Continuing Education Activity

Acute myeloid leukemia (AML) is a rapidly progressing myeloid neoplasm characterized by the clonal expansion of primitive hematopoietic stem cells, known as blasts, in the bone marrow. This expansion results in ineffective erythropoiesis and megakaryopoiesis, clinically manifesting as relatively rapid bone marrow failure compared to chronic and indolent leukemias. This leads to inadequate production of red blood cells and platelets. The recent consensus guidelines established by the European LeukemiaNET (ELN) in 2022 have emphasized molecular characterization and risk stratification for individuals with AML, providing updated data on these aspects.

Treatment options vary depending on patient-specific factors, and hematopoietic stem cell transplant remains the only curative therapy. Although the administration of multiagent induction chemotherapy can achieve complete remission, allogeneic stem cell transplantation is the only established curative therapy. Despite advancements in therapeutic approaches, prognosis remains suboptimal, especially among the older populations. This activity explores the appropriate timing for considering this condition in the differential diagnosis and outlines proper evaluation methods. In addition, this activity emphasizes the crucial role of the interprofessional healthcare team in providing care for patients affected by this condition.

Objectives:

• Identify characteristic clinical features and laboratory findings indicative of acute myeloid leukemia during patient evaluation.

• Implement evidence-based diagnostic and therapeutic strategies for acute myeloid leukemia management in accordance with established guidelines.

• Select appropriate induction and consolidation therapies tailored to individual patient characteristics and disease risk for patients with acute myeloid leukemia.

• Collaborate with multidisciplinary healthcare teams to develop comprehensive care plans and provide support for patients throughout their acute myeloid leukemia journey.

Introduction

Acute myeloid leukemia (AML) is a rapidly progressing myeloid neoplasm characterized by the clonal expansion of immature myeloid-derived cells, known as blasts, in the peripheral blood and bone marrow. This expansion results in ineffective erythropoiesis and megakaryopoiesis, clinically manifesting as relatively rapid bone marrow failure compared to chronic and indolent leukemias. This leads to inadequate production of red blood cells and platelets. 

Although the administration of multiagent induction chemotherapy can induce complete remission, allogeneic stem cell transplantation is the only established curative therapy. Despite advancements in therapeutic approaches, prognosis remains suboptimal, especially among the older populations.[1][2][3].

Etiology

The European LeukemiaNet (ELN) 2022 consensus recommendations offer a valuable framework for classifying AML based on mutational profile.[4][5][6] However, before providers can truly grasp and access this framework, they need to comprehend the origins and pathways of the disease. For example, patients with high and very high-risk myelodysplastic syndrome (MDS), clinically characterized by the presence of transfusion-dependent cytopenias and peripheral blasts, are at increased risk of AML evolution and necessitate vigilant surveillance.[7]

Patients with myeloproliferative neoplasms, which include myelofibrosis, essential thrombocythemia, polycythemia vera, and chronic myeloid leukemia, may also progress or evolve into a higher-grade myeloid neoplasm such as AML.[8] Indications of such progression in these preexisting conditions vary based on the baseline clinical phenotype (eg, thrombocytosis in a patient with essential thrombocythemia), but a common presentation involves declining blood counts alongside peripheral blast elevations. Collectively, these conditions, including MDS and myeloproliferative neoplasms, as well as other disease states, such as aplastic anemia, may lead to what is termed as secondary AML.[9]

Another group of patients at risk for AML includes patients who have previously received chemotherapy for other malignancies. Patients who have been exposed to alkylating agents or radiation (eg, patients receiving breast cancer-directed cyclophosphamide) may develop MDS/AML with chromosome 5 or 7 abnormalities. Such sequelae commonly occur 5 to 7 years after exposure.[10] Other chemotherapeutic agents, particularly topoisomerase inhibitors, may also lead to AML but are associated with 11q23 rearrangements.[11] These phenomena characterize what is effectively known as therapy-related MDS/AML.

