ACUTE MYELOID
LEUKEMIA (AML)

Exploring dysfunctional pathways, mechanisms, and biomarkers in AML to
discover new insights into the progression of the disease.

190,000

cases of AML are diagnosed globally each year.1

147,000

persons will die from AML globally each year.1

INCIDENCE AND MORTALITY

AML is the most common acute leukemia diagnosed in adults and the leading cause of leukemia deaths in the US and globally.

  • An estimated 20,380 people¬†in the US were diagnosed during 2023, and 11,310 people died from the disease.3
  • FIve-year survival rates (~32%) have not significantly improved in the past 15 years.3

AML is generally a disease of older people and is uncommon before the age of 45.2

  • In the US, 85.4% of cases are diagnosed in persons older than 44 years.3
  • The median age at diagnosis is 69 years.3

AML is an aggressive, fast-growing, molecularly and clinically heterogeneous disease characterized by the rapid proliferation and accumulation of abnormal, immature myeloid blasts in the peripheral blood, bone marrow, and/or other tissues that can result in the suppression of normal hematopoiesis.4-6 Highly expressed BCL-2 proteins in AML cells act as gate-keepers to prevent cell death.13

AML is a clonal malignancy that can develop de novo, as a secondary malignancy (therapy-related- or t-AML) following cytotoxic therapy (including alkylating agents, topoisomerase inhibitors, and antimetabolites, and/or myeloablative radio-chemotherapy), or secondary to myelodysplastic syndromes (MDS).4,7

  • Both¬†de novo¬†and secondary AML develop through a multistep process that involves the acquisition of a variety of genetic alterations, which may induce:6,8
    • A block in cell differentiation
    • Increased cell proliferation
    • An adverse impact on epigenetic control
  • More specifically, genetic alterations and abnormalities contribute to AML pathogenesis due to their effects on tumor suppressor genes and the dysregulation of intracellular signaling pathways, apoptosis, epigenetic mechanisms, and mitochondrial metabolism.6,8,9

According to the World Health Organization WHO 2016, a diagnosis of AML is made based on the presence of 20% or more blasts in the bone marrow or peripheral blood and is further defined by cytogenetic and molecular genetic changes.4

The WHO was updated in 2022 and a new International Consensus Consortium (ICC) classification system was released in 2022 that employs different blast thresholds to define AML in certain situations. While there is no minimum threshold in the WHO criteria for AML with defining genetic abnormalities (with the exception of 20% required for AML with BCR::ABL1 and AML with CEBPA bZIP mutation), the ICC requires at least 10% blasts in the bone marrow or peripheral blood for defining AML with recurrent genetic abnormalities. For all other AML subgroups, the 20% blasts threshold was retained by the WHO. However, the ICC introduced a new category of MDS/AML with 10%‚Äď19% blasts in the bone marrow or peripheral blood, in recognition of the similarities in biology and prognosis between these patients and those with ‚Č•20% myeloblasts.20.21

AML is a highly heterogenous disease. Expanded understanding of the molecular pathogenesis of AML has led to the identification of diagnostic and prognostic markers.4,10

New European Leukemia Network (ELN) 2022 recommendations, which include an update to the 2017 risk classification were recently published. The new 2022 risk classification integrates knowledge from novel molecular findings and recent trial results, as well as emphasizes dynamic risk based on response assessment, such as measurable residual disease (MRD) negativity.14 However, the recommendations are largely based on intensively treated patients, so future adjustments may be needed for patients who are treated with less-intensive therapies.14

Risk Category       2022 ELN Risk18
Favorable
  • t(8;21)(q22;q22.1)/RUNX1::RUNX1T1
  • inv(16)(p13.1q22) or t(16;16)(p13.1q22)/CBFB::MYH11
  • Mutated NPM1 w/o FLT3-ITD
  • bZIP in-frame mutated CEBPA
Intermediate
  • Mutated NPM1 with FLT3-ITD
  • Wild-type NPM1 with FLT3-ITD
  • t(9;11)(p21.3;q23.3)/MLLT3::KMT2A
  • Cytogenetic and/or molecular abnormalities not categorized as favorable or adverse
Adverse
  • t(6;9)(p23;q34.1)/DEK::NUP214
  • t(v;11q23.3)/KMT2A-rearranged
  • t(9;22)(q34.1;q11.2)/BCR::ABL1
  • t(8;16)(p11:p13)/KAT6A::CREBBP
  • inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2,MECOM(EVI1)
  • t(3q26.2;v)/MECOM(EVI1)-rearranged
  • -5 or del(5q); -7; -17/abn(17p)
  • Complex or monosomal karyotype
  • Mutated ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2
  • Mutated TP53

In an analysis of 513 patients from the multicenter Beat AML cohort, the median overall survival across ELN 2022 favorable-, intermediate-, and adverse-risk groups was not reached, 16.8, and 9.7 months, respectively (median follow-up of 36 months). The ELN 2022 recommendations more accurately stratified survival between patients with intermediate- or adverse-risk AML treated with induction chemotherapy compared with ELN 2017 recommendations .19

Patients are stratified according to risk category by multiple factors to determine the ability to receive intensive induction therapy.14

The standard therapy for AML patients eligible for intensive induction therapy has not changed significantly in the past 40 years.6,8

The standard is induction therapy with 7+3 combination chemotherapy (7 days of cytarabine and 3 days of an anthracycline) followed by consolidation therapy to maintain remission (high-dose chemotherapy). Some eligible patients with intermediate/poor risk disease may also receive a stem cell transplant along with consolidation therapy

Outcomes remain poor, with high rates of relapse for most patients. Older patients pose a difficult therapeutic challenge due to comorbidities and poor performance status, which may render them ineligible for intensive therapy.11 Survival in older patients who are unable to receive intensive treatment is 5-10 months.15

Five-Year Survival by Year of Diagnosis (2000-2018)2

An increased understanding of the pathophysiology of AML has facilitated the development of novel, molecularly targeted therapies. However, these recent additions may only benefit certain patients due to the heterogeneity of the disease.

Advances in the understanding of AML biology and genetics are being translated into strategies for targeting mutated proteins and dysregulated pathways. While these therapies address a number of areas of unmet need in AML, much clinical research and biomarker analysis remains to be done to expand and optimally implement these agents.17

One of the examples of these advancements is the BCL-2 protein.  The BCL-2 protein is overexpressed in up to 70% of AML cases; elevated levels of BCL-2 correlate with poor prognosis and chemoresistance.12,16

CD123 expression is low on normal hematopoietic stem cells but overexpressed in multiple hematological malignancies, including AML and blastic plasmacytoid dendritic cell neoplasm (BPDCN).22 CD123 overexpression is associated with aggressive disease characteristics in AML.23

Relevant Cancer Targets

BCL-2

Learn about how BCL-2 plays a role in tumor survival and is a rational target for therapeutic intervention.MORE>

CD123

Learn about CD123 and its overexpression in hematological cancers.

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