Acute Myeloid Leukemia¶
Chapter 109 | Part 4: Oncology and Hematology
KEY CLINICAL POINTS¶
- AML is a clonal hematopoietic malignancy characterized by uncontrolled proliferation of immature myeloid cells, with a median age of 69 years and 5-year survival <32%.
- Genetic abnormalities (e.g., t(8;21), inv(16), t(15;17)) and chromosomal abnormalities (e.g., complex karyotype, TP53 mutations) are central to classification and prognosis.
- Treatment is risk-stratified based on age, cytogenetics, and molecular markers, with intensive chemotherapy (7+3 regimen) for younger patients and hypomethylating agents/venetoclax for older patients.
- MRD monitoring via flow cytometry and molecular assays is critical for risk stratification and treatment decisions.
- Allogeneic HCT is recommended for non-favorable-risk patients <75 years, while supportive care and targeted therapies (e.g., IDH inhibitors) are used for unfit patients.
1. DEFINITION & OVERVIEW¶
Acute myeloid leukemia (AML) is a heterogeneous group of clonal hematopoietic malignancies characterized by the proliferation of immature myeloid cells. It is the most common acute leukemia in adults, with a median age of 69 years. AML is uniformly fatal without treatment, with 5-year survival <32% in the U.S. The disease is classified by genetic and cytogenetic abnormalities, with WHO and ELN systems guiding risk stratification.
Table 109-1: WHO 2022 Subtypes of Myeloid Neoplasms with Germline Predisposition¶
| Subtype | Genetic Abnormality |
|---|---|
| Germline CEBPA P/LP variant | CEBPA-associated familial AML |
| Germline DDX41 P/LP variant | |
| Germline TP53 P/LP variant | Li-Fraumeni syndrome |
| Germline RUNX1 P/LP variant | Familial platelet disorder with myeloid malignancy |
| Germline GATA2 P/LP variant | GATA2 deficiency |
| Bone marrow failure syndromes | |
| Severe congenital neutropenia (SCN) | |
| Shwachman-Diamond syndrome (SDS) | |
| Fanconi anemia (FA) | |
| Telomere biology disorders | |
| RASopathies (e.g., Noonan syndrome) |
| Subtype | Genetic Abnormality |
|---|---|
| Down syndrome | |
| Germline SAMD9 P/LP variant | MIRAGE syndrome |
| Germline SAMD9L P/LP variant | SAMD9L-related ataxia pancytopenia syndrome |
| Biallelic germline BLM P/LP variant | Bloom syndrome |
Table 109-2: WHO 2022 Classification of Acute Myeloid Leukemia¶
| Subtype | Genetic Abnormality |
|---|---|
| Acute promyelocytic leukemia with PML::RARA fusion | t(15;17)(q22;q12) |
| Acute myeloid leukemia with RUNX1::RUNX1T1 fusion | t(8;21)(q22;q22.1) |
| Acute myeloid leukemia with CBFB::MYH11 fusion | t(16;16)(p13.1;q22) |
| Acute myeloid leukemia with DEK::NUP214 fusion | t(6;9)(p23.3;q34.1) |
| Acute myeloid leukemia with RBM15::MRTFA fusion | t(11;16)(q23.3;p13.3) |
| Acute myeloid leukemia with BCR::ABL1 fusion | t(9;22)(q34.1;q11.2) |
| Acute myeloid leukemia with KMT2A rearrangement | t(11;19)(q23.3;p13.3) |
| Acute myeloid leukemia with NPM1 mutation | NPM1 mutation |
| Acute myeloid leukemia with CEBPA mutation | CEBPA mutation |
| Acute myeloid leukemia, myelodysplasia-related | History of MDS or MPN |
| Acute myeloid leukemia with other defined genetic alterations | Other mutations |
| Acute myeloid leukemia, defined by differentiation | Minimal differentiation, maturation, etc. |
Table 109-3: 2022 ELN Risk Classification of AML by Genetics¶
| Risk Category | Genetic Abnormality |
|---|---|
| Favorable | t(8;21)/RUNX1::RUNX1T1, inv(16)/CBFB::MYH11, mutated NPM1 (without FLT3-ITD), bZIP CEBPA mutation |
| Intermediate | Wild-type NPM1 with FLT3-ITD, t(9;11)/MLLT3::KMT2A, complex karyotype |
| Adverse | t(6;9)/DEK::NUP214, t(9;22)/BCR::ABL1, t(8;16)/KAT6A::CREBBP, inv(3)/GATA2, mutated TP53, monosomal karyotype |
1.1 Pathogenesis¶
AML arises from clonal expansion of hematopoietic stem cells with acquired mutations (e.g., DNMT3A, TET2, ASXL1) and chromosomal abnormalities. Germline predispositions (e.g., CEBPA, RUNX1, TP53) increase risk. Therapy-related AML (t-AML) is associated with prior chemotherapy/radiation.