Additional environmental exposures, including radiation, tobacco smoke, and benzene, also contribute to the risk of AML.[12] Despite these known risk factors, most cases of AML still arise de novo without an attributable etiology.

Epidemiology

The annual incidence of new cases in both men and women is approximately 4.3 per 100,000 population, totaling over 20,000 cases per year in the United States alone.[13] The median age at the time of diagnosis is about 68, with a higher prevalence observed among non-Hispanic Whites. Furthermore, males exhibit a higher incidence compared to females, with a ratio of 5:3.

Pathophysiology

AML is characterized by the clonal proliferation of undifferentiated myeloid precursors, known as blasts, within the bone marrow compartment. Extensive research, both past and ongoing, investigates the communication pathways of these cells within the bone marrow. However, this proliferation primarily stems from the accumulation of diverse genomic and cytogenetic abnormalities. The clinical manifestations of this process result in ineffective erythropoiesis, megakaryopoiesis, and bone marrow failure. 

AML is a highly heterogeneous disease that requires individualized cytogenetic and molecular characterization. However, broadly speaking, the disease can be categorized into favorable, intermediate, or high-risk groups based on the criteria outlined in the aforementioned ELN 2022 guidelines.[6] Genetic abnormalities that characterize favorable risk disease include chromosomal translocations t(8;21)(q22;q22.1) or inv(16)(p13.1q22). Patients who lack FLT3-ITD (internal tandem duplication) mutations without mutated NPM1 or with CEBPA (bZIP in-frame) mutations are also categorized as favorable risk.

A study even reported that NPM1 mutations were present in up to 35% of patients with AML.[14] Intermediate-risk AML is diagnosed in the presence of any FLT3-ITD mutation or t(9;11)(p21.3;q23.3, or MLL:KMT2A rearrangement). Lastly, high-risk AML categorization can be diagnosed in the presence of several cytogenetic or molecular aberrancies, which notably include monosomy 5/del 5q or 7/deletion 7q, other monosomal or complex karyotype (≥3 unrelated abnormalities), or mutations in ASXL1, EZH2, SRSF2, or TP53. 

Runt-related transcription factor (RUNX1) is an essential component of hematopoiesis and is also known as AML1 protein or core-binding factor subunit alpha-2 (CBFA2). RUNX1 is located on chromosome 21 and is frequently translocated with the ETO (Eight Two One)/RUNX1T1 gene located on chromosome 8q22, creating an AML-ETO or t(8;21)(q22;q22) AML, which is seen in about 12% of AML cases. These mutations, commonly associated with trisomies 13 and 21, show resistance to standard induction therapy.

Mutations in isocitrate dehydrogenase (IDH) are oncogenic and present in 15% to 20% of all AML cases and 25% to 30% of patients with cytogenetically normal AML, with a higher prevalence in older individuals. Additionally, TP53 mutations are associated with a poor prognosis and resistance to chemotherapy.

History and Physical

Due to ineffective erythropoiesis and bone marrow failure, patients may experience various symptoms, including recurrent infections, anemia, easy bruising, excessive bleeding, headaches, and bone pain. Generalized weakness, fatigue, shortness of breath, and chest tightness may also be observed, depending on the degree of anemia. The time course associated with such symptoms is relatively rapid, often on the order of days to weeks.

Common physical examination findings in AML include pallor, bruising, and hepatosplenomegaly, while lymphadenopathy is rare. Myeloid sarcoma, a myeloid equivalent, may present as thickened, hyperpigmented, coarse skin lesions. Disseminated intravascular coagulation (DIC), characterized clinically by oral mucosal hemorrhages, purpura, extremity petechiae, and bleeding from intravenous line sites, is common in AML.

Evaluation

AML should be suspected in individuals presenting with rapid (within days or a few weeks) unexplained cytopenias (decreased leukocytes, hemoglobin, or platelets), circulating blast cells in peripheral blood, easy bruising or bleeding, or recurrent infections. In some cases, patients may present with renal failure due to auto-tumor lysis syndrome (auto-TLS), which, even in the absence of prior chemotherapy, is considered an oncologic emergency.[15][16][17][18] Characteristic laboratory findings indicative of auto-tumor lysis, stemming from high tumor burden and rapid cell turnover, often include elevated LDH, uric acid, potassium, and phosphorus levels.

