# Acute Myeloid Leukemia

## Introduction

Acute myeloid leukemia (AML) is a clonal hematopoietic neoplasm characterized by the accumulation of myeloid blasts in the bone marrow and blood, traditionally defined by 20% or more myeloid blasts in the marrow or blood by WHO criteria, though certain genetic abnormalities now define AML regardless of blast count. The incidence is approximately 4.3 per 100,000 per year, with a median age at diagnosis of 68 years. Outcomes are strikingly disparate across risk groups, with cure rates exceeding 60% in favorable-risk disease but falling below 10% in adverse-risk elderly patients. The WHO 5th Edition (2022) and the International Consensus Classification (2022) represent a paradigm shift toward genetics-first classification, in which the defining genetic abnormality takes precedence over blast morphology and percentage.

## Classification (WHO 5th Edition 2022)

### AML with Defining Genetic Abnormalities (blast threshold may be <20%)

The WHO 5th Edition recognizes a series of AML subtypes defined by recurrent genetic abnormalities, several of which can be diagnosed with blast counts below the traditional 20% threshold. AML with t(8;21)(q22;q22.1)/RUNX1-RUNX1T1 is one of the two core-binding factor leukemias and carries a favorable prognosis, occurring more commonly in younger patients. AML with inv(16)(p13.1q22) or t(16;16)/CBFB-MYH11 is the other core-binding factor AML and also carries a favorable prognosis. AML with t(15;17)(q24.1;q21.2)/PML-RARA defines acute promyelocytic leukemia, a biologically and therapeutically distinct entity discussed separately below.

AML with t(9;11)(p21.3;q23.3)/MLLT3-KMT2A is the most common KMT2A (MLL) rearrangement and is classified as intermediate risk, while AML with other KMT2A rearrangements is generally adverse. AML with t(6;9)(p22.3;q34.1)/DEK-NUP214 carries an adverse prognosis. AML with inv(3)(q21.3q26.2) or t(3;3)/GATA2, MECOM is associated with a very adverse outcome. AML with NPM1 mutation, the most commonly mutated gene in AML at approximately 30% of cases, carries a favorable prognosis in the absence of adverse features. AML with in-frame bZIP CEBPA mutation, present in 5 to 10% of AML, is also a favorable-risk entity. AML with t(9;22)(q34.1;q11.2)/BCR-ABL1 is rare and must be distinguished from chronic myeloid leukemia in blast crisis, which has fundamentally different treatment implications.

### AML Defined by Differentiation (if no defining genetic abnormality)

When no defining genetic abnormality is identified, AML is classified based on the lineage and degree of myeloid differentiation. Subtypes include AML with minimal differentiation, AML without maturation, AML with maturation, acute myelomonocytic leukemia, acute monoblastic and monocytic leukemia, acute erythroid leukemia, and acute megakaryoblastic leukemia. These morphologic categories are of decreasing prognostic importance as molecular profiling becomes central to risk stratification.

### Therapy-Related Myeloid Neoplasm

Therapy-related myeloid neoplasms arise after exposure to cytotoxic therapy and are classified as a diagnostic qualifier rather than a separate entity in the updated classification. Prior exposure to alkylating agents is associated with a latency of 5 to 7 years and is frequently accompanied by deletions of chromosomes 5q and 7q or complex karyotype. Prior topoisomerase II inhibitor exposure carries a shorter latency of 1 to 3 years and is typically associated with balanced translocations involving KMT2A at 11q23. Therapy-related disease generally carries a poor prognosis.

## Risk Stratification (ELN 2022)

### Favorable Risk

The 2022 European LeukemiaNet (ELN) risk stratification identifies favorable-risk AML as including t(8;21)/RUNX1-RUNX1T1 (without adverse mutations), inv(16)/CBFB-MYH11, NPM1 mutated without FLT3-ITD, and bZIP in-frame CEBPA mutations. Patients in this category have an expected 5-year overall survival of approximately 60 to 70%.

### Intermediate Risk

Intermediate-risk AML includes NPM1 mutated with concurrent FLT3-ITD, wild-type NPM1 with FLT3-ITD without additional adverse features, t(9;11)/MLLT3-KMT2A, and cytogenetic or molecular abnormalities not classified as favorable or adverse. Expected 5-year overall survival in this group is approximately 30 to 40%.

