41 Acute Myeloid Leukemia
- AML dx: ≥20% blasts in BM/PB
- Exception: t(15;17), t(8;21), inv(16), t(16;16)—AML at any blast %
- Key prognosticators: age, cytogenetics, NPM1, CEBPA, TP53, IDH1/IDH2
- Favorable: NPM1 w/o FLT3-ITD, CEBPA biallelic → ↑ CR, longer OS
- Adverse: TP53, complex karyotype, −5/−7 → ↓ response
- Fit pts: 7+3 (cytarabine + daunorubicin ± midostaurin if FLT3-ITD)
- Consolidation: HiDAC for favorable; allo-HCT for intermediate/adverse
- Unfit pts: ven+aza (venetoclax + azacitidine) or HMA monotherapy
- APL (t(15;17)): ATRA + ATO (no chemo); EFS 80-90%; DIC watch
41.1 Introduction
- Definition: Clonal stem/progenitor malignancy w/ ≥20% blasts in BM/PB
- Results: marrow failure (infection, anemia, bleeding)
- Incidence: 20K cases/yr in US; median dx age 69y
- Outcomes: 32% 5-yr OS in <65y; 10% in >65y (comorbidities, burden)
- Etiology: de novo (most); risk w/ chemo, RT, predisposition syndromes
41.2 Clinical Manifestations
- Marrow infiltration effects: fever, fatigue, bone pain, HSM, bleeding
- Tissue involvement: skin, gingiva, CNS (especially monocytic AML)
- Leukostasis complications: coagulopathy, DIC, differentiation syndrome
41.3 Diagnosis
41.3.1 Diagnostic Workup
- BM exam: aspiration & biopsy → blast %, morphology, lineage
- Flow cytometry: immunophenotyping by multiparameter assay
- Cytogenetics + FISH: recurrent abnormalities (t(8;21), inv(16), t(15;17), etc.)
- Molecular testing: FLT3, NPM1, CEBPA, IDH1/IDH2, TP53, ASXL1
- LP w/ CNS prophylaxis: if high WBC or CNS concern
41.4 Classification
- WHO 2022: Molecular/cytogenetic (not morphology)
- Blast threshold eliminated for NPM1-mut, t(8;21), inv(16), t(15;17), KMT2A
- ICC 2022: ≥10% blasts for these entities
- Major prognostic subgroups:
- Balanced: t(15;17) [APL], t(8;21), inv(16) [CBF-AML]
- Mutations: NPM1, CEBPA, IDH1/IDH2, splicing (SF3B1, SRSF2, U2AF1)
- Complex: ≥3 abnormalities; often TP53-mut
41.5 Risk Stratification
41.5.1 ELN 2022 Risk Stratification (Table 41-2)
| Risk | Genetics |
|---|---|
| Favorable | t(8;21), inv(16), NPM1 w/o FLT3-ITD, CEBPA biallelic |
| Intermediate | NPM1 w/ FLT3-ITD, wt-NPM1 w/ FLT3-ITD, t(9;11) |
| Adverse | Complex/monosomal karyotype, TP53, FLT3-ITD (high AR), ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1 |
41.5.2 Molecular Markers
- Favorable: NPM1±CEBPA → ↑ chemosensitivity, longer OS
- Adverse: TP53 (50% w/ complex karyotype) → ↓ CR, poor OS
- Myelodysplasia-associated: ASXL1, BCOR, EZH2, RUNX1, SF3B1 → ↓ prognosis
- Complex karyotype: ≥3 abn in 15–20% of AML; worse outcomes
41.5.3 Measurable Residual Disease (MRD)
- Definition: Leukemic blasts detectable by flow, qPCR, or ddPCR
- Threshold: >0.03% post-induction/consolidation = adverse prognosis
- Use: Emerging role in consolidation therapy guidance
41.6 Treatment
41.6.1 Remission Induction
Fit patients (age <60–65, ECOG 0–2): - 7+3: Cytarabine 100–200 mg/m² × 7d + daunorubicin 90 mg/m² × 3d - CR rate: 70–80% <60y, 50–55% >60y - FLT3-ITD? Add midostaurin or sorafenib (↓ relapse) - Repeat if aplasia w/ CR2 goal
Unfit patients (age >75, poor performance, comorbidities): - HMA monotherapy: Azacitidine 50–100 mg/m² d1–7 q28d - OS: ~10 mo vs 2–5 mo w/ supportive care - Venetoclax + HMA: CR 50–80% in fit-unfit; consider ≥75y or unfit - IDH inhibitors: If IDH1/IDH2-mut (ivosidenib, enasidenib)
41.6.2 Consolidation/Posttremission Therapy
- HiDAC (favorable risk, <60y):
- Cytarabine 3 g/m² IV q12h d1,3,5 × 2–4 cycles
- DFS ↑ vs SD consolidation; OS ↑ ~20% at 4y
60y: Use 1.5 g/m² (↑ CNS toxicity @ HD)
- Allo-HCT (intermediate/adverse risk, CR1):
- RFS 45–52% intermediate, 20–31% adverse at 3y
- Myeloablative vs RIC by age, comorbidities
- TP53-mut: ↑ TRM; consider early referral
- Graft-vs-leukemia effect improves OS vs chemo alone
- Maintenance (post-CR if no allo-HCT):
- Azacitidine 75 mg/m² d1–14 q28d (QUAZAR trial)
- OS ↑ ~10 mo vs placebo in >55y ineligible for HCT