Obtaining a peripheral blood smear is crucial when any (or all) of these features are present upon initial presentation. Characteristic features, in addition to generalized thrombocytopenia, include blasts, which are large, immature leukocytes with a high nuclear-to-cytoplasmic ratio, irregular nuclear contour, and smooth chromatin with prominent or multiple nucleoli. Blasts typically have cytoplasm that appears pale or deep blue with a variably eosinophilic hue. Additionally, the presence of schistocytes may be observed in cases of concurrent DIC.

Notably, a specific subtype of AML—acute promyelocytic leukemia (APL)—exhibits a distinctive and pathognomonic feature on peripheral blood morphology of abundant cytoplasmic Auer rods, which resemble clumps of azurophilic granules elongated like needles. Collectively, the presence of 20% or more blasts in peripheral blood, as confirmed by immunophenotyping (flow cytometry), is diagnostic of AML. Early involvement of hematologists and hematopathologists is recommended in suspected cases of AML to confirm the diagnosis.

Oncologic emergencies associated with AML include neurologic impairment, including visual deficits, and respiratory distress with parenchymal infiltrates due to leukostasis, DIC, and TLS, as previously mentioned.[19] Following the confirmation of an AML diagnosis, recommended tests should be ordered, including electrocardiography (ECG) and 2-dimensional (2D) echocardiography, to anticipate potential cardiotoxic effects (eg, from anthracycline therapies).

Treatment / Management

Induction Therapy—General Considerations

All induction regimens discussed in forthcoming sections are potentially toxic to the bone marrow and can induce cytopenias and renal failure, particularly in the setting of either auto-tumor lysis, as discussed earlier, or TLS following chemotherapy. Electrolyte imbalances, notably hyperkalemia and hyperphosphatemia, are also common manifestations of TLS, underscoring the importance of establishing baseline cardiac structure and function through methods such as 2D echocardiography, ECG, and telemetry both before and throughout therapy. Another crucial aspect of induction therapy in AML is close hemodynamic monitoring, particularly temperature, within dedicated oncology units. This monitoring is essential as recovery from white blood cell (WBC) count can take up to 28 days, increasing the risk of neutropenic fever during this period.

Notably, before initiating induction therapy, it is crucial to involve bone marrow transplant (BMT) specialists early, particularly for patients with intermediate- or high-risk disease, according to the ELN 2022 criteria mentioned earlier. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative therapy for AML and should be considered for any patient with intermediate- or high-risk disease who achieves complete remission.

Induction Therapy—Regimen Selection

Induction therapy represents the standard of care for all patients with AML, and decisions regarding the selection of induction chemotherapy should not be solely based on age. In younger patients (typically aged 70 or younger), individuals who are deemed fit (ECOG ≤2), and those with de novo AML without complex (ie, ≤3 abnormalities) or poor-risk characteristics, the preferred regimen is the "7+3" protocol. This regimen involves a continuous infusion of cytarabine (ie, Ara-C) for 7 days combined with anthracycline administration on days 1 to 3. When using daunorubicin, a dosage of 90 mg/m²/d has been associated with improved overall survival.[20] 

In patients with complex or poor-risk cytogenetics, secondary, or therapy-related AML, FLAG is the preferred regimen.[21] In addition, for patients aged 18 to 75 receiving standard 7+3 induction therapy with FLT3-ITD mutations, quizartinib should also be added as per the results of QUANTUM.[22] In older patients (typically aged 70 or older) and people who are deemed fit, the most commonly utilized regimen is a combination of a hypomethylating agent—either azacitidine or decitabine—and Bcl-2 inhibitor/BH3 mimetic therapy of venetoclax.[23] 

Adults who are deemed unfit for therapy may receive the best supportive care. If patients achieve complete remission, the hypomethylating agent + venetoclax regimen can be continued indefinitely, although the duration of treatment should be carefully evaluated through a comprehensive risk/benefit assessment involving the physician, family, and patient.

