Acute Myeloid Leukemia (AML)

• Acute myeloid leukemia (AML) is characterized by infiltration of blood, bone marrow, and other tissues by proliferative, clonal, poorly differentiated hematopoietic cells.
• Untreated AML is uniformly fatal.

Incidence

• In 2020, there were approximately19,940 new AML cases in the United States.
• AML accounts for 1.3% of all cancer cases and 31% of new acute leukemias.
• AML causes 62% of leukemic deaths.
• AML is mostly diagnosed in older patients, with a median age of 67 years at diagnosis.
• Long-term AML survival is infrequent; Only 27% of patients survive 5 years.

Etiology

• Most AML cases are idiopathic, arising from a limited number of mutations accumulating with age.
• Genetic predisposition, radiation, chemical/occupational exposures, and drugs have been implicated in AML development, but AML cases with established etiology are rare.
• Blood cells from 5-6% of normal individuals aged >70 years contain "premalignant" mutations linked to clonal expansion.
• CHIP, or clonal hematopoiesis of indeterminate potential, is associated with blood cancer evolution and other medical conditions.
• Clonal expansion increases the risk of hematologic malignancy 10-fold.
• Additional "hits" are needed to drive CHIP toward leukemia.
• CHIP patients have increased risk of cardiovascular mortality.
• Monocyte infiltration accelerates atherosclerotic plaque development and alters cardiac remodeling.
• Altered relationships between hematopoietic stem cells and the bone marrow microenvironment increase the likelihood of clone survival, additional mutations, and leukemia development.
• Whether CHIP identification will provide therapeutic opportunities remains to be seen.

Genetic Predisposition

• Myeloid neoplasms typically occur sporadically in adults, but inherited predisposition is also possible.
• Myeloid neoplasms with germline predisposition represent a significant group of diseases.
• Germline mutations associated with increased risk of myeloid neoplasm development include CEBPA, DDX41, RUNX1, ANKRD26, ETV6, and GATA2.
• Myeloid neoplasms with germline predisposition are a feature of clinical syndromes, including bone marrow failure disorders (such as Fanconi anemia) and telomere biology disorders (such as dyskeratosis congenita).
• Several genetic syndromes with somatic cell chromosome aneuploidy, such as Down syndrome with trisomy 21, are associated with increased AML incidence.
• Down syndrome-associated AML in young children is acute megakaryocytic subtype and associated with mutation in the GATAI gene.

WHO 2016 Classification of Myeloid Neoplasms with Germline Predisposition

• Myeloid neoplasms with germline predisposition without a preexisting disorder or organ dysfunction: e.g. acute myeloid leukemia with germline CEBPA mutation

• Myeloid neoplasms with germline predisposition and preexisting platelet disorders e.g. Myeloid neoplasms with germline RUNX1 mutation

• Myeloid neoplasms with germline predisposition and other organ dysfunction e.g. Myeloid neoplasms with germline GATA2 mutation

• Myeloid neoplasms associated with bone marrow failure syndromes

• Myeloid neoplasms associated with telomere biology disorders

• Myeloid neoplasms associated with Noonan syndrome

• Myeloid neoplasms associated with Down syndrome

• The WHO classification defines biologically distinct groups based on cytogenetic and molecular abnormalities, clinical features, and light microscope morphology.

• Myeloid neoplasms with germline predisposition are featured in the WHO classification.

Chemical, Radiation, and Other Exposures

• Anticancer drugs are the leading cause of therapy-associated AML.
• Alkylating agent-associated leukemias appear 4-6 years after exposure, with multilineage dysplasia and monosomy/aberrations in chromosomes 5 and 7.
• Topoisomerase II inhibitor-associated leukemias appear 1-3 years after exposure, with AML with monocytic features and aberrations involving chromosome 11q23.
• Exposure to ionizing radiation, benzene, chloramphenicol, phenylbutazone, and other drugs can result in bone marrow failure that may evolve into AML, but this is uncommon.

