Is there Acute Myeloid Leukemia (AML)?

Acute Myeloid Leukemia (AML) Exists and Is a Well-Defined Hematologic Malignancy

Yes, Acute Myeloid Leukemia (AML) is a real and well-characterized hematologic malignancy that represents the most common form of acute leukemia in adults. 1

Definition and Epidemiology

AML is a clonal hematopoietic malignancy characterized by the accumulation of poorly differentiated myeloid cells with ≥20% blasts in peripheral blood or bone marrow. 2, 3 The disease results from clonal expansion of myeloid blasts in the peripheral blood and bone marrow, disrupting normal hematopoiesis and ultimately leading to bone marrow failure. 1, 4

Incidence and Demographics

• The age-adjusted annual incidence rate of AML is 3.7-4.3 per 100,000 persons in the United States. 1, 5
• In European adults, the incidence is 5-8 cases per 100,000 individuals annually, with a steep increase to 15-25 per 100,000 in patients over 70 years. 1, 3
• AML accounts for the largest number of annual deaths from leukemias in the United States, with approximately 14,590 new cases and 10,370 deaths estimated in 2013. 1
• The median age at diagnosis is approximately 67-70 years, with higher incidence in males. 1, 3
• The mortality rate is approximately 4-6 per 100,000 per year. 1, 3

Diagnostic Criteria

The diagnosis of AML requires ≥20% blasts in bone marrow or peripheral blood, with comprehensive ancillary studies including morphology, immunophenotyping, cytogenetics, and molecular genetics. 1, 2

Essential Diagnostic Components

• Bone marrow aspirate and/or peripheral blood examination with evaluation of at least 500 nucleated cells is mandatory. 2
• Morphological examination using cytochemistry and immunohistochemistry is required for accurate classification. 1, 2
• Immunophenotyping by flow cytometry with a panel sufficient to distinguish AML from other acute leukemias is essential. 2, 3
• Cytogenetic analysis including conventional karyotyping and FISH is mandatory for proper classification and risk stratification. 2, 3
• Molecular genetic testing including FLT3-ITD, NPM1, CEBPA, and RUNX1 mutation analysis is crucial for diagnosis and risk assessment. 2, 4

Important Diagnostic Exception

In patients with recurrent cytogenetic abnormalities including t(15;17), t(8;21), t(16;16), or inv(16), a diagnosis of AML may be made with <20% blasts in an appropriate clinical setting. 1

Disease Characteristics

AML is a genetically complex, dynamic disease with heterogeneous molecular profiles, treatment response, and prognosis. 4, 6

Common Genetic Alterations

The most commonly altered genes include FLT3, NPM1, DNMT3A, IDH1, IDH2, TET2, RUNX1, NRAS, and TP53, with incidence varying by patient age, history of antecedent hematologic cancer, and previous exposure to chemotherapy or radiotherapy. 4

Clinical Presentation

• AML typically presents with rapid onset of symptoms attributable to bone marrow failure. 6
• The disease may be fatal within weeks or months when left untreated. 6
• Coagulopathy is common at presentation, particularly in acute promyelocytic leukemia (APL), which constitutes approximately 10% of AML cases. 1

Risk Stratification

Risk assessment includes patient age, initial leukocyte count, AML subtype, karyotype data, molecular markers, and medical comorbidities. 1, 3

Favorable-Risk Features

• APL with t(15;17)(q22;q12) is considered favorable risk. 1, 3
• Core binding factor AML with t(8;21) and inv(16) are favorable prognostic factors. 1, 3
• Biallelic CEBPA mutation with normal cytogenetics is associated with favorable outcomes. 3

Adverse Prognostic Factors

• Elderly patients (>60 years) have adverse prognosis, particularly with MDR-positivity or unfavorable genetic changes. 1, 3
• Antecedent or concomitant myelodysplastic syndrome is an adverse prognostic factor. 1, 3
• Complex aberrant karyotypes indicate poor prognosis. 1

Treatment Principles

Treatment is divided into induction and consolidation chemotherapy, with therapy planned with curative intent whenever feasible. 1, 3

Standard Induction Therapy

Standard induction regimens for patients aged <60 years are based on cytarabine plus an anthracycline (daunorubicin 45-60 mg/m² daily for 3 days or idarubicin 12 mg/m² daily for 3 days), achieving complete remission rates of 60-70%. 1

FDA-Approved Targeted Therapy

Midostaurin (RYDAPT) is indicated in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy for adult patients with newly diagnosed FLT3 mutation-positive AML. 7 This combination demonstrated superior overall survival compared to placebo plus standard chemotherapy (HR 0.77; 95% CI 0.63,0.95; p=0.016). 7

Recent Therapeutic Advances

Since 2017, multiple molecularly targeted therapies have been approved, including midostaurin, gilteritinib, and quizartinib targeting FLT3 variants; ivosidenib and olutasidenib targeting IDH1 variants; and enasidenib targeting IDH2. 4 The approval of hypomethylating agents combined with venetoclax has revolutionized therapy in older adults, extending survival over monotherapy. 4

Critical Clinical Pitfalls

• Never start chemotherapy before obtaining satisfactory material for all diagnostic tests, as this compromises accurate classification and risk stratification. 2
• Do not rely solely on molecular genetic or FISH testing without conventional cytogenetic analysis, as this provides incomplete prognostic information. 2
• Recognize hyperleukocytosis (WBC >100,000/μL) as a medical emergency requiring immediate intervention with apheresis or hydroxyurea. 2
• In patients with clinical and pathologic features of APL, start ATRA upon first suspicion without waiting for genetic confirmation, as early initiation may prevent lethal bleeding complications. 1

Prognosis

The 5-year survival for AML is approximately 24%, making it the acute leukemia with the shortest survival. 5 However, more than 80% of patients with APL can be cured using ATRA-based induction regimens followed by appropriate consolidation. 1