mutations appears within months in a third of relapsing patients; combinations and next-generation inhibitors are needed.
• Early death from infection and cytopenias on venetoclax-based therapy in the very old; optimal venetoclax duration is untested in randomised trials.

1. What were the first checkpoint inhibitor and the first ADC ever approved?
   Answer

   Ipilimumab (2011) was the first checkpoint inhibitor; gemtuzumab ozogamicin (Mylotarg, 2000) was the first ADC, withdrawn in 2010 and re-approved in 2017.
2. What is the first menin inhibitor and who is it for?
   Answer

   Revumenib (Revuforj, Syndax), approved 2024 for relapsed KMT2A-rearranged acute leukaemia and 2025 for NPM1-mutant AML.
3. Why does venetoclax work in leukaemia?
   Answer

   It blocks BCL-2, the protein that stops leukaemia cells from self-destructing, so the built-in death programme (apoptosis) can run; used in CLL (fixed duration with obinutuzumab) and AML (with azacitidine).

• ELN 2022 recommendations: https://ashpublications.org/blood/article/140/12/1345/485817
• NCCN AML guidelines: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411
• Wikipedia: https://en.wikipedia.org/wiki/Acute_myeloid_leukemia
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411