Classification

• The WHO classification defines distinct groups based on cytogenetic and molecular abnormalities, clinical features, and light microscope morphology.
• Myeloid neoplasms with germline predisposition are included in the WHO classification.

WHO 2016 Classification of Acute Myeloid Leukemia and Related Neoplasms

• Acute myeloid leukemia (AML) with recurrent genetic abnormalities
• AML with t(8;21)(q22;q22); RUNX1-RUNX1T1
• AML with inv(16)(p13.1q22) or t(16;16) (p13.1;q22); CBFB-MYH11
• Acute promyelocytic leukemia with PML-RARA
• AML with t(9;11) (p21.3;q23.3); MLLT3-KMT2A
• AML with t(6;9)(p23;q34.1); 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
• Provisional entity: AML with BCR-ABL1
• AML with mutated NPM1
• AML with biallelic mutations of CEBPA
• Provisional entity: AML with mutated RUNX1
• AML with myelodysplasia-related changes
• Therapy-related myeloid neoplasms
• AML, not otherwise specified (NOS)
• 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
• Myeloid sarcoma
• Myeloid proliferations related to Down syndrome
• Transient abnormal myelopoiesis (TAM)
• Myeloid leukemia associated with Down syndrome
• Marrow blast count of ≥20% is required, except for AML with the recurrent genetic abnormalities t(15;17), t(8;21), inv(16), or t(16;16).

Clinical Features

• Therapy-related AML is a distinct entity that develops following prior chemotherapy (e.g., alkylating agents, topoisomerase II inhibitors) or ionizing radiation.
• AML with myelodysplasia-related changes is recognized by morphology and medical history of antecedent myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasm.

Genetic Findings

• Subtypes of AML are based on the presence or absence of specific, recurrent cytogenetic, and/or genetic abnormalities.

• Acute promyelocytic leukemia (APL) is based on the presence of either the t(15;17) (q22;q12) cytogenetic rearrangement or the PML-RARA fusion product of the translocation.

• Core binding factor (CBF) AML is designated based on the presence of t(8;21)(q22;q22), inv(16) (p13.1q22), or t(16;16)(p13.1;q22) or the respective fusion products RUNX1-RUNX1T1 and CBFB-MYH11.

• Several cytogenetic or genetic AML subtypes often associate with a specific morphologic appearance, such as a complex karyotype (and/or mutation of TP53) and AML with myelodysplasia-related changes.

• Only one abnormality is invariably associated with specific morphologic features: t(15;17)(q22;q12) or the molecular fusion PML-RARA with APL.

• The mutation of nucleophosmin (nucleolar phosphoprotein B23, numatrin, NPM1), especially when co-occurring with fms-related tyrosine kinase 3 (FLT3), often presents with "cup-shaped" nuclear morphology.

• Recurring chromosomal abnormalities in AML may also be loosely associated with specific clinical characteristics.

• More commonly associated with younger age are t(8;21) and t(15;17) and with older age, del(5q), del(7q), and mutated TP53.

• Myeloid sarcomas are associated with t(8;21); disseminated intravascular coagulation (DIC) is associated with t(15;17).

• 11q23 aberrations and monocytic leukemia are associated with extramedullary sites of involvement at presentation, especially gingival hypertrophy.

• High leukocyte count is commonly observed with NPM1 or FLT3 mutation.

• the WHO classification also recognizes fusion genes or specific genetic mutations with a role in leukemogenesis.

• Unique clinical therapy with retinoic acid and arsenic trioxide has revolutionized the care of APL patients (see "Treatment of Acute Promyelocytic Leukemia" section).

• The WHO classification of AML expands as knowledge of specific genetic or cytogenetic aberrations grows.

• Several AML subtypes are defined by the presence of genetic mutations rather than chromosomal aberrations.

• AML with mutated NPM1 and AML with biallelic mutated CEBPA are associated with more favorable clinical outcome.

• FLT3 activating mutations are present in ~30% of adult AML patients and have negative prognostic impact.

• Aberrant activation of the FLT3-encoded protein provides increased proliferation and antiapoptotic signals to the myeloid progenitor cell.