### Adverse Risk

Adverse-risk AML encompasses a broad array of unfavorable genetic features including t(6;9)/DEK-NUP214, KMT2A rearrangements other than MLLT3-KMT2A, inv(3) or t(3;3)/GATA2-MECOM, t(9;22)/BCR-ABL1, complex karyotype (3 or more abnormalities), monosomal karyotype, del(5q), monosomy 5, monosomy 7, del(7q), del(17p) or TP53 mutation, and mutations in ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2. FLT3-ITD with a high allelic ratio in the absence of NPM1 mutation is also classified as adverse. Expected 5-year overall survival in this category is only 10 to 20%.

| ELN 2022 Risk | Genetic Abnormalities | 5-Year OS | Transplant in CR1 |
|---|---|---|---|
| Favorable | t(8;21)/RUNX1-RUNX1T1; inv(16)/CBFB-MYH11; NPM1 mutated without FLT3-ITD; bZIP in-frame CEBPA | ~60-70% | Only if MRD-positive |
| Intermediate | NPM1 + FLT3-ITD; wild-type NPM1 with FLT3-ITD (no adverse features); t(9;11)/MLLT3-KMT2A; other not classified | ~30-40% | Yes, if donor available |
| Adverse | t(6;9); non-MLLT3 KMT2A rearrangements; inv(3)/t(3;3); t(9;22); complex/monosomal karyotype; -5/del(5q), -7/del(7q), del(17p); TP53, ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2 mutations | ~10-20% | Yes, strongly indicated |

<image>A comprehensive ELN 2022 risk stratification table for AML displayed as a three-column layout (Favorable, Intermediate, Adverse). For each risk category, list the genetic abnormalities that define it. Use color coding: green for favorable, yellow for intermediate, red for adverse. Include the expected outcomes for each category: 5-year OS approximately 60-70% favorable, 30-40% intermediate, 10-20% adverse. At the bottom, show a treatment decision algorithm: favorable → intensive chemotherapy (transplant in CR1 only if MRD+), intermediate → intensive chemo then transplant in CR1, adverse → intensive chemo then transplant in CR1 (or clinical trial). Include molecular markers with their prognostic impact arrows (FLT3-ITD, NPM1, CEBPA, TP53, ASXL1). Clean medical education table format.</image>

## Treatment - Intensive Chemotherapy

### Induction

The standard intensive induction regimen for AML is the "7+3" protocol, consisting of continuous infusion cytarabine at 100 to 200 mg/m2 for 7 days combined with an anthracycline, either daunorubicin at 60 to 90 mg/m2 or idarubicin at 12 mg/m2, administered intravenously for 3 days. This regimen achieves complete remission rates of 60 to 80% in younger adults and 40 to 60% in older adults. For patients with FLT3-mutated AML, midostaurin at 50 mg orally twice daily on days 8 through 21 is added to 7+3 based on the RATIFY trial, which demonstrated an overall survival benefit with this addition. Gemtuzumab ozogamicin, an anti-CD33 antibody-drug conjugate, is added for favorable and intermediate-risk disease based on the ALFA-0701 trial, which showed improved event-free survival when gemtuzumab ozogamicin at 3 mg/m2 was administered on days 1, 4, and 7 of induction.

CPX-351 (Vyxeos), a liposomal formulation of daunorubicin and cytarabine at a fixed 5:1 molar ratio, has been shown to be superior to conventional 7+3 for secondary AML and therapy-related AML, with a median overall survival of 9.6 months compared to 5.9 months. A day 14 bone marrow biopsy is performed to assess for residual disease, and re-induction is considered if more than 10% blasts remain.

### Consolidation

Consolidation therapy is guided by the ELN risk category. For favorable-risk AML, high-dose cytarabine (HiDAC) at 3 g/m2 every 12 hours on days 1, 3, and 5 is administered for 3 to 4 cycles, achieving cure rates of approximately 60 to 70% without the need for transplant in most patients. For intermediate-risk AML, 1 to 2 cycles of HiDAC are followed by allogeneic HSCT in first complete remission if a suitable donor is available. For adverse-risk AML, allogeneic HSCT in first complete remission represents the strongest indication for transplant, and hypomethylating agent maintenance following transplant may improve outcomes.

### Measurable Residual Disease (MRD)

MRD assessment has become a central component of AML management. Detection methods include multiparameter flow cytometry (with a sensitivity of 10^-3 to 10^-4) and molecular techniques such as RT-qPCR for specific fusion transcripts or mutations (with sensitivity of 10^-4 to 10^-6). MRD positivity after consolidation is a strong independent adverse prognostic factor across all risk groups. The clinical implications are nuanced: MRD-positive favorable-risk patients should be considered for transplant despite their otherwise favorable genetics, while MRD-negative adverse-risk patients still benefit from transplant given the inherent biological aggressiveness of their disease.

## Treatment - Unfit/Older Patients

### Venetoclax + Azacitidine

The combination of venetoclax with azacitidine has transformed the treatment landscape for older and unfit AML patients who are ineligible for intensive chemotherapy. The VIALE-A trial demonstrated a composite complete remission rate (CR/CRi) of 66.4% compared to 28.3% with azacitidine alone, and a median overall survival of 14.7 months compared to 9.6 months. This combination is now the standard of care for this population. Venetoclax is administered at a target dose of 400 mg daily following a ramp-up period to mitigate tumor lysis syndrome risk. Dose adjustment is essential when concurrent azole antifungals are used for CYP3A4-mediated drug interactions; with posaconazole or voriconazole, the venetoclax dose should be reduced to 100 mg daily. Prolonged cytopenias are the most significant toxicity and are managed through venetoclax dose interruptions and cycle shortening (21-day rather than 28-day venetoclax dosing) rather than treatment discontinuation.