Lastly, if APL is suspected, then the treatment should be initiated with all-trans retinoic acid (ATRA), and diagnosis should be confirmed either by peripheral blood immunophenotyping, bone marrow biopsy, or fluorescence in situ hybridization (FISH) for t(15;17)/PML::RARA. If the WBC count is more than 10 K/μL (considering high-risk by Sanz criteria), full induction therapy with ATRA + arsenic trioxide and anthracycline should not be initiated until the diagnosis is confirmed.[24]

Response Assessment

In young, fit individuals undergoing a 7+3 or FLAG-based induction regimen, a bone marrow biopsy should ideally be performed after induction therapy around the time of peripheral count recovery, particularly when the absolute neutrophil count exceeds 1000/μL and platelet count exceeds 100 K/μL with no blasts present. Complete remission can be considered if the marrow shows no morphological evidence of leukemia with less than 5% blasts by aspirate differential, consistent with peripheral blood count values. The timing of post-induction therapy bone marrow biopsy remains a topic of debate. Although some advocate for performing it upon full count recovery (which corresponds with approximately 28 days), others argue for a universal performance at day 14 to ensure that residual leukemia is not present and the marrow appears chemo-ablated (as expected). 

In older patients undergoing induction therapy with hypomethylating agent + venetoclax, the median response time ranges from 1.2 to 1.4 months.[25] Accordingly, the initial bone marrow biopsy following induction is typically conducted after at least 2 complete cycles of therapy, each lasting 28 days. 

Consolidation Therapy

Despite achieving a complete response with optimal induction therapy, minimal residual disease often persists, necessitating consolidation therapy to mitigate the risk of relapse by eliminating residual disease. In patients who have received 7+3 induction therapy, consolidation therapy is initiated with high-dose cytarabine, also known as HiDAC. Those who received FLAG during induction should undergo additional cycles of the same regimen during consolidation. Additionally, all patients with intermediate- or high-risk disease, regardless of the regimen, who are suitable candidates, should be offered allogeneic HSCT for complete remission, overseen by experienced BMT physicians at a high-volume center.[25][26][27][28]

Relapsed/Post-HSCT Acute Myeloid Leukemia

Several agents are available for patients experiencing relapsed AML with specific mutations identified through molecular sequencing techniques. Fms-like tyrosine kinase 3 (FLT3) inhibitors, such as gilteritinib, may be recommended and have demonstrated higher complete remission rates than salvage chemotherapy in this patient population.[29] Patients with IDH1 mutations, either in the relapsed setting or among older populations, unfit individuals unsuitable for induction therapy, should be offered ivosidenib or olutasidenib.[30][31] Similarly, individuals with IDH2 mutations under the same designation may be offered enasidenib.[32] Sorfaneib is approved as maintenance therapy following allogeneic HSCT for patients with FLT3-ITD mutations.[33]

Transfusional Support

All blood products must undergo irradiation to prevent transfusion-related graft versus host disease.

Differential Diagnosis

Other diseases with presentations similar to AML include Acute lymphoblastic leukemia, anemia, aplastic anemia, B-cell lymphoma, bone marrow failure, chronic myelogenous leukemia, lymphoblastic lymphoma, MDS, myelophthisic anemia, and primary myelofibrosis.

Staging

In the past, the French-American-British (FAB) system classified AML into 8 subtypes—FAB M0 to M7—as mentioned below.

• M0: Undifferentiated AML
• M1: AML with minimal maturation
• M2: AML with maturation
• M3: APL
• M4: Acute myelomonocytic leukemia
• M5: Acute monocytic leukemia
• M6: Acute erythroid leukemia
• M7: Acute megakaryocytic leukemia

In 2016, the World Health Organization (WHO) revised the classification of AML, categorizing it into the following groups:

• AML with recurrent genetic abnormalities
• AML with myelodysplasia-related changes
• Therapy-related myeloid neoplasms
• AML, not otherwise specified (NOS)
• Myeloid sarcoma
• Myeloid proliferations related to Down syndrome.