• FLT3-ITD occurs preferentially in patients with cytogenetically normal AML (CN-AML), useful as a prognosticator and to predict response to therapies.

• FLT3 allelic ratio provides information beyond the mere presence or absence of the FLT3-ITD mutation.

• Patients with FLT3-ITD "low" allelic ratio (<0.5) fare better, those with FLT3-ITDhigh have an adverse prognostic impact; patients with both mutated NPM1 and FLT3-ITD with an allelic ratio >0.5 are intermediate risk.

• AML with BCR-ABL1 fusion is a new provisional entity to recognize rare cases that may benefit from BCR-ABL TKI therapy.

Immunophenotypic Findings

• Immunophenotyping can be important in quickly distinguishing AML from acute lymphoblastic leukemia and for identifying some subtypes of AML.
• Multiparameter flow cytometry is increasingly used for measurable residual disease (MRD) measurement after remission.

Prognostic Factors

• Chromosome and molecular investigations at diagnosis currently provide the most important prognostic information.
• WHO has categorized patients as having favorable, intermediate, or adverse risk based on structural and/or numerical chromosomal or genetic aberrations.
• Patients with t(15;17) have a very good prognosis (~85% cured), those with t(8;21) and inv(16) have a good prognosis (~5% cured)
• Those with no cytogenetic abnormality have an intermediate outcome risk (~40% cured).
• TP53 mutation, complex karyotype, t(6;9), inv(3), or -7 indicate a very poor prognosis. The monosomal karyotype has been suggested to adversely influence the outcome of AML patients other than those with t(15;17), t(8;21), or inv(16) or t(16;16).
• Lack of favorable cytogenetic abnormalities indicates the importance of testing for mutated genes.
• Mutations of CEBPA predict favorable outcome.

Molecular Prognostic Markers in AML

• Genes Included in the WHO Classification and ELN Reporting System

• NPM1 mutations (Favorable)

• CEBPA mutations (Favorable)

• FLT3-ITD (Depends on allelic ratio and NPM1 mutational status)

• Genes Encoding Receptor Tyrosine Kinases

• KIT mutation (Adverse)

• FLT3-TKD (Unclear)

• Genes Encoding Transcription Factors

• RUNX1 mutations (Adverse)

• Genes Encoding Epigenetic Modifiers

• ASXL1 mutations (Adverse)

• DNMT3A mutations (Adverse)

• IDH mutations (IDH1 and IDH2) (Adverse)

• Deregulated Genes

• BAALC overexpression (Adverse)

• ERG overexpression (Adverse)

• MN1 overexpression (Adverse)

• EVI1 overexpression (Adverse)

• Deregulated MicroRNAs

• miR-155 overexpression (Adverse)

• miR-3151 overexpression (Adverse)

• miR-181a overexpression (Favorable)

• In addition to NPM1, CEBPA, FLT3, and TP53 mutations, aberrations in other genes may be used for prognostication.

• Among these genes are receptor tyrosine kinases (KIT), transcription factors (RUNX1, WTI), and epigenetic modifiers (ASXL1, DNMT3A, IDH1, IDH2, KMT2A, and TET2).

• Mutations of ASXL1 and RUNX1 are associated with adverse outcome and, due to conflicting reports, data remain unclear on the prognostic impact of other mutations.

• Drug approvals have been made due to novel drugs effectively targeting gene subsets.

• In addition to gene mutations, deregulation of expression levels of coding genes and microRNAs provides prognostic information.

• BAALC, ERG, MN1, MDS1, and EVII complex locus overexpression predict poor outcome.

• MicroRNA overexpression of miR-155 and miR-3151 predicts unfavorable outcome and miR-181a predicts favorable outcome.

• Even with an increasing amount of predictive markers, it is recognised that many patients have at least two or more prognostic gene mutations, combinations are more informative than single markers.

• Epigenetic changes (DNA methylation and histone modification) contribute to leukemogenesis and may associate with the previously discussed prognostic gene mutations.