1.2 Classification¶
WHO classification integrates genetic abnormalities (e.g., PML-RARA, RUNX1-RUNX1T1) and cytogenetics. ELN risk stratification uses molecular markers (e.g., NPM1, FLT3, CEBPA) to guide therapy.
2. EPIDEMIOLOGY¶
AML incidence is 20,380 new cases/year in the U.S. (2023). It is the most common acute leukemia in adults, with 1% of all cancers and 31% of acute leukemias. Risk factors include age (>60 years), Down syndrome, myelodysplastic syndromes, and exposure to alkylating agents/radiation. Germline predispositions (e.g., CEBPA, RUNX1, TP53) increase risk.
2.1 Incidence and Demographics¶
AML is most common in adults >60 years, with a median age of 69 years. Incidence peaks in 60–70 years. 5-year survival is <32% in the U.S. AML is the leading cause of leukemia-related deaths (62% of cases).
2.2 Risk Factors¶
Age >60 years, Down syndrome, myelodysplastic syndromes, prior chemotherapy/radiation, and germline mutations (e.g., CEBPA, RUNX1, TP53) are major risk factors. Environmental exposures (benzene, ionizing radiation) contribute to t-AML.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
AML arises from clonal expansion of hematopoietic stem cells with mutations in epigenetic regulators (DNMT3A, TET2, ASXL1) and chromosomal abnormalities. Germline predispositions (e.g., CEBPA, RUNX1, TP53) and acquired mutations (e.g., NPM1, FLT3) drive leukemogenesis. Therapy-related AML (t-AML) is linked to prior chemotherapy/radiation.
3.1 Genetic Abnormalities¶
Common mutations include NPM1 (30% of AML), CEBPA (10–15%), FLT3 (30% of adult AML), and KMT2A rearrangements. Chromosomal abnormalities (e.g., t(15;17), t(8;21), inv(16)) are associated with distinct subtypes and prognoses.
3.2 Predisposing Conditions¶
Germline syndromes (e.g., Fanconi anemia, Bloom syndrome) and acquired conditions (e.g., myelodysplastic syndromes) increase AML risk. Chromosomal instability and defective DNA repair mechanisms contribute to leukemogenesis.
4. CLINICAL FEATURES¶
Symptoms include fatigue, fever, bleeding, and infections. Physical findings may include splenomegaly, hepatomegaly, and skin infiltration. Hematologic findings include anemia, thrombocytopenia, and leukocytosis. MRD detection via flow cytometry and molecular assays is critical for prognosis.
4.1 Symptoms and Signs¶
Nonspecific symptoms (fatigue, weight loss) progress to bleeding, fever, and infections. Monocytic subtypes may present with gum hypertrophy or skin infiltration. CNS involvement may cause headaches or visual changes.
4.2 Hematologic Findings¶
Anemia (normocytic/normochromic), thrombocytopenia, and leukocytosis are common. AML blasts may have Auer rods, abnormal nuclear morphology, and cytoplasmic granules. Bone marrow infiltration may cause pain or organ dysfunction.
5. DIFFERENTIAL DIAGNOSIS¶
AML must be differentiated from other leukemias (e.g., ALL), myelodysplastic syndromes, and reactive hematologic disorders. Morphologic features (e.g., Auer rods) and genetic testing aid differentiation.
5.1 Other Leukemias¶
Acute lymphoblastic leukemia (ALL) is distinguished by lymphoid blasts and CD19 expression. AML with monocytic features may mimic chronic myelomonocytic leukemia (CMML).
5.2 Myelodysplastic Syndromes¶
MDS may evolve into AML (AML-MR). Distinguishing features include dysplastic morphology, clonal evolution, and the presence of blasts (>20%).
6. INVESTIGATIONS & DIAGNOSIS¶
Diagnosis requires CBC, peripheral smear, bone marrow biopsy, flow cytometry, and genetic testing. MRD detection via PCR or next-gen sequencing is critical for risk stratification.
