Acute Myeloid LeukemiaEdit

Acute myeloid leukemia (AML) is a cancer of the blood and bone marrow marked by rapid expansion of abnormal myeloid blasts. These malignant cells crowd the marrow, impair normal blood cell production, and can spill into the peripheral blood and other organs. AML is the most common acute leukemia in adults, with incidence rising sharply with age. It arises from accumulated genetic and epigenetic changes in hematopoietic progenitor cells, and its biology is influenced by a spectrum of cytogenetic and molecular subtypes that guide prognosis and therapy. For diagnosis and classification, clinicians rely on a combination of peripheral blood findings, bone marrow examination, and detailed genetic testing bone marrow cytogenetics molecular testing.

This disease does not present as a single uniform entity but rather encompasses a set of disorders defined by shared clinical features and diverse genetic drivers. Management requires a multidisciplinary approach that combines chemotherapy, risk-adapted consolidation, and supportive care, with selective use of targeted therapies and transplantation. The evolving landscape of cytogenetics and molecular abnormalities testing has refined risk stratification and individualized treatment plans, reflecting a shift toward precision medicine within hematology European LeukemiaNet guidelines t(15;17).

Overview

AML is driven by the abnormal accumulation of immature myeloid cells, or blasts, within the bone marrow that fail to mature into functional white blood cells. The resulting cytopenias (anemia, neutropenia, thrombocytopenia) contribute to fatigue, infection risk, and bleeding tendencies. In addition to bone marrow failure, AML can cause systemic symptoms such as fever, weight loss, and night sweats. The disease is highly heterogeneous at the molecular level, and this heterogeneity is a major determinant of response to therapy and long-term outcomes. Key genetic subtypes include recurrent abnormalities such as [[t(8;21)|t(8;21)], inv(16), t(15;17)]] that carry distinct prognostic implications and therapeutic sensitivities APL.

Classification and prognosis have evolved with advances in cytogenetics and molecular profiling. The latest risk stratification frameworks combine cytogenetic abnormalities with selective mutations such as NPM1 mutation, FLT3-ITD, IDH1, IDH2, and others to categorize patients into favorable, intermediate, or adverse risk groups. This stratification informs decisions about induction intensity, consolidation strategies, and the potential role of allogeneic hematopoietic stem cell transplantation in first remission for suitable candidates ELN.

Pathophysiology and subtypes

AML arises when hematopoietic progenitors acquire mutations that block differentiation and promote self-renewal of malignant blasts. The disease can present de novo or evolve from prior exposures or hematologic conditions such as myelodysplastic syndromes. Specific translocations and mutations have direct implications for treatment. For example, the subset with the t(15;17) translocation defines acute promyelocytic leukemia (APL), a distinct AML variant that responds dramatically to differentiation therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) when used together or sequentially APL.

Key concepts and terms frequently encountered in AML biology include: - myeloid lineage blasts and differentiation arrest - measurable residual disease as a marker of treatment response - cytogenetics and molecular mutations that define risk - epigenetic alterations influencing gene expression without changing DNA sequence

Epidemiology

AML incidence increases with age and shows a male predominance in many populations, though outcomes differ by age, comorbidity, and disease biology. Risk factors include prior exposure to certain cytotoxic therapies (for example, alkylating agents or topoisomerase inhibitors), benzene exposure, and tobacco use. In children, AML is less common than acute lymphoblastic leukemia, but specific subtypes such as acute myeloid leukemia with Down syndrome–associated biology warrant special consideration. Epidemiologic patterns underpin the emphasis on age- and biology-tailored therapy and the need for access to advanced diagnostics across health systems cancer epidemiology.

Clinical presentation and diagnosis

Patients commonly present with fatigue, pallor, easy bruising or bleeding, infections, or related symptoms from marrow failure. Physical findings may include pallor, petechiae, gingival bleeding, and sometimes organomegaly or lymphadenopathy. Diagnostic workup typically includes: - Complete blood count and peripheral smear showing circulating blasts and cytopenias peripheral smear - Bone marrow aspirate and biopsy to confirm marrow involvement and assess morphology - Immunophenotyping by flow cytometry to characterize lineage and aberrant markers - Cytogenetic analysis and targeted molecular testing to identify recurrent abnormalities and mutations - Evaluation for MRD after therapy to gauge depth of response

AML is not defined by a single test. Integrated diagnostics using morphologic, immunophenotypic, cytogenetic, and molecular data guide classification and prognosis and inform treatment planning. See for example bone marrow biopsy and flow cytometry for diagnostic characterization.