• Therapeutic progress based on advances in understanding the role of epigenetic changes in AML is unfolding with IDHI and/or IDH2 inhibition using novel active enzymes.

• Several other factors are associated with outcome in AML, including age at diagnosis and a history of antecedent hematologic disorders.

• Cytopenia is a clinical feature associated with a lower complete remission (CR) rate and shorter survival time.

• Treatment with cytotoxic agents for other malignancies is also usually difficult to treat, as with older patients overall.

• Other factors associated with worse outcome are a poor performance status and a high presenting leukocyte count.

• Following leukemia therapy, achievement of CR is associated with better outcome and longer survival.

• Circulating blasts should be absent in circulating studies and the bone marrow should contain <5% blasts, and Auer rods should be absent.

• Extramedullary leukemia should not be present upon examination.

Clinical Presentation

• Patients with AML usually present with nonspecific symptoms that begin gradually or abruptly and are the consequence of anemia, leukocytosis, leukopenia/leukocyte dysfunction, or thrombocytopenia.
• Nearly half have symptoms for ≤3 months before the leukemia is diagnosed.
• Fatigue, anorexia, and weight loss are common.
• Common signs of abnormal hemostasis (bleeding, easy bruising), and bone pain.
• Rare instances present symptoms from a myeloid sarcoma (a tumor mass consisting of myeloid blasts).
• Monosomy 7, trisomy 8, 11q23 rearrangement, inv(16), trisomy 4, t(8;21) may precede or coincide with blood and/or marrow involvement by AML.
• Patients presenting with isolated myeloid sarcoma typically develop blood and/or marrow involvement quickly thereafter and cannot be cured with local therapy (radiation or surgery) alone.
• Physical findings include fever, infection, and hemorrhage at diagnosis.
• Splenomegaly, hepatomegaly, lymphadenopathy, and "bone pain" may be present less commonly.
• Retinal hemorrhages are detected in 15% of patients.

Hematologic Findings

• Anemia is usually present at diagnosis, although it is not typically severe.
• The median presenting leukocyte count is 15,000/μL.
• The cytoplasm often contains primary (nonspecific) granules, and the nucleus shows fine, lacy chromatin with one or more nucleoli characteristic of immature cells.
• Abnormal rod-shaped granules called Auer rods are not uniformly present, but when they are, AML is virtually certain.
• Both morphologic and functional platelet abnormalities can be observed.

Pretreatment Evaluation

• Thorough evaluation and initiation of appropriate therapy should follow.
• Studies should evaluate the overall functional integrity of the major organ systems (cardiovascular, pulmonary, hepatic, and renal systems).

Initial Diagnostic Evaluation and Management of Adult Patients with AML History

• Increasing fatigue or decreased exercise tolerance (anemia
• Excess bleeding or bleeding from unusual sites (DIC, thrombocytopenia)
• Fevers or recurrent infections (neutropenia)
• Headache, vision changes, nonfocal neurologic abnormalities (CNS leukemia or bleed)
• Family history of AML (Fanconi, Bloom, or Kostmann syndromes or ataxia-telangiectasia)
• History of cancer (exposure to alkylating agents, radiation, topoisomerase II inhibitors)
• Occupational exposures (radiation, benzene, petroleum products, paint, smoking, pesticides)
• Performance status (prognostic factor)
• Ecchymosis and oozing from IV sites (DIC, possible acute promyelocytic leukemia)
• Fever and tachycardia (signs of infection)
• Papilledema, retinal infiltrates, cranial nerve abnormalities (CNS leukemia)
• Gym hypertrophy (leukemic infiltration, most common in monocytic leukemia)
• Skin infiltration, most common in monocytics
• Possible laboratory and radiologic studies include complete blood count, chemistry tests, and clotting studies
• Interventions for specific patients include dental evaluation, lumbar puncture

Treatment

• Divided into two phases, induction and postremission (consolidation)
• Initial goal is to induce CR, then further therapy must be given to prolong survival and achieve cure.
• Therapy choices based on the patient's age, fitness, and cytogenetic/molecular risk.
• Intensive therapy with cytarabine and anthracycline increases the cure rate of AML in younger patients.
• Older patients, the benefit of intensive therapy is controversial in all but favorable-risk patients; novel approaches are being pursued to select.