AML with recurrent genetic abnormalities includes the following: 

• AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1
• AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
• APL with t(15;17)(q22;q12); PML-RARA
• AML with t(9;11)(p21.3;q23.3); MLLT3-KMT2A
• AML with t(6;9)(p23;q24); DEK-NUP214
• AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM
• AML (megakaryoblastic) with t(1;22)(p13.3;q13.3); RBM15-MKL1
• AML with mutated NPM1

 AML NOS includes the following:

• AML with minimal differentiation
• AML without maturation
• AML with maturation
• Acute myelomonocytic leukemia
• Acute monoblastic/monocytic leukemia
• Pure erythroid leukemia
• Acute megakaryoblastic leukemia
• Acute basophilic leukemia
• Acute panmyelosis with myelofibrosis

Based on its etiology, AML can be categorized into 3 main types—de novo AML, which arises spontaneously; secondary AML (s-AML), which evolves from prior myeloproliferative disorders or MDS; and therapy-related AML, resulting from exposure to chemotherapeutic agents, radiation therapy, or toxins.

The latest 2022 guidelines established by the ELN are now considered the standard for leukemia classification. Perhaps a notable alteration in these guidelines is the modification to the blast threshold needed to define disease, particularly in the presence of recurrent genetic abnormalities, set at 10% or more. Additionally, new types of AML with recurrent genetic abnormalities have been included as follows:

• AML with in-frame bZIP-mutated CEBPA
• AML with t(9;22)(q34.1;q11.2)/BCR::ABL1

Prognosis

Prognosis in AML depends on an individual patient's cytogenetic and molecular characterization. A favorable-risk AML, for instance, can be diagnosed in the presence of translocation of specific chromosomal material, including t(8;21), t(15;17), and inversion of chromosome 16, or t(16;16). Higher-risk cytogenetic aberrancies or mutations, such as t(6;9)(p23.3;q34.1) or mutations in ASXL1 and U2AF1, generate a higher risk and indicate a less favorable prognosis. Adverse outcomes have been noted with older age, WBC count (>100,000 at diagnosis), secondary or therapy-related AML, and the presence of leukemic cells in the central nervous system.

Recent techniques, including PCR and flow cytometry, can detect the presence of minimal residual disease in patients with complete remission. Persistently elevated levels of RUNX1-RUNX1T1, despite induction therapy, in patients with t(8;21) AML are associated with an increased incidence of relapse.

Enhancing Healthcare Team Outcomes

AML, although rare among adults, can rapidly lead to fatalities if not promptly diagnosed and managed expeditiously by an interprofessional healthcare team comprising oncologists, hematologists, hematopathologists, clinical pharmacists, and nurses experienced in chemotherapy administration.

Pharmacists should provide comprehensive education to the patient regarding the chemotherapeutic regimen, covering both its benefits and potential adverse effects. Meanwhile, oncology nurses are critical in treatment administration and vigilantly monitoring for any potential complications. Additionally, nurses are crucial in educating patients and their families, particularly regarding infection prevention measures such as handwashing, fruit and vegetable rinsing, avoiding crowded places, and promptly seeking medical attention if fever develops in the outpatient setting.

Interventional radiologists are crucial in placing long-term venous catheters and conducting necessary imaging studies. Primary care physicians are responsible for educating patients on infection control measures and immunizations and managing other medical conditions. Dieticians provide valuable support in nutritional management, while social workers ensure that a patient receives comprehensive support to successfully undergo treatment.

After discharge from the inpatient setting, patients are advised to convene a weekly multidisciplinary conference to assess the initial management of AML and any ongoing care, such as consolidative chemotherapy or allogeneic stem cell transplantation, if deemed appropriate. An interprofessional approach to evaluation and management is paramount for achieving optimal patient outcomes.[34][35]