Classification and prognosis

The current framework emphasizes genetic and molecular drivers: - Recurrent cytogenetic abnormalities such as t(8;21) and inv(16) are associated with favorable or intermediate risk, depending on accompanying mutations. - The t(15;17) translocation defines acute promyelocytic leukemia (APL), a highly curable AML subset with differentiation therapy. - Mutations in genes like NPM1 without concurrent adverse risk factors can indicate favorable risk, while mutations such as TP53, complex karyotypes, or multiple adverse abnormalities usually indicate higher risk.

Most risk stratification systems integrate cytogenetics with mutations in genes such as FLT3-ITD and CEBPA to categorize patients into favorable, intermediate, or adverse risk groups. These risk categories guide decisions on induction regimens, the need for allogeneic transplantation, and the intensity of consolidation therapy. The goal is to maximize cure chances while balancing treatment-related toxicity, especially in older patients or those with comorbidities.

Treatment approaches

Treatment is typically staged and individualized, combining induction chemotherapy to achieve remission with consolidation strategies to improve long-term control. The strategy varies by age, fitness, disease biology, and access to care.

Induction chemotherapy: The backbone for many patients is a multi-agent regimen often referred to as a 7+3 approach, consisting of cytarabine for seven days plus an anthracycline for three days. The exact drugs and dosing may be tailored to patient factors and specific AML subtypes, with modifications guided by risk stratification and comorbidity 7+3 regimen.
Consolidation therapy: For patients in complete remission, consolidation may involve high-dose cytarabine (HiDAC) or lower-intensity regimens depending on age and risk. In higher-risk disease or when relapse risk remains substantial, allogeneic hematopoietic stem cell transplantation (HSCT) in first remission may be recommended for eligible patients allogeneic HSCT.
Acute promyelocytic leukemia (APL): This subtype is treated with differentiation therapy using all-trans retinoic acid (ATRA) in combination with arsenic trioxide (ATO) or traditional chemotherapy, yielding high cure rates when administered promptly and appropriately APL.
Targeted and novel therapies: The treatment landscape includes targeted agents such as FLT3 inhibitors (e.g., midostaurin for newly diagnosed FLT3-mutated AML and gilteritinib for relapsed/refractory disease) and IDH inhibitors (e.g., ivosidenib and enasidenib). Liposomal cytarabine daunorubicin (CPX-351) provides a regimen option for certain older patients. Antibody-drug conjugates like gemtuzumab ozogamicin have a role in selected cases, particularly in favorable-risk disease where appropriate. Ongoing research explores combinations with immune therapies and other targeted agents targeted therapy CAR-T approaches and MRD-guided treatment planning MRD.
Supportive care: Across all stages, supportive care—blood product transfusions, infection prophylaxis, growth factors, and management of complications—plays a critical role in enabling effective therapy and maintaining quality of life.

Special considerations and controversies

Treatment decisions in AML increasingly depend on a balance between efficacy and tolerability, especially for older adults or those with significant comorbidity. Controversies in the field often center on: - Intensity of induction therapy in older or frail patients versus use of lower-intensity regimens or hypomethylating agent–based approaches. Clinicians weigh expected remission rates against treatment-related toxicity and patient preferences. - The role of allogeneic transplantation in first remission for intermediate- or adverse-risk AML, considering transplant-related mortality and long-term survival versus relapse risk with non-transplant strategies. - Access and cost considerations for expensive targeted therapies and novel regimens, which can vary by health system and payer policy. - The optimal use and sequencing of FLT3 and IDH inhibitors, including the potential benefits of combination therapy versus monotherapy in different risk groups and disease stages. - The use of MRD assessment to guide treatment intensity and the decision to proceed to transplant, reflecting ongoing debate about MRD thresholds and timing.

These topics are debated in clinical guidelines and multidisciplinary discussions, with the common aim of improving survival while reducing treatment burden. See discussions under clinical guidelines and health economics for broader policy perspectives on access and cost.

Outcomes and prognosis

Outcomes vary widely based on age, performance status, and AML biology. Younger patients with favorable-risk features can achieve long-term remissions and potential cure with aggressive therapy and transplantation in selected cases. Older patients or those with adverse-risk biology typically have higher relapse rates and shorter overall survival, although novel therapies and optimized supportive care have improved outcomes for many. Ongoing research continues to refine risk-adapted strategies and to expand the use of targeted agents and immunotherapies in diverse patient populations clinical trials.