AML Review: Emerging Subtypes, Diagnostics, and Prognosis

Acute myeloid leukemia (AML) is a heterogeneous blood cancer arising from genetic and molecular abnormalities in myeloid precursor cells. Despite research advances, AML remains challenging to treat due to its diverse subtypes and variable responses to therapy.

Recent discoveries have refined the molecular landscape of AML, improving classification, diagnostics, and targeted treatments. Keeping pace with these advancements is essential for optimizing patient outcomes.

Key Molecular Drivers

AML develops through a complex interplay of genetic mutations, chromosomal rearrangements, and epigenetic modifications. Among the most frequently implicated genetic alterations are mutations in FLT3, NPM1, and DNMT3A. FLT3 mutations, particularly internal tandem duplications (FLT3-ITD), drive aggressive disease progression by activating tyrosine kinase signaling, leading to unchecked proliferation of leukemic blasts. NPM1 mutations, often co-occurring with FLT3 or DNMT3A mutations, define a subset of AML with a more favorable prognosis in the absence of adverse cytogenetic features.

Chromosomal abnormalities such as t(8;21), inv(16), and t(15;17) play a defining role in AML classification. These translocations frequently result in fusion proteins that disrupt normal hematopoietic differentiation. The RUNX1-RUNX1T1 fusion from t(8;21) interferes with transcriptional regulation, while the CBFB-MYH11 fusion from inv(16) impairs core-binding factor function. These structural alterations also serve as therapeutic targets, as seen with all-trans retinoic acid (ATRA) and arsenic trioxide in acute promyelocytic leukemia (APL), driven by the PML-RARA fusion.

Epigenetic dysregulation further complicates AML, with mutations in TET2, IDH1/2, and ASXL1 altering DNA methylation and histone modification. IDH1 and IDH2 mutations produce the oncometabolite 2-hydroxyglutarate, which inhibits DNA demethylation and blocks differentiation. These changes contribute to treatment resistance, as aberrant methylation patterns influence drug sensitivity.

Major Subtypes

AML is categorized into distinct subtypes based on genetic, cytogenetic, and morphologic characteristics, influencing disease progression and treatment response. The 2022 World Health Organization (WHO) classification and International Consensus Classification (ICC) integrate molecular markers to enhance diagnostic precision.

Core-binding factor (CBF) AML includes t(8;21) RUNX1-RUNX1T1 and inv(16) CBFB-MYH11, which disrupt transcription factors essential for hematopoiesis. These subtypes generally respond well to intensive chemotherapy, particularly high-dose cytarabine, with long-term survival rates exceeding 60% in younger patients. However, secondary mutations, such as KIT alterations, increase relapse risk. Genomic profiling helps stratify patients within this category, guiding treatment decisions.

APL, driven by the PML-RARA fusion from t(15;17), is biologically and clinically distinct. This translocation disrupts retinoic acid receptor signaling, blocking differentiation and leading to promyelocyte accumulation. APL responds well to ATRA and arsenic trioxide, achieving remission rates over 90%. However, early mortality remains a concern due to disseminated intravascular coagulation (DIC), necessitating prompt therapy initiation. Risk-adapted strategies now minimize chemotherapy exposure in low-risk patients while maintaining durable remissions.

AML with myelodysplasia-related changes (AML-MRC) includes cases with a history of myelodysplastic syndromes (MDS) or specific cytogenetic abnormalities, such as deletions in chromosomes 5 and 7. This subtype is frequently associated with mutations in RNA splicing (SF3B1, SRSF2) and chromatin modification (ASXL1, EZH2) genes, leading to ineffective hematopoiesis. AML-MRC often resists standard chemotherapy, making hypomethylating agents and emerging targeted therapies critical treatment options. Prognosis remains poor compared to de novo AML, particularly in older patients.

Clinical Indicators

AML often presents with symptoms of bone marrow failure due to leukemic infiltration. Fatigue, pallor, and dyspnea arise from anemia, while thrombocytopenia leads to easy bruising, petechiae, and prolonged bleeding. Neutropenia increases infection risk, with bacterial and fungal pathogens posing significant threats. Fever is common but may indicate infection rather than leukemic activity.