Table 109-4: Initial Diagnostic Evaluation of AML¶
| Category | Tests |
|---|---|
| History | Fatigue, bleeding, fever, splenomegaly, family history |
| Physical Exam | Ecchymosis, fever, CNS signs, splenomegaly |
| Laboratory | CBC, chemistry panel, clotting studies, viral serologies |
| Imaging | Chest X-ray, MRI for CNS involvement |
| Bone Marrow | Aspirate and biopsy, flow cytometry, molecular studies |
| Supportive Care | Central venous access, dental evaluation |
6.1 Laboratory Tests¶
CBC with differential, peripheral smear, and bone marrow biopsy. Flow cytometry identifies immunophenotypic markers (e.g., CD13, CD117, CD34).
6.2 Genetic and Cytogenetic Testing¶
Karyotyping, FISH, and PCR detect chromosomal abnormalities (e.g., t(15;17), t(8;21)) and mutations (e.g., NPM1, FLT3). MRD monitoring uses sensitive assays (e.g., NPM1 PCR).
7. MANAGEMENT & TREATMENT¶
Treatment is risk-stratified. Induction therapy (7+3 regimen) with cytarabine and anthracyclines is standard for younger patients. Older patients receive hypomethylating agents or venetoclax. Allogeneic HCT is recommended for non-favorable-risk patients <75 years.
Table 109-5: Novel Therapies in AML¶
| Therapy | Mechanism | Approval Status |
|---|---|---|
| Midostaurin | FLT3 inhibitor | Approved |
| Gilteritinib | FLT3 inhibitor | Approved |
| Quizartinib | FLT3 inhibitor | Approved |
| Enasidenib | IDH2 inhibitor | Approved |
| Therapy | Mechanism | Approval Status |
|---|---|---|
| Ivosidenib | IDH1 inhibitor | Approved |
| Venetoclax | BCL-2 inhibitor | Approved |
| Liposomal cytarabine | Antimetabolite | Approved |
| Azacitidine | Hypomethylating agent | Approved |
| Glasdegib | Hedgehog inhibitor | Under investigation |
7.1 Induction Therapy¶
Standard regimen: cytarabine (100–200 mg/m²/day ×7) + anthracycline (daunorubicin 60–90 mg/m² ×3). Gemtuzumab ozogamicin may be added for CBF AML. APL uses all-trans retinoic acid (ATRA) and arsenic trioxide.
7.2 Postremission Therapy¶
Consolidation with intermediate-dose cytarabine, allogeneic HCT, or targeted therapies (e.g., FLT3 inhibitors). Venetoclax is used with hypomethylating agents in older patients.
7.3 Supportive Care¶
Platelet and RBC transfusions, antifungal/antibiotic prophylaxis, and growth factor support. Central venous access is critical for chemotherapy administration.
8. PROGNOSIS & COMPLICATIONS¶
Prognosis is stratified by cytogenetics (favorable: t(8;21), inv(16); adverse: complex karyotype, TP53 mutations). Complications include infections, GVHD, and treatment-related toxicity. AML with NPM1 mutation has better outcomes than TP53-mutated disease.
8.1 Survival Rates¶
Favorable-risk AML (t(8;21), inv(16)) has 55–85% 5-year survival. Adverse-risk AML (complex karyotype, TP53 mutations) has <10% survival. Older patients have worse outcomes due to comorbidities.
8.2 Complications¶
Infections (neutropenia), GVHD (allogeneic HCT), and treatment-related toxicity (e.g., myelosuppression, organ damage). APL may present with DIC and intracranial hemorrhage.
9. SPECIAL CONSIDERATIONS¶
Pregnancy requires careful management to avoid teratogenic effects. Elderly patients benefit from hypomethylating agents/venetoclax. CHIP patients have increased risk of AML and cardiovascular disease.
9.1 Pregnancy¶
Avoid chemotherapy during the first trimester. Use of azacitidine/venetoclax is preferred. Monitor for fetal complications and maternal infections.
9.2 Elderly Patients¶
Use of hypomethylating agents (azacitidine) or venetoclax with low-intensity chemotherapy. Allogeneic HCT is considered for non-favorable-risk patients <75 years.
9.3 CHIP and Cardiovascular Risk¶
Patients with clonal hematopoiesis (CHIP) have increased AML risk and cardiovascular complications. Management includes cardiovascular risk modification and early detection of clonal evolution.
10. KEY POINTS & CLINICAL PEARLS¶
AML is a heterogeneous disease requiring risk-stratified therapy. Genetic testing and MRD monitoring are critical for prognosis. Allogeneic HCT is the best relapse-prevention strategy for non-favorable-risk patients. Targeted therapies (e.g., IDH inhibitors) improve outcomes in specific subtypes.