41.6.3 Relapsed/Refractory AML
General: - Most relapses w/in 2–3y; poor prognosis - CR duration prognostic: <6mo → unlikely salvage response; >6mo → may respond - 2nd remission shorter than 1st; refer allo-HCT if CR2
Targeted therapy (if harboring mutations): - Gilteritinib (FLT3-ITD): CRi 34% vs 15% w/ conventional salvage; +allo-HCT - Quizartinib (FLT3): Alternative selective inhibitor - Ivosidenib (IDH1-mut): CR/CRi 25–40%; response ~9mo - Enasidenib (IDH2-mut): Similar efficacy to ivosidenib
Salvage regimens: - FLAG-IDA (fludarabine, cytarabine, G-CSF, idarubicin) - MEC (mitoxantrone, etoposide, cytarabine) - Clofarabine + cytarabine
41.7 Special Populations
41.7.1 Acute Promyelocytic Leukemia (t(15;17), PML-RARA)
Diagnosis & Risk: - Morphology: Abnormal promyelocytes w/ Auer rods, dense granules - Flow: CD13, CD33, HLA-DR, CD34, CD117, CD11b typically absent/low - Risk stratification: Low = WBC <10K; high = WBC ≥10K - Urgent: Hospitalize immediately; start ATRA before confirmation
Treatment (same all risk tiers): - ATRA + ATO: Standard of care (no chemo) - ATRA 45 mg/m² d1–90 in 2 div doses - ATO 0.15 mg/kg IV daily - CR ~90%; EFS 80–90%; long-term cure 70–80% - Consolidation: ATRA ± chemotherapy × 2 cycles (optional) - Monitoring: Molecular (PML-RARA RT-PCR) for 3y post-remission - Allo-HCT: Reserved for relapse/loss of molecular remission
Supportive Care: - DIC management: Goal fibrinogen >30–50 mg/dL, INR <1.5 - Differentiation syndrome (ATRA/ATO effect): - Pulmonary infiltrates, respiratory distress, SIRS-like → ↓ ATRA dose or d/c - Add corticosteroids if moderate-severe - Avoid: Hyperleukocytosis; consider cytoreduction if WBC >100K
41.7.2 Germline AML Predisposition
- Indications for testing: Early AML, FHx hematologic malignancy, syndromic features
- Common mutations (Table 41-4):
- DDX41: ~50% of germline predisposition in adults; favorable prognosis
- TP53: Li-Fraumeni syndrome; ↓ outcomes, complex karyotype
- CEBPA, GATA2, RUNX1: Dominant syndromes w/ AML risk
- Prognosis: DDX41-mut typically favorable despite MRD+ status
- TP53-mut: ↑ TRM w/ allo-HCT; consider early referral
41.7.3 Pediatric AML
- Epidemiology: 20% of childhood acute leukemia
- Genetics (differ from adults):
- KMT2A rearrangements: 25% childhood, 50% infants
- Oncogenic translocations > somatic mutations
- DNMT3A, IDH1/IDH2 rare; RAS pathway ↑
- Treatment: Intensive chemo (cytarabine-based); better outcomes vs adults
- Consolidation: HiDAC + allo-HCT per risk stratification
| Drug class | Indication |
|---|---|
| CC-486 | Oral formulation of azacitidine |
| CPX-351 | Liposomal cytarabine/daunorubicin |
| Enasidenib | Inhibitor of mutant IDH2 |
| Gemtuzumab ozogamicin | Anti-CD33 antibody-drug conjugate |
| Gilteritinib | Second-generation tyrosine kinase inhibitor |
| Glasdegib | Inhibitor of hedgehog signaling pathway |
| Ivosidenib | Inhibitor of mutant IDH1 |
| Midostaurin | First-generation tyrosine kinase inhibitor |
| Olutasidenib | Inhibitor of mutant IDH1 |
| Quizartinib | Second-generation tyrosine kinase inhibitor |
| Venetoclax | Selective B-cell lymphoma-2 inhibitor |
41.8 Clinical Pearls
- Get mutation panel @ diagnosis: NPM1, CEBPA, FLT3-ITD, IDH1/IDH2, TP53
- Favorable: NPM1 w/o FLT3-ITD, CEBPA biallelic → better CR, longer OS
- Adverse: TP53, complex karyotype → ↑ need for HCT, worse outcomes
- APL = medical emergency: Hospitalize; start ATRA before confirmation
- DIC monitoring essential; watch for differentiation syndrome
- ATRA + ATO alone (no chemo); cure rate 80–90%
- Fit >60y or unfit: Ven+aza or HMA monotherapy more tolerable
- Avoid 7+3 toxicity if ECOG >2 or comorbidities significant
- Options: IDH/FLT3 inhibitors, azacitidine alone
- Post-CR strategy: HiDAC or allo-HCT based on risk group
- Intermediate/adverse: Early HCT referral preferred
- Favorable: HiDAC consolidation; HCT reserved for relapse