Leukemic burden can lead to organ-specific complications. Hepatosplenomegaly may occur due to extramedullary infiltration, while lymphadenopathy is less common than in lymphoid malignancies. Leukostasis, caused by excessive circulating blasts, can result in respiratory distress and neurological symptoms such as headaches and dizziness, particularly when white blood cell counts exceed 100,000/µL. This condition often requires urgent intervention with leukapheresis and cytoreductive therapy. Gingival infiltration, seen in monocytic subtypes, presents as gum hypertrophy and can be an early diagnostic clue.

Severe complications include DIC, particularly in APL, where excessive promyelocyte granule release triggers clotting and hemorrhagic complications. Patients may exhibit concurrent thrombotic and bleeding tendencies, requiring careful management with transfusions and targeted therapy. Tumor lysis syndrome, seen in highly proliferative cases, leads to life-threatening electrolyte imbalances, including hyperkalemia and hyperphosphatemia. Preventative measures such as aggressive hydration and uric acid-lowering agents are often necessary.

Diagnostic Methods

AML diagnosis relies on morphological assessment, flow cytometry, cytogenetics, and molecular testing. Peripheral blood smears and bone marrow aspirates reveal increased myeloblasts with high nuclear-to-cytoplasmic ratios, prominent nucleoli, and, in some cases, Auer rods—needle-like inclusions that strongly suggest AML.

Flow cytometry characterizes surface and cytoplasmic markers unique to AML. Aberrant expression of CD34, CD117, and myeloid-associated antigens like CD13 and CD33 helps differentiate AML from other hematologic malignancies. Immunophenotyping also distinguishes subtypes, such as APL, which often presents as CD34-negative and CD117-positive with strong CD64 and CD11c expression.

Cytogenetic analysis via karyotyping and fluorescence in situ hybridization (FISH) identifies structural chromosomal abnormalities that influence treatment. Recurrent translocations, such as t(8;21) and inv(16), define CBF-AML, while complex karyotypes, including deletions in chromosomes 5 and 7, indicate a more aggressive disease course. Next-generation sequencing (NGS) has revolutionized AML diagnostics by detecting mutations in FLT3, NPM1, and IDH1/2, which aid in risk stratification and guide targeted therapy selection.

Treatment Strategies

AML treatment has evolved with conventional chemotherapy, targeted agents, and immunotherapies. Treatment selection depends on patient factors such as age, comorbidities, and molecular risk stratification. Younger, fit patients typically receive intensive induction chemotherapy with a cytarabine and anthracycline combination, known as the “7+3” regimen. This approach aims to achieve complete remission by eradicating leukemic blasts while preserving normal hematopoiesis. Patients with favorable-risk cytogenetics, such as CBF-AML, often respond well, while those with adverse mutations, such as TP53 alterations, exhibit lower response rates and increased relapse risk.

Targeted therapies have transformed AML management. FLT3 inhibitors like midostaurin and gilteritinib improve outcomes in FLT3-mutated disease, particularly when combined with chemotherapy or used in relapsed settings. IDH1 and IDH2 inhibitors, such as ivosidenib and enasidenib, promote leukemic cell differentiation, offering alternatives to cytotoxic chemotherapy. For older patients or those unfit for intensive therapy, hypomethylating agents like azacitidine and decitabine provide a less toxic option, often combined with the BCL-2 inhibitor venetoclax to enhance response rates. These regimens have expanded treatment possibilities, demonstrating improved survival in clinical trials.

Prognostic Factors

AML prognosis is influenced by genetic, clinical, and treatment-related variables. Cytogenetic abnormalities remain key predictors, with favorable-risk groups, such as those with t(8;21) or inv(16), showing higher remission rates and prolonged survival. In contrast, complex karyotypes, monosomal karyotypes, and TP53 mutations are associated with resistance to conventional therapy and poor survival, often necessitating alternative treatment approaches.

Minimal residual disease (MRD) is a critical prognostic indicator, offering insight into treatment response and relapse risk. MRD assessment through flow cytometry or molecular techniques detects residual leukemic cells not evident through standard evaluation. Persistent MRD after induction therapy significantly increases relapse risk, prompting considerations for intensified therapy or transplantation. Additionally, patient factors such as age and performance status influence survival, with older individuals experiencing lower remission rates and increased treatment-related complications. As therapeutic strategies advance, MRD-directed interventions and risk-adapted approaches will remain central to improving AML outcomes.