Induction Chemotherapy

• Most commonly used induction regimens consist of combination chemotherapy with cytarabine and an anthracycline (e.g., daunorubicin, idarubicin).
• With the 7 and 3 regimen, it is now established that 45 mg/m² dosing of daunorubicin results in inferior outcomes; patients receive higher doses.
• Patients given reinduction with same therapy after failure from one induction, may add gemtuzumab ozogamicin.

Post-Remission Therapy

• Induction given for a CR1 but wihout will eventually lead to relapse, need for additional therapy.
• As with induction, the type of postremission therapy is selected for each individual patient based on age, fitness, and cytogenetic/molecular risk.
• Novel therapies include trials.
• Transplantation for relapse-prevention by transplant in treatment.
• Transplant recommended for patience less than 75 without favorable-risk disease and has an HLA match.
• The benefit of GVL in relapse risk reduction is offset by increased morbidity and mortality from complications of allogeneic HCT including graft-versus-host disease (GVHD).
• Salvage or maintenance following relapse is not guaranteed for care.

Novel Therapies in Clinical Development in Acute Myeloid Leukemia (AML)

• Protein kinase inhibitors

• FLT3 inhibitors (midostaurin, quizartinib, gilteritinib, crenolanib, sorafenib)

• KIT inhibitors

• PI3K/AKT/mTOR inhibitors

• Epigenetic modulators

• New DNA methyltransferase inhibitors (SGI-110) Chemotherapeutic agents

• CPX-351 (liposomal cytarabine and daunorubicin, especially in secondary AML) Antibodies and immunotherapies

• Monoclonal antibodies against CD33, CD44, CD47, CD123, CLEC12A

• Trials comparing allogeneic HCT with either intensive chemotherapy or with autologous HCT have shown improved duration of remission with allogeneic HCT.

• Long-term outcomes with conventional chemotherapy for older patients are dismal; transplantation for such patients is expanding as a more comprehensive treatment.

• Limited information shows for allogeneic HCT with intensive chemotherapy of autologous HCT.

• Improved remission rate is recorded for allogeneic HCT over chemotherapy, or high rates, in patients.

• Better care is being delivered to patients more frequently in the current setting.

• The choice between consolidation with chemotherapy or with transplant will affect survival or treatment.

• AML and other care may also reduce and improve the reduction observed with allogeneic HCT as a result of the allogeneic.

• Improved care in patients for reduction may be due from treatment or GVHD.

Supportive Care

• Measures geared to supporting patients through weeks of recovery a must, for effective AML therapy.
• Patients with AML should be treated in centers expert in providing supportive care.
• Adequate and prompt blood bank support critical to AML therapy with platelets needed.

Treatment for Refractory or Relapsed AML

• For all CR patients, length is predictive of response to salvage chemotherapeutic
• Patients with shorter length have issues of resistance, so its typically hard for chemotherapy alone.
• Many have new agents coming to market, as treatment comes after a lot of prior therapy.

Treatment of Acute Promyelocytic Leukemia

• APL is a highly curable AML subtype, and ~85% of these patients achieve long-term survival with current approaches through new studies.

• Treatment (ATRA = retinoic acid) is still standard, and new care models are coming to mark, to improve outcomes for patients.

• Patients in molecular, cytogenetic, or clinical relapse should be salvaged but are not yet fully clear for patients with this, with the exception of ATO.

• Most data shows for transplants with prior therapy in settings with remissions.

This resource discusses Acute Myeloid Leukemia (AML), a condition marked by the infiltration of blood, bone marrow, and other tissues by proliferative, clonal, poorly differentiated hematopoietic cells. It covers the incidence, etiology, and other important facts about AML. Untreated AML is uniformly fatal.