### Low-Dose Cytarabine + Venetoclax

The VIALE-C trial evaluated the combination of venetoclax with low-dose cytarabine as an alternative for patients unable to receive azacitidine, providing another option in this setting.

### Targeted Monotherapy Options

Ivosidenib, an IDH1 inhibitor, achieves a CR/CRi rate of approximately 30% as monotherapy in IDH1-mutated AML and has been combined with azacitidine in the AGILE trial, where the combination produced a CR/CRi rate of 53%, establishing a new standard for IDH1-mutated AML in older patients. Enasidenib, an IDH2 inhibitor, achieves a CR/CRi rate of approximately 20% as monotherapy in IDH2-mutated relapsed or refractory AML. Gilteritinib, a FLT3 inhibitor, is approved for FLT3-mutated relapsed or refractory AML based on the ADMIRAL trial, which demonstrated a median overall survival of 9.3 months compared to 5.6 months with salvage chemotherapy.

## Acute Promyelocytic Leukemia (APL)

### Unique Biology and Presentation

Acute promyelocytic leukemia is defined by the t(15;17)/PML-RARA fusion, which blocks myeloid differentiation at the promyelocyte stage. The clinical presentation is distinguished by a life-threatening coagulopathy that combines features of disseminated intravascular coagulation with hyperfibrinolysis and the release of procoagulant factors from abnormal promyelocyte granules. The coagulation profile typically demonstrates an elevated D-dimer, low fibrinogen, and prolonged prothrombin time. This coagulopathy is the leading cause of early death, with the highest mortality occurring within the first 24 to 48 hours from hemorrhagic complications, most commonly intracranial hemorrhage. APL must be regarded as a medical emergency.

### Treatment

For low and intermediate-risk APL (defined by a white blood cell count of 10,000 per microliter or less), the combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) without conventional chemotherapy is now the standard of care. The landmark APL0406/GIMEMA trial demonstrated that ATRA plus ATO was superior to ATRA plus chemotherapy, with event-free survival of 97% versus 80% and overall survival of 99% versus 93%. ATRA is administered at 45 mg/m2/day divided into two doses and continued until complete remission, while ATO is given at 0.15 mg/kg/day intravenously. For high-risk APL (white blood cell count above 10,000 per microliter), ATRA and ATO are combined with either idarubicin or gemtuzumab ozogamicin to manage the higher tumor burden. APL is now recognized as the most curable form of leukemia, with overall survival exceeding 95% with modern therapy.

Differentiation syndrome is a potentially life-threatening complication that occurs in 25 to 30% of patients treated with ATRA or ATO. It manifests with fever, dyspnea, weight gain, pulmonary infiltrates, and pleural or pericardial effusions, resulting from the rapid differentiation and activation of leukemic promyelocytes. Treatment consists of dexamethasone at 10 mg intravenously twice daily, with temporary discontinuation of ATRA or ATO in severe cases.

### Supportive Care in APL

Aggressive management of the coagulopathy is critical during the early treatment period. Cryoprecipitate should be administered to maintain fibrinogen levels above 150 mg/dL, and platelet transfusions should target a count above 30,000 to 50,000 per microliter. The single most important clinical directive in APL management is that ATRA must not be withheld while awaiting cytogenetic confirmation; treatment should be initiated immediately based on clinical suspicion and the morphologic appearance of abnormal promyelocytes.

## Key Clinical Pearls
- APL is a medical emergency: start ATRA immediately on clinical suspicion (promyelocytes, DIC); do not wait for FISH/cytogenetics
- Venetoclax + azacitidine has transformed outcomes for older/unfit AML patients; manage prolonged cytopenias with dose modifications rather than discontinuation
- FLT3-ITD is the most common adverse mutation in AML (~25%); midostaurin during induction and gilteritinib for relapse are standard
- NPM1 mutation is the most common favorable mutation (~30%); responds well to intensive chemotherapy; monitor NPM1 transcript for MRD
- ELN 2022 adverse-risk AML should proceed to allogeneic HSCT in CR1 whenever feasible
- IDH1/2 mutations are actionable targets: ivosidenib (IDH1) combined with azacitidine (AGILE trial) is a breakthrough for IDH1-mutated AML in older patients

## References
1. Dohner H, et al. Diagnosis and Management of AML in Adults: 2022 ELN Recommendations. Blood. 2022;140(12):1345-1377.
2. DiNardo CD, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia (VIALE-A). N Engl J Med. 2020;383(7):617-629.
3. Stone RM, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation (RATIFY). N Engl J Med. 2017;377(5):454-464.
4. Lo-Coco F, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia (APL0406). N Engl J Med. 2013;369(2):111-121.
5. Montesinos P, et al. Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia (AGILE). N Engl J Med. 2022;386(16):1519-1531.